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Exhibit 10.72
AGREEMENT FOR SUPPLY OF MATERIAL
This AGREEMENT FOR SUPPLY OF MATERIAL (the "AGREEMENT"), among
CONNAUGHT LABORATORIES LIMITED, a Pasteur Merieux Connaught company,
incorporated under the laws xx Xxxxxxx, Xxxxxx with offices at 0000
Xxxxxxx Xxxxxx Xxxx, Xxxxxxx, Xxxxxxx, Xxxxxx X0X 0X0, ("PMC")
and
IMCLONE SYSTEMS INCORPORATED, a company existing and organized under
the laws of Delaware, USA with offices at 000 Xxxxxx Xxxxxx, Xxx Xxxx,
XX, XXX 00000, ("IMCLONE")
and
MERCK KGaA, a company incorporated under the laws of Germany with
offices at Xxxxxxxxxxx Xxxxxxx 000, 00000 Xxxxxxxxx, Xxxxxxx, ("MERCK")
is effective as of this 1st day of January, 1997 ("EFFECTIVE DATE"), with
respect to the following facts and circumstances:
WHEREAS PMC has a proprietary interest in and manufactures and sells a
product known as BCG vaccine, consisting of BCG in vaccine formulation with its
accompanying diluent in a 10-dose vial presentation (hereinafter the "BCG
MATERIAL"); and
WHEREAS ImClone and Merck severally have a proprietary interest in a
monoclonal anti-idiotypic antibody known as BEC2 (hereinafter "BEC2") and
jointly are performing clinical and pre-clinical research relating to the
treatment and/or prophylaxis of certain human cancers by administration of the
BEC2; and
WHEREAS ImClone and Merck intend to administer a combination therapy of
BEC2 and BCG Material to certain patients with small cell lung carcinoma
("SCLC") in a multi-national Phase III clinical trial being conducted in Europe,
Australia and the United States (hereinafter the "XXXXX TRIAL") pursuant to the
protocol(s) and investigators' brochure(s) (hereinafter the "CLINICAL TRIAL
PROTOCOL") attached hereto as Exhibit "A"; and
WHEREAS, ImClone and Merck may administer a combination therapy of BEC2
and BCG Material to other patients in such additional clinical trials that are
necessary or advisable in the sole discretion of ImClone and Merck in connection
with or in furtherance of the XXXXX Trial (the "ADDITIONAL CLINICAL TRIALS");
and
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WHEREAS ImClone and Merck are interested in securing a supply of the
BCG Material to be administered with BEC2 in the XXXXX Trial and any such
Additional Clinical Trials, and PMC is willing to supply the BCG Material to
ImClone and Merck on the terms set forth herein.
NOW THEREFORE, in consideration of the foregoing and for other good and
valuable consideration, the receipt and sufficiency of which is hereby
acknowledged, the parties hereby agree as follows:
1. Trials to be Conducted; Status of Recipient
ImClone and Merck are conducting the XXXXX Trial and any Additional
Clinical Trials together, and will receive supplies of the BCG Material together
or independently for the sole purpose of conducting the XXXXX Trial and the
Additional Clinical Trials (the XXXXX Trial and the Additional Clinical Trials
are collectively referred to herein as the "CLINICAL TRIALS"). ImClone and Merck
shall be referred to for the purposes herein as the "RECIPIENT" and the term so
used shall mean ImClone and Merck together or either of them. ImClone and Merck
shall be jointly and severally liable in respect of the obligations set forth in
this Agreement, except as specifically noted hereinbelow.
2. Supply and Acceptance of Delivery
2(a). Quantities of the BCG Material
Subject to the terms of this Agreement and during the seven
(7) year period following the Effective Date (hereinafter the "Supply Period"),
PMC shall supply to the Recipient, and the Recipient shall accept delivery from
PMC of, the BCG Material for use in and during the Clinical Trials on the
following dates, in the following quantities and with the following expiry
dating:
(i) 2,000 vials with February/2000 expiry dating to
be shipped to ImClone for the XXXXX Trial by no later than
July 30, 1998 according to PMC's shipping procedures and
labelled according to ImClone's reasonable labelling
requirements as set forth in Exhibit "B";
(ii) 2,000 vials with February/2000 expiry dating to
be shipped to Merck for the XXXXX Trial within five (5)
business days of written notice from Merck to PMC, according
to PMC's shipping procedures and labelled according to Merck's
reasonable labelling requirements as set forth in Exhibit "C";
(iii) 500 vials with February/2000 expiry dating to
be shipped to Merck for the XXXXX Trial as soon as possible,
but in no event later than four (4) months, following written
notice from Merck to PMC, according to PMC's shipping
procedures and labelled according to Merck's reasonable
labelling requirements as set forth in Exhibit "C";
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(iv) such additional vials with such expiry dates and
shipment dates as shall be reasonably requested by ImClone and
Merck for conduct of the Clinical Trials, subject to the
provisions of Section 4(a) below and further subject to the
following:
(A) Recipient shall not request, for any two (2) year
period after December 31, 1999 during the Supply Period, any
additional vials in a quantity that is in excess of 4,000
vials in the aggregate;
(B) Recipient shall not request any additional vials
during the years 1998 and 1999;
(C) Recipient shall not request any vials after the
expiration of the Supply Period; and
(D) Recipient shall request additional vials for the
conduct of Additional Clinical Trials only in those countries
in which the XXXXX Trial is being or has been conducted.
The parties acknowledge that the restrictions set forth in (A)
and (B) above have been derived from PMC's review of its planned production and
known commitments for the BCG Material during the Supply Period. In the event
Recipient requires vials of the BCG Material for the conduct of the Clinical
Trials that exceed such limitations, the parties will discuss whether PMC's then
planned production and known commitments would allow for the supply of such
additional BCG Material.
2(b). Cost of Supply
The parties agree that, subject to compliance by Recipient to
the terms of this Agreement, PMC shall supply the BCG Material during the Supply
Period to Recipient at no cost for the Recipient's use in the Clinical Trials.
2(c). Delivery; Risk of Loss
At Recipient's cost, PMC shall deliver or arrange for the
delivery of the BCG Material to Recipient, FOB at a point or points of
destination selected by Recipient, to a reputable carrier. Prior to any
delivery, Recipient shall forward import permits or other documents, as required
for shipment, to PMC to the attention of Xx. Xxx Xxxxxxx, Logistics Coordinator,
(facsimile: 416-667-2275). Upon delivery of the BCG Material, Recipient shall
assume all risk of loss or damage for the BCG Material so delivered. All
temperature monitoring devices shall be returned by Recipient to PMC to the
attention of Xx. Xxxxxxx.
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2(d). Technical Services Assistance
Upon the reasonable request by Recipient, and in consideration
of payment by ImClone of PMC's costs and services fees at a rate of One hundred
and seventy ($170.00) dollars per hour for clinical/medical personnel and
Ninety-eight ($98.00) dollars per hour for regulatory/logistics personnel, PMC
shall make, and has made, available its clinical/medical and
regulatory/logistics personnel (at their usual place of employment or by
telephone) to provide reasonable levels of technical assistance to the Recipient
in connection with PMC's Regulatory Manufacturing Documentation for the BCG
Material or in connection with the Recipient's Regulatory Filings required for
the Clinical Trials. ImClone shall pay PMC, by no later than July 15, 1998, the
amount of Twenty-eight thousand ($28,300.00) dollars, representing the sum of:
(i) $5,000.00 for the BCG vaccine/BEC2 compatibility test
studies conducted and related technician time;
(ii) $15,680.00 for 160 hours of regulatory/logistics services
assistance provided by Xxx. Xxxxx Xxxxxx-Xxxxx, Supervisor,
Regulatory Affairs;
(iii) $2,720.00 for 16 hours of clinical/medical services
assistance provided by Xx. Xxxxx Xxxxxx and/or Xx. Xxxxxx
Xxxxxx; and,
(iv) $4,900.00 for 50 hours of regulatory/logistics services
assistance provided by Xx. Xxx Xxxxxxx, Logistics Coordinator.
ImClone agrees to pay for any further technical services
provided by PMC and tests conducted by or on behalf of PMC, in connection with
this Agreement or the Clinical Trials, at the hourly rates agreed to herein and
the costs to PMC of any such tests. The parties agree that the currency for
payment shall be Canadian dollars.
2(e). Negotiations for Future Commercial Supply
In the event that the Recipient wishes to seek registration
for the combination therapy of BEC2 and BCG Material, Recipient shall notify PMC
in writing. PMC and the Recipient agree that within sixty (60) days of said
written notice from the Recipient, the parties shall initiate good faith
negotiations toward the securing of a commercial supply agreement for the
purchase by Recipient of BCG Material with terms satisfactory to both parties,
including without limitation, purchase price. Failure to reach such agreement
during the Term within twelve months (12) of initiation of negotiations, or as
of such earlier time when it is clear that the parties cannot reach such
agreement, shall be grounds for termination of this Agreement by either PMC or
Recipient, upon thirty (30) days written notice to the other.
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3. Preparation and Conduct of the XXXXX Trial
3(a). Regulatory Filings; Manufacturing Regulatory Documentation
At Recipient's sole cost, Recipient shall file and be the
owner of record for all Regulatory Filings developed by the Recipient relating
to the Clinical Trials. "REGULATORY FILING" shall mean a filing with a
regulatory agency, for example, the US Food and Drug Administration ("FDA"),
that concerns the Clinical Trials. Recipient owns and shall retain all right,
title and interest in and to BEC2 (and any improvements, progeny, derivatives or
related materials thereof) and the Regulatory Filings. PMC shall permit the
Recipient to cross-reference PMC's Product License Application Supplement and
Drug Master File for BCG Material and/or otherwise excerpt portions of or
describe PMC's Product License Application Supplement and Drug Master File in
the Regulatory Filings, to enable the Recipient to complete Regulatory Filings
required for the Clinical Trials. Notwithstanding the foregoing, the parties
agree that despite Recipient's cross-referencing PMC's Product License
Application Supplement and Drug Master File for BCG Material and/or otherwise
excerpting portions of or describing PMC's Product License Application
Supplement and Drug Master File in the Regulatory Filings, PMC owns, and shall
retain all right, title and interest in and to the BCG Material (and any
improvements, progeny, derivatives or related materials thereof) and the
Manufacturing Regulatory Documentation. "MANUFACTURING REGULATORY DOCUMENTATION"
shall mean a Product License Application, Drug Master File or any other
regulatory filing or documentation owned, developed, submitted or prepared by or
on behalf of PMC and filed with appropriate regulatory authorities that contains
information concerning the BCG Material, including but not limited to
information concerning the BCG Material contained in the Regulatory Filings
which is excerpted from or describes PMC's Product License Application or Drug
Master File or other regulatory filing by or on behalf of PMC which concerns the
BCG Material, which information, Recipient agrees and undertakes, shall be
deemed and treated as Confidential Information. All non-public information
provided by one party to the other in preparing Regulatory Filings and the
Manufacturing Regulatory Documentation shall be deemed to be Confidential
Information of the disclosing party for the purposes of this Agreement.
3(b). Protocols for Clinical Trials; Results
At Recipient's sole cost, Recipient shall be responsible for
the design, implementation, and evaluation of any human clinical studies used to
obtain clinical data for use in preparing Regulatory Filings related to the
Clinical Trials. Recipient shall conduct the Clinical Trials in compliance with
current Good Clinical Practices ("cGCP") pursuant to FDA regulations. Recipient,
at its sole cost, shall provide PMC with a complete copy of the protocols and
investigators' brochures for the Clinical Trials, as well as copies of all
reports, abstracts and publications (subject to Section 5(c) herein) concerning
the data and results of the Clinical Trials. All right, title and interest in
and to the data and results of the Clinical Trials shall vest in Recipient;
provided that any information relating to the BCG Material shall remain the sole
property of PMC.
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3(c). Adverse Reaction Reporting
Recipient shall promptly notify PMC of any serious adverse
reactions which result from the conduct of the Clinical Trials on the same basis
that such reporting is made to the appropriate regulatory authorities. Such
notices shall be sent by Recipient to PMC to the attention of Xxx. Xxxxx
Xxxxxx-Xxxxx, Supervisor, Regulatory Affairs (facsimile: 416-667-2912). For this
purpose, it is understood that an adverse reaction is subject to expedited
reporting to appropriate regulatory authorities if such adverse reaction
constitutes an "unexpected adverse reaction" and if the minimum criteria for
expedited reporting are met (as such criteria are set forth in the ICH Topic
E2A: Clinical Safety Data Management - Definitions and Standards for Expedited
Reporting, June 1, 1995). An "UNEXPECTED ADVERSE REACTION" is one the nature or
severity of which is not consistent with the information in the relevant source
document (i.e., the most recent version of the investigators' brochure). It is
further understood that "SCLC-related Deaths" are the end-points of the XXXXX
Trial and are, therefore, not subject to expedited reporting.
3(d). PMC's Notice in Connection With Actions by Regulatory Authorities
PMC shall promptly notify Recipient of any threatened or
pending actions by regulatory authorities which may reasonably be believed to
affect the safety or efficacy claims of the BCG Material or to affect the supply
commitment contained in this Agreement. Any form of such notice that is not in
writing shall be promptly followed by notice in writing.
3(e). Recipient's Notice in Connection With Actions by Regulatory
Authorities
Recipient shall promptly notify PMC of any threatened or
pending actions by regulatory authorities which may reasonably be believed to
affect the safety or efficacy claims of BEC2 or of the combination therapy of
BEC2 and BCG Material or to affect the Clinical Trials. Any form of such notice
that is not in writing shall be promptly followed by notice in writing.
3(f). Recipient's Provision of Updated Investigators' Brochure
For the purpose of keeping PMC apprised of the status of the
Clinical Trials, Recipient shall provide to PMC a copy of all updated
investigators' brochures which Recipient is required to file with the FDA or
other regulatory agency anywhere.
4. Availability and Manufacture of BCG Material and of BEC2
4(a). BCG Material for Clinical Trials
During the Supply Period, PMC shall supply the BCG Material in
the quantities and according to the terms set forth in Sections 2(a)(i), (ii),
(iii) and (iv); provided, however, that with respect to the quantities and terms
set forth in Section 2(a)(iii) and (iv), PMC shall only be required to use
reasonable commercial efforts to make available to Recipient such BCG Material
as may be requested for the Additional Clinical Trials. With respect to the BCG
Material
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requested pursuant to Sections 2(a)(iii) and 2(a)(iv), in the event of Force
Majeure or of supply shortage or production constraint, PMC shall allocate the
available quantities of BCG Material among PMC, its affiliates, customers and
distributors, including Recipient, in a commercially reasonable manner. Each lot
of BCG Material released to the Recipient for the Clinical Trials shall be
manufactured in compliance with current Good Manufacturing Practices ("cGMP")
pursuant to FDA regulations and according to manufacturing information in the
Manufacturing Regulatory Documentation. PMC shall, or shall cause a third party
to, perform quality control testing of the BCG Material released to the
Recipient to establish compliance with any release specifications required by
the Manufacturing Regulatory Documentation.
4(b). BEC2 for Clinical Trials
During the Term, Recipient shall use reasonable commercial
efforts to have sufficient quantities of BEC2 for use in the Clinical Trials. In
the event of Force Majeure or of supply shortage or production constraint,
Recipient shall notify PMC as soon as possible so as to permit PMC to allocate
the above-noted quantities of BCG Material among PMC, its affiliates, customers
and distributors at PMC's sole discretion. Each lot of BEC2 released by
Recipient for the Clinical Trials shall be manufactured in compliance with cGMP
pursuant to FDA regulations and according to manufacturing information in the
Regulatory Filings. Recipient shall, or shall cause a third party to, perform
quality control testing of BEC2 to establish compliance with any release
specifications required by the Regulatory Filings.
4(c). BCG Material Specifications
PMC shall provide BCG Material to the Recipient in the
available vialed formulations and vial sizes specified in the then current
Manufacturing Regulatory Documentation. PMC shall have no obligation under this
Agreement to develop any other vial sizes or formulations of BCG Material for
the Recipient. PMC shall use reasonable commercial efforts to maintain the
integrity and consistency of all specifications applicable to BCG. In the event
that PMC deems it necessary to revise any specifications, procedures or
Manufacturing Regulatory Documentation applicable to BCG Material, PMC shall
provide reasonable advance notice of any such revision to the Recipient for the
sole purpose of permitting Recipient to revise the Clinical Trial Protocol or
Regulatory Filings, as required. All specification changes that result in
procedures or limits that exceed or differ from those set forth in the
Manufacturing Regulatory Documentation shall be submitted to the FDA before
being implemented to the extent the FDA so requires such submission.
4(d). Documentation
Upon acceptance by Recipient of delivery of the BCG Material,
PMC shall provide the Recipient with a Certificate of Analysis applicable to
each lot of BCG Material delivered to the Recipient. Complete batch records and
sufficient retention samples for the BCG Material delivered to the Recipient
shall be maintained at PMC for inspection at any time by the Recipient at PMC's
place of business upon reasonable prior written notice to PMC. Any
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confidential or proprietary information of PMC or of its affiliates contained in
such records or samples shall be deemed to be Confidential Information of PMC.
4(e). PMC Facility Audits
Upon reasonable prior written notice to PMC, the Recipient may
(but shall not be required to) have its representatives, acting reasonably,
audit PMC's production of the BCG Material to be used in the Clinical Trials for
compliance with cGMP; provided however that such representatives shall have
first signed a confidentiality agreement with PMC. Recipient and its
representatives shall comply with all applicable health, safety, environmental
and security laws and with PMC's policies and procedures while present at PMC's
facilities.
4(f). Recall or Withdrawals
In the event that a party is notified of a recall or
withdrawal of BEC2 or of the BCG Material in any country, or believes such
recall or withdrawal is necessary, it shall immediately notify the other
parties. The parties will consult on the necessity of, and appropriate actions
and mutually acceptable procedures to be taken in connection with, a recall or
withdrawal. If such recall or withdrawal is undertaken, the parties shall
cooperate in taking all reasonable and appropriate action necessary to complete
such recall or withdrawal in a timely fashion.
5. Confidentiality and Disclosure
5(a). General Obligations of Confidentiality
For a period of ten (10) years following any disclosure of
Confidential Information hereunder, the Recipient and PMC shall maintain in
confidence the respective Confidential Information received or obtained from the
other, and use such Confidential Information solely for the purposes
contemplated and permitted by this Agreement. Each party shall maintain
communications to the other parties in confidence. Each party acknowledges that
all Confidential Information exchanged or developed hereunder shall be owned by
the transferor and shall continue to be owned by the transferor following
transfer. "CONFIDENTIAL INFORMATION" shall mean any and all confidential or
proprietary information owned by PMC (or its affiliates) or by the Recipient or
either of ImClone or Merck (or their affiliates) that is provided to the other
parties. Confidential Information shall not be deemed to include information
that:
(i) is or becomes known publicly through no fault of the
receiving party;
(ii) is learned by the receiving party from a third party
entitled to disclose it;
(iii) is developed by the receiving party independently of
information obtained from the disclosing party as shown by the receiving party's
written records;
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(iv) is already known to the receiving party before receipt
from the disclosing party, as shown by prior written records; or
(v) is released with the prior written consent of the
disclosing party.
5(b). Permitted Disclosures
Notwithstanding Section 5(a) hereof, PMC and the Recipient
shall, upon prior written notice to the other parties and only to the extent
necessary, have the right to disclose the other parties' Confidential
Information to regulatory or government agencies for the purposes of preparing
or supplementing any Regulatory Filing or Manufacturing Regulatory
Documentation, as applicable, or of otherwise assisting in securing
institutional or government approval to clinical test the BCG Material, or as
required by law within each country where the Clinical Trials are being
conducted.
5(c). Publications
The parties acknowledge that the data and results arising from
the Clinical Trials should be published and presented except to the extent where
such publication or presentation would be reasonably expected to materially
diminish the commercial value of the BCG Material, or to affect the
patentability of the BCG Material or any improvements thereof. The parties
further acknowledge that the Clinical Trials are multi-centre studies. Recipient
undertakes and shall ensure that the data and results arising from the Clinical
Trials shall not be published or presented by Recipient, by the coordinating
investigators or by other participating individuals or entities, until such time
as the Clinical Trials are completed and the data and results are analyzed
thereafter. Upon completion of the XXXXX Trial, Recipient shall ensure that a
cooperative clinical administrative body, comprising the coordinating
investigators, shall prepare a report which will include a statistical analysis
and an appraisal of the final data and results from a medical viewpoint. Interim
publication or presentation of the Clinical Trials would include only
demographic data, for publicity purposes. Any publication, abstract or
presentation, whether verbal or written, of such data, results or report, or
excerpts or interpretations thereof, shall be submitted by Recipient to PMC for
review, pursuant to the following conditions:
(i) Recipient shall ensure that any article, paper,
manuscript, report, data, results, abstract, poster or notes shall not be
published or presented until the completion of the XXXXX Trial and after
analysis of the final results of the XXXXX Trial;
(ii) Recipient shall ensure that any such publication or
presentation acknowledges the contribution of the parties and their employees,
representatives or consultants as co-authors or as otherwise appropriate; and
(iii) Recipient shall ensure that the publishing party deliver
to PMC, at least sixty (60) days in advance of any such publication or
presentation, any article, paper, manuscript, report, data, results, abstract,
poster or notes proposed to be published or presented, in order to permit PMC,
acting reasonably:
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(A) to apply for patents or make such other filings
or registrations as deemed advisable,
(B) to object to any part of such proposed
publication or presentation on the basis that it would be
reasonably expected to materially diminish the value of the
BCG Material and information related thereto,
(C) to require that any Confidential Information be
deleted from any such proposed publication or presentation, or
(D) to revise such proposed publication or
presentation accordingly.
Recipient undertakes and shall ensure that similar publication and presentation
procedures will be established for any Additional Clinical Trials.
5(d). Use of Names or Trademarks
The parties shall not originate any press release
concerning the entering into of this Agreement or the subject matter hereof
without the prior written approval of the other parties, which approval shall
not be unreasonably withheld. The parties shall not have the right to use the
name or any trade name or trademark of the other parties without prior written
approval. Reference to the existence of this Agreement may be made in the
regular course of business of the parties in informational disclosures
describing the business of the parties, upon prior written notice to the other
parties.
6. Warranties and Representations
6(a). Warranties and Representations of PMC.
Subject to Section 7(a), PMC represents and warrants to the
Recipient that:
(i) PMC is a corporation duly organized, validly existing and
in good standing and has all necessary corporate power to enter into and perform
its obligations under this Agreement;
(ii) the execution, delivery and performance of this Agreement
by PMC have been duly authorized and approved by all necessary corporate action,
and the Agreement is binding upon and enforceable against PMC in accordance with
its terms (subject to bankruptcy and similar laws affecting the rights of
creditors generally);
(iii) each lot of the BCG Material delivered to the Recipient
for the Clinical Trials shall be manufactured, tested and released in compliance
with cGMP and the applicable Manufacturing Regulatory Documentation; and
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(iv) any documentation provided to the Recipient by PMC
concerning the BCG Material or Manufacturing Regulatory Documentation shall be
accurate to the best of PMC's knowledge and ability.
6(b). Warranties and Representations of the Recipient
Recipient and each of ImClone and Merck represents and
warrants to PMC that:
(i) Recipient consist of corporations duly organized, validly
existing and in good standing and have all necessary corporate power to enter
into and perform their obligations under this Agreement;
(ii) the execution, delivery and performance of this Agreement
by the Recipient have been duly authorized and approved by all necessary
corporate action, and the Agreement is binding upon and enforceable against the
Recipient in accordance with its terms (subject to bankruptcy and similar laws
affecting the rights of creditors generally);
(iii) Recipient shall use BCG Material in compliance with all
applicable laws and regulations and shall conduct the Clinical Trials in
compliance with cGMP and cGCP;
(iv) Recipient is not aware of any special or unusual hazards
that would arise as a result of the combination of BEC2 and BCG Material for the
Clinical Trials to be conducted by Recipient;
(v) each lot of BEC2 for the Clinical Trials shall be
manufactured, tested and released in compliance with cGMP and the applicable
Regulatory Filings; provided that, in connection with such release only, each of
ImClone and Merck provides such warranty and representation with respect to the
territories in which they respectively are responsible for the conduct of the
Clinical Trials;
(vi) any documentation concerning the Clinical Trials, BEC2 or
Regulatory Filings shall be accurate to the best of Recipient's knowledge and
ability; and
(vii) Recipient does not guarantee any particular results from
the conduct of the Clinical Trials.
7. Limitation of Liability; Indemnification
7(a). Limitation of Liability
PMC has limited knowledge or awareness of, and has no control
over, the manner in which the Recipient intends to use the BCG Material. PMC
shall not be liable for any losses, damages, costs or expenses of any nature
incurred or suffered by the Recipient or by a third party, arising out of any
dispute or other claims or proceedings (including, without limitation, product
liability claims and claims by a third party alleging infringement of its
intellectual property rights
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by the use or sale of BCG Material), made or brought as a result of the Clinical
Trials or against the Recipient, nor shall PMC be responsible in any way for
dealing with any such disputes, claims or proceedings, except to the extent that
any such dispute, claim or proceeding arises from (a) a breach by PMC of any
warranty set forth in Section 6(a) hereof, or (b) any failure by PMC to
manufacture, test, document or release the BCG Material in compliance with cGMP
and the applicable Manufacturing Regulatory Documentation. PMC shall not be
responsible for any interruption in supply that is caused by Force Majeure.
EXCEPT AS SET FORTH IN SECTION 6(a) HEREOF, PMC MAKES NO WARRANTIES, EXPRESS OR
IMPLIED, WRITTEN OR ORAL, INCLUDING WITHOUT LIMITATION ANY WARRANTIES OF
MERCHANTABILITY, OF FITNESS FOR A PARTICULAR PURPOSE OR OF NON-INFRINGEMENT OF
THIRD PARTY PATENTS. PMC SHALL NOT BE LIABLE FOR ANY LOSS, CLAIM, DAMAGE,
EXPENSE OR LIABILITY, OF ANY KIND OR NATURE, WHICH MAY ARISE FROM OR IN
CONNECTION WITH THIS AGREEMENT OR WITH THE CLINICAL TRIALS OR FROM THE USE,
HANDLING OR STORAGE OF BCG MATERIAL, BEC2 OR THEIR ANCILLARY MATERIALS BY
RECIPIENT OR BY ANY AFFILIATES, EMPLOYEES, AGENTS, CONTRACTORS, INVESTIGATORS OR
REPRESENTATIVES OF RECIPIENT. NO PARTY TO THIS AGREEMENT SHALL BE ENTITLED TO
RECOVER FROM THE OTHER PARTIES ANY SPECIAL, INCIDENTAL, CONSEQUENTIAL OR
PUNITIVE DAMAGES.
7(b). Recipient's Right to Indemnification
PMC hereby agrees to indemnify, defend and hold harmless
Recipient and its affiliates, officers, directors, employees and representatives
(collectively, the "RECIPIENT'S INDEMNITEES") from and against any liabilities,
claims, damages, costs, expense (including reasonable attorneys' fees), and
actions (collectively, "CLAIMS") arising out of or resulting from (i) the
failure by PMC to manufacture, test, document or release the BCG Material in
compliance with cGMP and the applicable Manufacturing Regulatory Documentation
or (ii) the breach by PMC or PMC's Indemnitees of any of its obligations or
warranties hereunder, except to the extent that any such Claims arise out of,
are based upon or result from the gross negligence or willful misconduct of
Recipient or Recipient's Indemnitees or a breach by Recipient or Recipient's
Indemnitees of any of Recipient's obligations or warranties under this Agreement
or under the Clinical Trial Protocol or Regulatory Filings. Recipient shall
promptly notify PMC of any Claims, upon becoming aware thereof, and permit PMC
at PMC's cost to defend against such Claims and shall cooperate with PMC in the
defense thereof. Recipient shall not enter into, or permit, any settlement of
any such Claims without the express written consent of PMC. Recipient may, at
its option and expense, have its own counsel participate in any proceeding that
is under the direction of PMC and will cooperate with PMC or its insurer in the
disposition of any such matter.
7(c). PMC's Right to Indemnification
Recipient hereby agrees to indemnify, defend and hold harmless
PMC and its affiliates, officers, directors, employees and representatives
(collectively, "PMC'S INDEMNITEES") from and against any liabilities, claims,
damages, costs, expense (including
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reasonable attorneys' fees), and actions (collectively, "CLAIMS") arising out of
or resulting from (i) the Clinical Trials, (ii) the failure by Recipient to
manufacture, test, document or release BEC2 in compliance with cGMP and the
applicable Regulatory Filings, (iii) the breach by Recipient or Recipient's
Indemnitees of any of Recipient's obligations or warranties under this Agreement
or under the Clinical Trial Protocol or Regulatory Filings, (iv) the possession,
processing, shipment, storage, handling, administration or disposal of any BCG
Material supplied to Recipient hereunder, or (v) the possession, manufacture,
sale, use, distribution, processing, shipment, storage, handling, administration
or disposal of BEC2 by Recipient whether or not any BCG Material is combined
thereto, except to the extent that any such Claims arise out of, are based upon
or result from the gross negligence or willful misconduct of PMC or PMC's
Indemnitees or a breach by PMC or PMC's Indemnitees of any of PMC's obligations
or warranties under this Agreement. PMC shall promptly notify Recipient of any
Claims, upon becoming aware thereof, and permit Recipient at Recipient's cost
to defend against such Claims and shall cooperate with Recipient in the defense
thereof. PMC shall not enter into, or permit, any settlement of any such Claims
without the express written consent of Recipient. PMC may, at its option and
expense, have its own counsel participate in any proceeding that is under the
direction of Recipient and will cooperate with Recipient or its insurer in the
disposition of any such matter.
7(d). Recipient's Insurance
Each of ImClone and Merck shall obtain and maintain separate
product liability insurance and clinical trial liability insurance (naming PMC
either as an additional insured or policy beneficiary), with an acceptable
insurer, in the minimum amount of US$10,000,000 per occurrence. Such insurance
may not be cancelled or terminated except upon thirty (30) days' prior written
notice to PMC. Such insurance shall be obtained and maintained at the sole cost
and expense of ImClone and Merck. From time to time, at the request of PMC,
ImClone and Merck will cause certificates of such insurance to be provided to
PMC evidencing compliance with their respective obligations set forth herein.
8. Term and Termination
8(a). Expiration
This Agreement shall commence on the Effective Date and shall
terminate six (6) months after the expiration of the Supply Period, unless
earlier terminated as provided in Sections 8(b), (c) and (d) hereof (the
"TERM").
8(b). Termination by Any Party
Any party shall have the right to terminate this Agreement,
immediately upon written notice of termination to the other parties in the event
that:
14
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(i) a party fails to perform or observe or otherwise breaches
any of its material obligations under this Agreement and such failure or breach
continues unremedied for a period of sixty (60) days after receipt by the
breaching party of a written notice thereof from the non-breaching party; and
(ii) a proceeding or case shall be commenced without the
application or consent of the other party and such proceeding or case shall
continue undismissed, or an order, judgment or decree approving or ordering any
of the following shall be entered and continue unstayed and in effect, for a
period of forty-five (45) days from and after the date service of process is
effected upon the other party, seeking (A) the other party's liquidation,
reorganization, dissolution or winding-up, or the composition or readjustment of
its debts, (B) the appointment of a trustee, receiver, custodian, liquidation or
the like of the other party or of all or any substantial portion of their
assets, or (C) similar relief in respect of the other party under any law
relating to bankruptcy, insolvency, reorganization, winding-up or the
composition or readjustment of debts.
8(c). Termination due to Cessation of Clinical Trials
In the event Recipient in its sole discretion ceases the
Clinical Trials, and so advises PMC in writing in advance, either Recipient or
PMC may terminate this Agreement upon thirty (30) days prior written notice to
the other parties.
8(d). Termination in Connection With Further Negotiation
This Agreement may be terminated by the Recipient or PMC in
connection with the failure, during the Term, to enter into a separate agreement
for future commercial supply of BCG Material, as further set forth in Section
2(e) hereof.
8(e). Effects of Termination
In the event of any termination of this Agreement, all amounts
previously invoiced and unpaid or owed to PMC shall be due and payable by
Recipient on the date of termination. Following termination of the Agreement,
the Recipient shall return to PMC or destroy, at PMC's option, any quantities of
BCG Material. The parties agree that: (i) the provisions of Section 2(e),
Article 3 and Article 6 shall survive the termination or expiration of this
Agreement; (ii) the provisions of Article 5 hereof shall survive the termination
or expiration of this Agreement for the term specified in that Article; and
(iii) the provisions of Article 7 hereof shall survive termination or expiration
of this Agreement only with respect to Claims that arose from acts or
circumstances that occurred prior to termination.
9. Miscellaneous
9(a). No Implied Waivers; Rights Cumulative
No failure on the part of PMC or the Recipient to exercise,
and no delay in exercising, any right, power, remedy or privilege under this
Agreement, or provided by statute or
15
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at law or in equity or otherwise, including, without limitation, the right or
power to terminate this Agreement, shall impair, prejudice or constitute a
waiver of any such right, power, remedy or privilege or be construed as a waiver
of any breach of this Agreement or as an acquiescence therein, nor shall any
single or partial exercise of any such right, power, remedy or privilege
preclude any other or further exercise thereof or the exercise of any other
right, power, remedy or privilege.
9(b). Notices
All notices, requests and other communications to PMC or the
Recipient hereunder shall be in writing (including telecopy or similar
electronic transmissions) and shall be personally delivered or sent by telecopy
(fax) or other electronic facsimile transmission or by registered mail, or
certified mail, return receipt requested, postage prepaid, or by other form of
courier requiring receipt in each case to the respective address specified below
(or to such address as may be specified in writing to the other party hereto)
and shall be effective upon receipt thereof:
CONNAUGHT LABORATORIES LIMITED
0000 Xxxxxxx Xxxxxx Xxxx
Xxxxxxx, Xxxxxxx, XXXXXX
X0X 0X0
Attn: Vice President and General Counsel
Facsimile: (000) 000-0000
with a copy to: Senior Vice President, and General Manager, Oncology Business Unit
Facsimile: (000) 000-0000
MERCK XXxX
Xxxxxxxxxxx Xxxxxxx 000
00000 Xxxxxxxxx, XXXXXXX
Attn: Xx. Xxxxxx Xxxx, License Department
Facsimile: 61 51 72 3378
with a copies to: Xx. Xxxxxx Xxx, Project Manager, Facsimile: 61 51 72 7580, and
Xxxxxx Xxxxx, TATONZ, Facsimile: 61 51 72 6905
IMCLONE SYSTEMS INCORPORATED
000 Xxxxxx Xxxxxx
Xxx Xxxx XX 00000
U.S.A.
Attn: General Counsel
Facsimile: (000) 000-0000
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9(c). Successors and Assigns
The terms and provisions of this Agreement shall inure to the
benefit of, and be binding upon, PMC, the Recipient, and their respective
successors and permitted assigns as provided in this Section. PMC and Recipient
shall have the right to assign or otherwise transfer any of its rights and
interests, or delegate any of its obligations, to an Affiliate of such party
provided that such Affiliate agrees in writing to carry out in full any
obligations that are assigned to it. PMC and Recipient shall have the right to
assign all of its rights and interests and delegate all of its obligations under
this Agreement to any entity that is the successor in interest to the assigning
party in any merger, consolidation or sale involving substantially all of the
business and assets of the assigning party. Any other assignment or delegation
shall only be valid and effective if the other parties have provided their
respective prior express written consent. Any attempt to assign or delegate any
portion of this Agreement in violation of this Section shall be null and void.
Subject to the foregoing, any reference to PMC or the Recipient hereunder shall
be deemed to include the successors thereto and permitted assigns thereof.
9(d). Force Majeure
No party shall be liable to the others, or be in default under
the terms of this Agreement, for its failure to fulfill its obligations
hereunder to the extent such failure arises for any reason or cause beyond its
control including, without limitation, strikes, lockouts, labor disputes, acts
of God, acts of nature, acts of governments or their agencies, fire, flood,
storm, power shortages or power failure, war, sabotage, inability to supply and
to obtain labor, raw materials, supplies, fuel or utilities, or inability to
obtain transportation, or any other circumstance or event beyond the reasonable
control of the party (each, "FORCE MAJEURE"), provided that the party relying on
the provisions of this Section 9(d) shall give notice to the other parties of
its inability to observe or perform the provisions of this Agreement. A party
shall notify the other parties if, at any time, it encounters a production or
manufacturing problem which in its reasonable opinion could reasonably be
expected to adversely affect its ability to supply BEC2 or BCG Material, as
applicable, for the Clinical Trials. Should such production or manufacturing be
so reduced, the party relying on these provisions shall have the right to
allocate such supply for its own use and among its affiliates, customers and
distributors, in such manner and on such basis as it may reasonably determine,
without compensation or penalty to the other parties.
9(e). Governing Law
This Agreement shall be governed by the laws of the Province of
Ontario. The parties specifically agree that the International Sale of Goods Act
does not apply hereto.
9(f). Entire Agreement
This Agreement, together with its Exhibits A, B and C,
constitutes, on and as of the Effective Date hereof, the entire agreement of and
among PMC, ImClone and Merck with respect to the subject matter hereof, and all
prior or contemporaneous understandings or
17
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agreements, whether written or oral, between or among PMC, ImClone or Merck with
respect to such subject matter are hereby superseded, as of the Effective Date.
9(g) Relationship
Each of the parties is an independent contractor. No party is,
and nothing in this Agreement shall constitute any party as the employer,
employee, principal, agent or partner of, or joint venturer with, any other
party. No party has authority to enter into any agreement on behalf of the other
parties or to bind the other parties in any other manner, and no party shall act
or omit to act so as to suggest that it has such authority. No party shall incur
any obligations or liabilities, express or implied, by reason of, or with
respect to, the actions or omissions of the other parties or of persons for whom
they are responsible.
9(h) Counterparts
This Agreement may be executed in two or more counterparts,
each of which shall be deemed an original but all of which together shall
constitute one and the same instrument.
IN WITNESS WHEREOF, the parties have caused this Agreement to be
executed by their duly authorized officers as of the Effective Date.
IMCLONE SYSTEMS INCORPORATED
By: ___________________________
Name: _________________________
Title: ________________________
MERCK KGaA
By: ___________________________ By: ____________________________
Name: _________________________ Name: __________________________
Title: ________________________ Title: _________________________
CONNAUGHT LABORATORIES LIMITED
By: ___________________________ By: ___________________________
Name: _________________________ Name: _________________________
Title: ________________________ Title:_________________________
18
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Exhibit "A" (Protocols, Investigators' Brochures)
to Agreement among PMC, ImClone and Merck effective as of January 1, 1997
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CLINICAL COORDINATOR: STATISTICIAN:
XX. X. XXXXXXXX X. XXXXXX
83, AV. X. XXXXXXX. BTE 11 83, AV. X. XXXXXXX. BTE 11
B-1200 BRUSSELS X-0000 XXXXXXXX
XXXXXXX BELGIUM
PHONE: + 00 0 000 00 00 PHONE: + 00 0 000 00 00
FAX: + 00 0 000 00 00 FAX: + 00 0 000 00 00
E-MAIL: XXX@XXXXX.XX E-MAIL: XXX@XXXXX.XX
CENTRAL DATA MANAGEMENT:
EORTC DATA CENTER
00, XX. X. XXXXXXX, XXX 00
X-0000 XXXXXXXX
BELGIUM
PHONE: + 00 0 000 00 00
FAX: + 00 0 000 00 00
REGISTRATION / RANDOMIZATION
EUROPE NORTH-AMERICA AUSTRALIA/NEW ZEALAND
EORTC DATA CENTER QUINTILES PACIFIC, INC. QUINTILES PTY, INC
PHONE: + 00 0 000 00 00 PHONE: + 000 000 0000 PHONE: + 00 000 000 000
FAX: + 00 0 000 00 00 FAX.: + 000 000 0000 FAX.: + 00 000 000 000
EUROCODE (MODEM): + 32 2 772 04 26
EUROCODE (X25): + 206 221 51 24
INTERNET: TELNET XXXXX.XXXXX.XX
XXXX://XXX.XXXXX.XX/XXXXXXXX
SAFETY DESKS
EUROPE NORTH-AMERICA AUSTRALIA/NEW ZEALAND
EORTC IMCLONE QUINTILES PTY, INC
INVESTIGATIONAL AGENT UNIT CLINICAL AFFAIRS CLINICAL HELPDESK
SAFETY DESK SAFETY DESK PHONE: + 00 000 000 000
PHONE: x00 0 000 0000 PHONE: + 000 000 0000 FAX.: + 00 000 000 000
FAX.: x00 0 000 0000 FAX.: + 000 000 0000 E- MAIL:
E- MAIL: E-MAIL: XXXXXXX@XXXX.XXX
XXXXXXXXXX@XXXXX.XX XXXXXXXXXX@XXXXXXX.XXX
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MONITORING / LOCAL DATA CENTER
EUROPE NORTH - AMERICA AUSTRALIA/NEW ZEALAND
EORTC DATA CENTER QUINTILES PACIFIC, INC. QUINTILES AUSTRALIA PTY
00, XX. X. XXXXXXX, XXX 11 331 A EAST XXXXXX AVE NORTHPOINT, 100 XXXXXX
X-0000 XXXXXXXX XXXXXXXX XXXX XXXXXX
XXXXXXX CA 94041 XXXXX XXXXXX XXX 0000
FAX: + 00 0 000 00 00 USA AUSTRALIA
FAX: x000 000 0000 FAX: x00 000 000 000
DRUG SUPPLY
EUROPE NORTH-AMERICA AUSTRALIA/NEW ZEALAND
XX. XXXXXX CLINICAL AFFAIRS DEPARTMENT XXXXXXX XXXXXXX
MERCK KGAA IMCLONE SYSTEMS INC. QUINTILES AUSTRALIA PTY
PHONE: x00 0000 00 0000 PHONE: x000 000 0000 PHONE: x00 000 000 000
FAX: x00 0000 00 0000 FAX: x000 000 0000 FAX: x00 000 000 000
SPONSORS
EUROPE, AUSTRALIA, AND NEW ZEALAND IN NORTH AMERICA
MERCK KGAA. IMCLONE SYSTEMS INC.
XXXXXXXXXXX XXX. 000 000 XXXXX XXXXXX
D-64271 DARMSTADT NEW YORK, NY,
GERMANY USA
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TABLE OF CONTENTS
1. TRIAL SUMMARY .................................................................. 8
2. RATIONALE ...................................................................... 10
2.1 ANTI-IDIOTYPIC ANTIBODIES .......................................... 10
2.2 BEC2 ANTI-IDIOTYPIC MONOCLONAL ANTIBODY ............................ 11
2.3 CLINICAL EXPERIENCE WITH BEC2 ...................................... 12
3. OBJECTIVES ..................................................................... 15
4. TRIAL DESIGN ................................................................... 15
4.1 GENERAL DESIGN ..................................................... 15
4.2 TREATMENT REGIMENS ................................................. 15
4.3 STRATIFICATION AT RANDOMIZATION .................................... 16
5. PATIENT POPULATION ............................................................. 17
5.1 AT REGISTRATION .................................................... 17
5.1.1 Inclusion criteria ......................................... 17
5.1.2 exclusion criteria ......................................... 17
5.2 AT RANDOMIZATION ................................................... 18
5.2.1 Inclusion criteria ........................................ 18
5.2.2 exclusion criteria ......................................... 18
6. DRUG INFORMATION ............................................................... 19
6.1 GENERAL INFORMATION ................................................ 19
6.2 BEC2/BCG VACCINE PREPARATION ....................................... 19
6.3 STORAGE ............................................................ 21
6.4 POSSIBLE ADVERSE EVENTS ............................................ 21
6.5 PACKAGING AND LABELING OF STUDY MEDICATION ......................... 22
6.6 CONCOMITANT TREATMENTS ............................................. 22
7. CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP ............................ 23
7.1 AT REGISTRATION .................................................... 23
7.2 RESTAGING (WITHIN 6 WEEKS AFTER END OF INDUCTION THERAPY)........... 23
7.3 AT RANDOMIZATION (WITHIN 6 WEEKS AFTER THE END OF INDUCTION THERAPY) 24
7.4 FIRST 12 WEEKS AFTER RANDOMIZATION ................................. 24
7.4.1 vaccination cohort ......................................... 24
7.4.2 observation cohort ......................................... 25
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7.5 DURING FOLLOW-UP ................................................... 26
7.5.1 First FU (6 months after randomization) .................... 26
7.5.2 Further FU (starting 9 months after randomization
till progression of disease) ..................................... 26
7.6 AFTER PROGRESSION OF THE DISEASE ................................... 26
7.7 SUMMARY TABLE ...................................................... 27
8. MONITORING AND REPORTING OF ADVERSE EVENTS AND ADVERSE DRUG
REACTIONS ......................................................................... 28
8.1 DEFINITIONS ........................................................ 28
8.2 REPORTING ADVERSE EVENTS ........................................... 28
8.2.1 Documentation of Adverse Events ............................ 28
8.2.2 General evaluation of side-effects ......................... 29
8.2.3 Toxic deaths ............................................... 29
8.2.4 Evaluation of toxicity ..................................... 29
8.3 REPORTING PROCEDURES ............................................... 29
8.3.1 reporting serious adverse events (SAE) or serious
adverse drug reactions (SADR) .................................... 29
8.3.2 reporting non-serious adverse events (AE) and non-
serious adverse drug reactions (ADR) ............................. 30
9. REGISTRATION AND RANDOMIZATION PROCEDURES ...................................... 31
9.1 PATIENT REGISTRATION ............................................... 31
9.2 PATIENT RANDOMIZATION .............................................. 32
10. FORMS AND PROCEDURES FOR COLLECTING DATA ...................................... 33
10.1 CASE REPORT FORMS AND SCHEDULE FOR COMPLETION ..................... 33
10.2 PRACTICAL CONSIDERATIONS AND DATA FLOW ............................ 35
11. STATISTICAL CONSIDERATIONS .................................................... 37
11.1 PRIMARY AND SECONDARY ENDPOINTS ................................... 37
11.2 SAMPLE SIZE DETERMINATION ......................................... 37
11.3 DESCRIPTION OF STATISTICAL ANALYSIS ............................... 38
11.3.1 Primary analysis .......................................... 38
11.3.2 Supportive analyses ....................................... 38
11.3.3 Interim Analysis .......................................... 38
11.3.4 Safety .................................................... 39
11.3.5 Quality of Life Assessment ................................ 39
11.3.6 Health Economics data analysis ............................ 40
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11.3.7 Independent Data Monitoring Committee ..................... 40
12. QUALITY OF LIFE EVALUATION .................................................... 41
12.1 OBJECTIVES ........................................................ 41
12.2 QUESTIONNAIRE ..................................................... 41
12.3 DESIGN ............................................................ 42
12.4 QOL DATA COLLECTION ............................................... 42
13. HEALTH ECONOMICS .............................................................. 43
13.1 OBJECTIVES ........................................................ 43
13.2 HEALTH ECONOMIC VARIABLES ......................................... 44
14. STEERING COMMITTEE ............................................................ 45
15. BIOLOGICAL EFFICACY GROUP ..................................................... 45
16. QUALITY ASSURANCE ............................................................. 45
16.1 CONTROL OF DATA CONSISTENCY ....................................... 45
16.2 EXTERNAL REVIEW OF RESPONSES ...................................... 46
16.3 ON-SITE QUALITY CONTROL ........................................... 46
17. ETHICAL CONSIDERATIONS ........................................................ 46
17.1 PATIENT PROTECTION ................................................ 47
17.2 SUBJECT IDENTIFICATION ............................................ 47
17.3 PATIENT INFORMATION ............................................... 47
17.4 PATIENT CONSENT ................................................... 48
18. INVESTIGATOR COMMITMENT STATEMENT ............................................. 49
18.1 CONFIDENTIALITY STATEMENT ......................................... 49
19. ADMINISTRATIVE RESPONSIBILITIES ............................................... 49
19.1 PROTOCOL AMENDMENTS ............................................... 50
19.2 DEVIATIONS FROM THE PROTOCOL ...................................... 50
20. TRIAL SPONSORSHIP / FINANCING ................................................. 50
21. PATIENT INSURANCE COVERAGE .................................................... 50
22. PUBLICATION POLICY ............................................................ 51
23. ADMINISTRATIVE SIGNATURES ..................................................... 52
24. LIST OF PARTICIPATING COUNTRIES ............................................... 53
25. REFERENCES .................................................................... 54
26. APPENDICES .................................................................... 59
26.1 APPENDIX I: PERFORMANCE STATUS SCALES ............................. 60
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26.2 APPENDIX II: DRUG MEDICATION GUIDELINES ........................... 61
26.2.1 Drug supply ............................................... 61
26.2.2 Disposal of study drugs ................................... 61
26.2.3 BEC2/BCG Vaccine Patient Dose Kit ......................... 61
26.3 APPENDIX III: EORTC QUALITY OF LIFE EVALUATION .................... 62
26.3.1 EORTC Quality of Life evaluation:
guidelines for administration of questionnaires ................... 62
26.3.2 EORTC QLQ - C30 (version 2.0.) ............................ 64
26.3.3 EORTC QLQ - LC13 .......................................... 66
26.3.4 EORTC Health Thermometer .................................. 67
26.4 APPENDIX IV: PATIENT INFORMATION / INFORMED CONSENT TEMPLATE ...... 68
26.5 APPENDIX V: COMMON TOXICITY CRITERIA (NCIC - CTC) SCALE ........... 73
26.6 APPENDIX VI: DECLARATION OF HELSINKI .............................. 85
26.7 APPENDIX VII: WORKING PROCEDURE ON DATA ENTRY ..................... 89
26.8 APPENDIX VIII: ANCILLARY STUDIES ON BIOLOGICAL EFFICACY ........... 90
26.8.1 General Considerations .................................... 90
26.8.2 Humoral Response .......................................... 91
26.8.3 Other ancillary studies which will be performed
in selected centers .............................................. 91
26.9 APPENDIX IX: PPD TESTING .......................................... 93
26.9.1 Test Kits ................................................. 93
26.9.2 General Remarks ........................................... 93
26.9.3 PPD Testing ............................................... 93
26.10 APPENDIX X: INDUCTION THERAPY FLOW CHART ......................... 97
26.11 APPENDIX XI: OVERALL STUDY FLOW CHART ............................ 98
26.12 APPENDIX XII: VACCINATION INSTRUCTIONS ........................... 99
26.13 APPENDIX XIII: LIST OF ABBREVIATIONS ............................. 100
26.14 APPENDIX XIV: STUDY ACKNOWLEDGMENT ............................... 102
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1. TRIAL SUMMARY
TITLE: The XXXXX study: Survival in an International phase III prospective
randomized LD small cell Lung cancer Vaccination study with Adjuvant BEC2 and
BCG,
OBJECTIVES: The trial is designed to test the impact on survival of an adjuvant
BEC2/BCG vaccination of LD SCLC patients after induction therapy.
TYPE OF SUBJECTS: Newly diagnosed patients with LD SCLC, who have a clinical
response (CR or PR) at re-staging after first line treatment (chemo -
radiotherapy + / - prophylactic cranial irradiation).
NUMBER OF SUBJECTS: Approx. 820 patients with LD SCLC will be registered at time
of diagnosis in order to be able to randomize 570 responding patients.
TRIAL DESIGN: Stratified, randomized, prospective, international intergroup
phase III trial.
TREATMENT REGIMENS:
Induction therapy
Each participating center will decide on one of the following three options of
first line chemotherapy, of which 4 or 5 cycles will be given:
Cisplatin (60 - 100 mg/m(carat)2, day 1) + VP 16 (80 - 120 mg/m(carat)2
day 1,2 and 3);
OR
Carboplatin (AUC 4 - 6 )* + VP 16 (80 - 120 mg/m(carat)2 day 1,2 and 3);
OR
Cyclophosphamide (>= 1000 mg/m(carat)2, day 1) + Doxorubicin
(>= 40 mg/m(carat)2 day 1) + Etoposide (80 - 120 mg/m(carat)2 day 1, 2 and
3);
Chest radiotherapy is mandatory (according to local policy, concomitant or
sequential)
Prophylactic cranial irradiation is highly recommended for patients with
complete response.
* Dose (mg) = target AUC (4 - 6) x (Glomerular filtration rate + 25).
GFR is based on the Xxxxxxxx-Xxxxx formula for creatinine clearance:
(140-age) X (weight in kg)
GFR = ------------------------------ x 0.85 (female) or x 1.00 (male)
72 x serum creatinine mg/100ml
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Trial treatment:
After 5, to a maximum of 7 months from diagnosis and within 6 weeks after
completion of ALL induction therapy, responding patients will be RANDOMIZED:
STANDARD ARM (OBSERVATION COHORT):
Best supportive care, but no cancer specific therapy (cytotoxic, radiation
or other tumor reductive therapy) can be given until documented
progression of disease
EXPERIMENTAL ARM (VACCINATION COHORT):
BEC2 (2.5 mg) + BCG intradermal injections (5 in total) at first day of
week 0, 2, 4, 6 and 10.
Stratification:
Institution, Karnofsky (60-70% vs. >= 80%), induction therapy ((VP16 in
combination with Cis or Carbo) vs. CDE), response (CR vs. PR) and radiation
(concomitant vs. sequential) at time point of randomization.
STATISTICAL CONSIDERATIONS:
Primary endpoint(s): Overall survival
Secondary endpoint(s): Progression free survival, Safety, QoL and Health
Economics.
Additional ancillary studies on biological efficacy will be performed.
Proposed start date: December 1997.
Analyses: Overall survival analysis will be performed when a total of 376 deaths
are reported. One interim analysis will be conducted when a total of 80 deaths
are reported.
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2. RATIONALE
The leading cause of cancer deaths in men and women in the USA is lung
cancer. Approximately 25% of all lung cancer patients have small cell lung
cancer (SCLC) (Xxxx XX et al., 1997) and despite the majority of these
patients being successfully treated with primary chemotherapy, often in
combination with thoracic irradiation, relapses are common. Despite
advances in primary chemotherapy, the median survival for patients with
small cell lung cancer (SCLC) has not changed significantly in the last 20
years.
The overall prognosis following completion of primary therapy is dependent
on the stage of the disease. Patients with limited stage of disease
(confined to the thoracic cavity), which accounts for approximately 40% of
SCLC cases, achieved responses in 85-95% and a CR rate from 40-60%, with a
median survival of 14 months and a two year relapse free survival of 20%
with chemotherapy only (Xxxxxxxx 1993).
The addition of chest radiation to chemotherapy in limited disease has
slightly increased survival. A meta-analysis of all randomized trials
indicated a 14% reduction in the mortality rate (Pignon et al. 1992).
Several attempts have been performed to prevent relapse in SCLC after
induction therapy. Among them, poor results have been obtained by
interferon's as maintenance therapy (Xxxx 1997). New approaches are
clearly indicated.
2.1 ANTI-IDIOTYPIC ANTIBODIES
Idiotopes are unique antigenic determinants of the variable region of
immunoglobulin molecules. Antibodies recognizing these idiotopes are
termed anti-idiotypic antibodies (anti-ids). The majority of anti-ids
recognize idiotopes within the framework region of the immunizing
monoclonal antibody, however, some anti-ids can be shown to recognize the
antigen binding site of the immunizing monoclonal antibody and mimic the
original antigen. Because of this property, they are of special interest
for their potential use as vaccines.
Immunization with anti-ids has been shown to induce protective immunity
against viral (Gaulton 1986, Ertl 1984, Xxxxxxx 1984), bacterial (Xxxxx
1984, XxXxxxxx 1984), and parasitic (Sacks 1985, Gryzych 1985) infections.
Anti-id vaccines that mimic carbohydrate or glycolipid antigens offer
potential advantages over vaccines utilizing the actual antigen. First,
anti-id vaccines can stimulate a humoral and possibly a cellular immune
response (Xxxxxx 1984), while carbohydrate antigens are not generally
effective in inducing cellular immunity. Second, anti-id vaccines may be
more immunogenic than the non-protein antigens they mimic. An
anti-idiotypic antibody mimicking bacterial lipopolysaccharide (LPS) was
effective in priming neonatal mice to develop a protective immune response
to LPS while LPS itself could not prime the mice (Xxxxx 1984).
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Several anti-ids have been raised against monoclonal antibodies
recognizing cell surface tumor antigens. Immunization of animals with
these anti-idiotypic antibodies has been shown to result in the generation
of antibodies which recognize the original tumor antigen. Some
investigators have also observed that animals immunized with
anti-idiotypic antibodies demonstrate a cellular immune response by
developing a specific delayed-type hypersensitivity reaction against the
tumor antigen (Nepom 1984, Xxxxxxxxxxxx 1986), although others have not
been able to demonstrate this (Xxxx 1989). Tumor protection studies in
mice have shown that immunization with anti-idiotypic monoclonal
antibodies can prevent tumor growth in vivo (Xxxxxxxxxxxx 1986, Xxxx
1987).
There has been limited experience with immunizing solid tumor patients
with anti-idiotypic monoclonal antibodies. In a report by Xxxxxxxxx et al
(1990), 37 patients with metastatic melanoma were treated with three to
twelve subcutaneous injections of MF11-30. No toxicity was observed. None
of the patients were induced to produce antibodies against melanoma.
However, one lymph node complete response was achieved which lasted 43
weeks. The same group (Xxxxxxxxx 1992), immunized patients with a
different anti-idiotypic monoclonal antibody, designated MK2-23,
conjugated to keyhole limpet hemocyanin and mixed with BCG (Bacille
Xxxxxxxx-Xxxxxx) as an adjuvant. Of 23 evaluable patients 14 (61%)
developed detectable antibodies against melanoma. Three patients
experienced a partial tumor response. Toxicity was largely related to the
BCG administration and consisted of erythema, induration, and occasional
ulceration at the injection sites. Substantial information is available on
the use of BCG in different types of cancers as monosubstance for the
investigational treatment of malignancies from the period when
non-specific immunotherapies were broadly tested in the clinic (Xxxxxxxxx
1997).
2.2 BEC2 ANTI - IDIOTYPIC MONOCLONAL ANTIBODY
The GD3 ganglioside is reported to be distributed in various tumor cell
lines in amounts ranging from 0 percent (colon carcinoma) to 100 percent
(metastatic melanoma and small cell lung cancer) (Xxxxxxx 1997, Xxxxxxxx
personal communication). An IgG3 monoclonal antibody, R24, which
recognizes the human melanoma GD3 ganglioside was raised in syngenic
[(C57BL X BALB/c)F1] mice. Additional syngenic mice were immunized with
the R24 monoclonal antibody which resulted in the formation of two
anti-idiotypic monoclonal antibodies, designated BEC2 and BEC3 (Xxxxxxx
1991). Both were screened for antibody production in New Zealand white
rabbits, which express the GD3 ganglioside on normal tissue (brain,
adrenal, thymus, spleen, small bowel) in distributions similar to that
seen in humans (Iwamori 1978, 1981; Sekine 1985). Both BEC2 and BEC3
induced anti-mouse and anti-R24 antibodies, but only BEC2 induced anti-GD3
antibodies (Xxxxxxx 1991). No toxicity's were observed in the rabbits
immunized with BEC2 and necropsy results showed no evidence of
inflammation within tissues known to express GD3.
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Numerous publications have reported increased immunogenicity, desired
serological responses, and mild toxicity's of anti-id MAb in combination
with adjuvants (Xxxxxxxxx 1990, 1992), aluminum salts (Glenny 1926) or
aluminum hydroxide-adsorbed vaccine preparations (Xxxxxxx 1966).
Vaccination with BEC2, a murine anti-idiotvpic monoclonal antibody, could
evoke specific IgM and IgG against GD3 in animal models (Xxxxxxx and
Houghton, 1991).
Based on these reports. ImClone Systems Inc., NY, NY sponsored and
conducted phase Ib/IIa studies with BEC2 alone and in combination with
various adjuvants.
2.3 CLINICAL EXPERIENCE WITH BEC2
Early clinical studies with BEC2 were initiated in 1992 in patients with
stage IV melanoma and small cell lung cancer and are summarized in the
INVESTIGATOR'S BROCHURE (ImClone/MerckKGaA, 1997).
Studies in melanoma:
Stage III and IV melanoma patients (n=134) were treated in 8 clinical
studies with BEC2 administered at doses ranging from 0.1 to 20.0 mg, with
and without adjuvant. BEC2 adverse events were not dose dependent and
adverse events most frequently reported were adjuvant related injection
site reactions, the severity of which was dependent of the adjuvant
administered. Grade 3 injection site reactions were reported with the use
of BCG, while injection site reactions associated with the use of all
other adjuvants were <= grade 2. In the largest of the 8 studies (n=31),
all of the BEC2 or BEC2 plus alum adjuvant related adverse events were
grade 1 or 2. The reported adverse events were injection site reactions.
In two other studies of BEC2 alone (n=15, n=6), adverse events were
limited to grade 1 except for one patient who developed a grade 2 fever.
The most common adverse events were mild and transient, and consisted of
flu-like symptoms (19%), fatigue (14%), and exacerbation of pre-existing
arthritic conditions (14%). The severity of adverse events in the other 5
studies were similar, although the frequency of reported events are lower.
Although high titer anti-BEC2 antibodies were detected in the majority of
patients treated and production appeared to be related to the adjuvant
preparation used, too few patients developed anti-GD3 antibodies to allow
conclusions to be drawn (Xxxxxxx 1994, XxXxxxxxx 1996).
In one study BEC2, given subcutaneously (s. c.) at a dose of 2.5 mg for
five bi-weekly doses, was tested in a group of 21 stage IV melanoma
patients. Eleven of the 21 patients developed antibodies against BEC2 but
only one developed antibodies against GD3 (Xxxxxxx et al., 1994). Xxxxxxx
suggested that the augmentation of immunogenicity, by addition of an
immune adjuvant, would result in high-titer antibodies against GD3
(Xxxxxxx, personal communication). In one report (XxXxxxxxx 1996) BEC2/BCG
as a fixed combination induced more humoral responses than the use of
other adjuvants or the Mab alone.
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Studies in SCLC:
GD3 is a ganglioside of particular interest as a target for immunotherapy
in SCLC as it is present on SCLC rumor cells (Grant et al., 1996;
Xxxxxx-Xxxxx, personal communication).
A pilot study in limited disease (LD) and extensive disease (ED) SCLC
patients (n = 8) receiving i.d. BEC2, combined with BCG adjuvant, was
reported during the ASCO 1996 meeting. The only grade 3 toxicity was local
skin reactions likely related to BCG vaccination. Grade 2 toxicity were
mainly fever and malaise. The median survival has not been reached after
36 months (Grant et al., 1996).
Updated summary information (n = 15) for the BEC2 trial in SCLC (Grant
1997)
Patients with Limited Disease (n = 8)
------------------------------------------------------------------------------------------------
Diagnosis End of induction Vaccination Last FU Survival Cause of death
(dd/mm/yy) therapy (dd/mm/yy) (dd/mm/yy) (dd/mm/yy) status
------------------------------------------------------------------------------------------------
07/04/92 17/09/92 12/02/93 15/04/97 dead progression
------------------------------------------------------------------------------------------------
28/09/92 15/03/93 31/08/93 13/06/97 alive
------------------------------------------------------------------------------------------------
13/11/92 05/04/93 27/07/93 29/06/97 alive
------------------------------------------------------------------------------------------------
11/11/94 24/04/95 13/10/95 29/07/96 dead chronic obstructive
pulmonary disease
------------------------------------------------------------------------------------------------
19/05/95 15/10/95 02/02/96 15/04/97 alive
------------------------------------------------------------------------------------------------
08/09/95 ??/??/95 26/04/96 08/04/97 alive
------------------------------------------------------------------------------------------------
04/10/95 15/03/96 31/05/96 03/01/97 dead progression
------------------------------------------------------------------------------------------------
21/07/95 19/02/96 07/06/96 07/01/97 dead progression
------------------------------------------------------------------------------------------------
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Patients with Extensive Disease (n = 7)
------------------------------------------------------------------------------------------------
Diagnosis End of induction Vaccination Last FU Survival Cause of death
(dd/mm/yy) therapy (dd/mm/yy) (dd/mm/yy) (dd/mm/yy) status
------------------------------------------------------------------------------------------------
06/07/92 08/01/93 12/02/93 24/03/94 dead progression
------------------------------------------------------------------------------------------------
??/10/92 05/10/93 01/06/93 02/07/97 alive
------------------------------------------------------------------------------------------------
??/09/92 22/03/93 15/06/93 18/02/94 dead progression
------------------------------------------------------------------------------------------------
05/07/94 15/06/95 07/12/95 19/02/96 dead motor vehicle
accident
------------------------------------------------------------------------------------------------
06/03/95 01/07/95 08/09/95 04/01/96 dead progression
------------------------------------------------------------------------------------------------
08/12/95 29/03/96 17/05/96 24/06/97 alive
------------------------------------------------------------------------------------------------
??/12/95 15/03/96 07/06/96 30/09/96 dead progression
------------------------------------------------------------------------------------------------
The 1997 toxicity and serology profiles remain essentially unchanged from
that reported in 1996.
All of the above data suggest that the GD3 ganglioside expressed by
melanoma and SCLC tumors are relevant targets for immune therapy using
BEC2 and this study will further investigate that opportunity in LD SCLC
patients.
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3. OBJECTIVES
The trial is designed to test the impact of an adjuvant BEC2/BCG vaccination of
LD SCLC patients on survival. Secondary endpoints are "Progression free
survival", Safety, QoL and Health Economics. Additional ancillary studies on
Biological Efficacy will be performed.
4. TRIAL DESIGN
4.1 GENERAL DESIGN
This is a stratified randomized prospective international intergroup phase III
trial. Patients are registered into the study after establishing the diagnosis
of primary LD SCLC before the start of the induction therapy or within the first
cycle of induction therapy, given that this therapy is according to what is
mandatory by the protocol.
4.2 TREATMENT REGIMENS
Induction therapy
Each participating center will decide on one of the following three options of
first line chemotherapy, of which 4 or 5 cycles will be given:
Cisplatin (60 - 100 mg/m(carat)2, day 1) + VP 16 (80 - 120 mg/ m(carat)2,
day 1,2 and 3);
OR
Carboplatin (AUC 4 - 6)* + VP 16 (80 - 120 mg/ m(carat)2, day 1,2 and 3);
OR
Cyclophosphamide (>= 1000 mg/ m(carat)2, day 1) + Doxorubicin
(>= 40 mg/m(carat)2, day 1) + Etoposide (80 - 120 mg/ m(carat)2, day 1, 2
and 3);
Chest radiotherapy is mandatory (according to local policy, concomitant or
sequential)
Prophylactic cranial irradiation is highly recommended for patients with
complete response.
* Dose (mg) = target AUC (4 - 6) x (Glomerular filtration rate + 25).
GFR is based on the Xxxxxxxx-Xxxxx formula for creatinine clearance:
(140-age) X (weight in kg)
GFR = ------------------------------ x 0.85 (female) or x 1.00 (male)
72 x serum creatinine mg/100ml
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Trial treatment:
Timing: After 5, to a maximum of 7 months from diagnosis and within 6 weeks
after completion of ALL induction therapy, responding patients will be
RANDOMIZED:
STANDARD ARM (OBSERVATION COHORT):
Best supportive care, but no cancer specific therapy (cytotoxic, radiation
or other tumor reductive therapy) can be given until documented
progression of disease
EXPERIMENTAL ARM (VACCINATION COHORT):
BEC2 (2.5 mg) + BCG intradermal injections (5 in total) at first day of
week 0, 2, 4, 6 and 10.
Treatment will always consist of 5 vaccinations over a period of 10 to 12
weeks unless one of the following should occur:
o intolerable toxicity precluding further treatment
o progression of disease
o patient refusal
o occurrence of pregnancy
Patients discontinuing therapy in the absence of progression should not receive
any other cancer treatment before their disease progresses, unless this is
clearly not in the interest of the patient. If a patient has not continued to
present him-/herself in the course of the study, the investigator must determine
the reason and the circumstances as completely and accurately as possible.
4.3 STRATIFICATION AT RANDOMIZATION
Patients will be stratified by institution, Karnofsky performance status (60-70%
versus 80-100%), induction therapy ((VP16 in combination with Cis or Carbo) vs.
CDE), radiation (concomitant vs. sequential) and response to induction therapy
(CR versus PR) using the minimization technique (Pocock & Simon 1975).
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5. PATIENT POPULATION
Please note that there are two time points in the trial where
inclusion/exclusion criteria will be checked:
REGISTRATION *
RANDOMIZATION (after restaging)
* within one month from start of induction therapy is allowed. However, it is
preferred to register before first line treatment
Before patient registration in the trial, written informed consent must be
obtained and documented according to national and local regulatory requirements
and the local rules followed in the institution.
= A patient who has not been registered will not be accepted for randomization.
5.1 AT REGISTRATION
5.1.1 INCLUSION CRITERIA
o Histo - cytological proven SCLC
o Limited disease (VA classification, Xxxxx 1973)
o Age >= 18years
o Karnofsky performance status >=60% (Appendix I)
o Patient should be fit enough to receive adequate chemo-radiotherapy
treatment
o Written informed consent
5.1.2 EXCLUSION CRITERIA
o Prior surgery, chemo-and/or radiotherapy for SCLC
o History of tuberculosis
o Known to be HIV positive
o Severe active infections such as hepatitis B
o Splenectomy or spleen radiation in history
o Prior therapy with proteins of murine origin
o Investigational agent or immune therapy within 1 month prior to
start induction therapy
o Serious unstable chronic illnesses
o Chronic use of SYSTEMIC antihistaminics, NSAID or systemic
corticosteroids
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o Any previous malignancy except adequately treated CIS of cervix or
non melanoma skin cancer or if previous malignancy was more than 5
years prior and there are no signs of recurrence
o Pregnancy, breast feeding or absence of adequate contraception for
fertile patients.
o Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and
follow-up schedule; those conditions should be assessed with the
patient before registration in the trial.
5.2 AT RANDOMIZATION
5.2.1 INCLUSION CRITERIA
o Patient completed adequate first line chemo-radiotherapy treatment
as mandated by the protocol
o Patients with clinical response at restaging (CR or PR) according to
the WHO handbook, Geneva 1979
o Purified Protein Derivative - negative to >= 5 TU (Tuberculin
Units), see Appendix IX
o Karnofsky performance status >= 60% (Appendix I)
o Adequate bone marrow, liver, heart and renal functions:
ASAT (GOT), serum creatinine< 1.5 x upper normal laboratory value,
WBC count> 3.0 x 10(carat)9/1 and
platelets count> 100 x 10(carat)9/1.
5.2.2 EXCLUSION CRITERIA
o Serious unstable chronic illnesses
o Chronic use of SYSTEMIC antihistaminics, NSAID or systemic
corticosteroids
o Active infections requiring SYSTEMIC antibiotics, antiviral, or
antifungal treatments
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6. DRUG INFORMATION
6.1 GENERAL INFORMATION
The BEC2 study agent, an anti-idiotypic murine monoclonal antibody, is released
for clinical use by ImClone Systems Inc., USA under appropriate manufacturing
conditions as those specified and stipulated in the United States Code of
Federal Regulations (US 21 CRF) and all guideline documents issued by the US
Food and Drug Administration as they pertain to biologic and
biotechnology-derived drugs as an injectable liquid in single use vials. Each
vial is designed to deliver 1.0 ml of a preservative-free solution containing
2.5 mg/ml of study agent. BEC2 will be supplied free of charge to the patient.
BCG study agents consist of one xxxxx xxxxx vial containing 1.5 mg of a
lyophilized powder and one vial containing 1.50 mL of an accompanying
preservative-free BCG diluent manufactured and released for clinical studies by
Pasteur Merieux Connaught, Canada. The lyophilized powder is an attenuated
strain of Mycobacterium bovis [Bacillus Calmette Xxxxxx (BCG)] containing 8 - 32
x 10(carat)6 colony-forming units (CFU)/mL when reconstituted with 1.50 mL of
BCG diluent. The BCG diluent consists of preservative-free phosphate buffered
normal saline (PBS) plus a surfactant (Tween 80) in a single use vial. The BCG
study agents will be supplied free of charge to the patient.
For the EORTC 08971 study, a single-dose vaccine package consisting of
instructions for preparation of the BEC2/BCG vaccine and five vials [1 each of
BEC2 for injection, lyophilized BCG powder, BCG diluent, preservative-free PBS
and a sterile empty vial]. The PBS and sterile, empty vial are additional study
supplies needed for the preparation of the BEC2/BCG vaccine. Each of the five
vials is individually labeled and the vaccine package is labeled in a
tamper-evident manner. Investigators are NOT to use any vaccine package or
components of a vaccine package in which the tamper-evident seal is broken. The
vaccine package will be supplied free of charge to the patient.
6.2 BEC2/BCG VACCINE PREPARATION
The BEC2/BCG vaccine will be prepared for administration by reconstituting the
BCG powder with BCG diluent and mixing appropriately. Three different volumes of
BCG diluent are to be used to reconstitute the BCG powder, 0.30 mL for Treatment
1, 1.20 mL for Treatment 2, and 1.50 mL for Treatment 3, 4, and 5, creating a
reconstituted BCG solutions containing l.0x10(carat)8, 2.5,x10(carat)7, and
2.0x10(carat)7 CFU/mL respectively. For Treatments 1 and 2, 0.2 mL of the
reconstituted BCG solution are to be mixed directly with BEC2 to create the
BEC2/BCG vaccine (No intermediate dilution's of the reconstituted BCG solution
are required for Treatments 1 and 2). Intermediate dilution's (1:4, 1:8 and
1:40) of the reconstituted BCG solution are required for Treatments 3, 4, and 5
prior to creating the BEC2/BCG vaccine. The intermediate dilution's are prepared
with a syringe by combining 1.00 mL, 0.50 mL, and 0.10 mL of the reconstituted
BCG solution with 3.00 mL, 3.50 mL, and 3.90 mL, respectively, of PBS in the
sterile empty vial and mixing appropriately. Combine 0.2 mL (of either the
reconstituted BCG solution for Treatments 1 and 2 or the intermediate dilution
of BCG for Treatments 3, 4, and 5) with the 1 mL (2.5 mg) vial of BEC2 solution
and mix appropriately. The final BCG concentrations in the BEC2/BCG vaccine will
be 2.0x10(carat)7, 5.0x10(carat)6, 1.0x10(carat)6, 5.0x10(carat)5 and
1.0x10(carat)5 CFU/dose for Treatments 1 through 5 respectively. Suggested
mixing procedures are summarized in the following table:
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VOLUME REQUIREMENTS FOR BEC2/BCG VACCINE PREPARATION
------------------------------------------------------------------------------------------------------------------
STEP 1 STEP 2 STEP 3 STEP 4 STEP 5 STEP 6
------------------------------------------------------------------------------------------------
Treatment BCG diluent PBS added Reconstituted BCG Reconstituted or XXX0 XXX0/XXX
Number added to to sterile added to sterile vial diluted BCG added to vaccine
BCG vial BEC2
powder
------------------------------------------------------------------------------------------------------------------
1 0.30 mL 0.00 mL 0.00 mL 0.20 ML 1.00 mL 1.20 mL
------------------------------------------------------------------------------------------------------------------
2 1.20 mL 0.00 mL 0.00 mL 0.20 mL 1.00 mL 1.20 mL
------------------------------------------------------------------------------------------------------------------
3 1.50 mL 3.00 mL 1.00 mL 0.20 mL 1.00 mL 1.20 mL
------------------------------------------------------------------------------------------------------------------
4 l.50 mL 3.5O mL 0.5O mL 0.20 m1 l.OO xX x.20 mL
------------------------------------------------------------------------------------------------------------------
5 l.50 mL 3.9O mL 0.lO mL 0.2O mL 1.OO xX x.20 mL
------------------------------------------------------------------------------------------------------------------
BEC2 alone N/A. N/A. N/A. N/A. 1.OO mL N/A.
------------------------------------------------------------------------------------------------------------------
A detailed handout with information on the preparation of the vaccine will be
distributed.
NOTE: Only components of the BEC2/BCG vaccine package are to be used for the
preparation of the BEC2/BCG vaccine. Under NO CIRCUMSTANCES are substitution of
other components allowed for the preparation of the BEC2/BCG vaccine.
The prepared BEC2/BCG vaccine must be refrigerated at +2(degree)C to +8(degree)C
(+36(degree)F to +46(degree)F) temperatures and protected from ambient light
prior to use. The immediate (within one hour of preparation) use of the BEC2/BCG
vaccine is highly recommended. Each 1.2 mL of BEC2/BCG vaccine will be injected
intradermally at multiple sites (for detailed instructions see Appendix XII).
The BEC2/BCG vaccine must not be injected into limbs with no lymph nodes
(surgical resection). Intravasal injection of the BEC2/BCG vaccine must be
avoided under all circumstances. Any equipment, supplies or receptacles that the
BEC2/BCG vaccine contacts should be disposed of at the investigational center as
infectious, chemotherapy or biohazardous waste.
CAUTION: - BCG is a live bacterial suspension and precautions must be taken for
the appropriate handling and disposal. NEVER REMOVE THE RUBBER STOPPER FROM ANY
VIAL CONTAINING LYOPHILIZED BCG POWDER OR BCG LIQUID. Simultaneous preparation
of BCG under a sterile hood with any other drug is to be avoided. Following BCG
preparation, disinfect the sterile hood by appropriate methods and allow
adequate time to re-sterilize before subsequent use.
PRECAUTION: - BCG is NOT to be administered to any patient as a single agent.
Patients may only receive intradermal injections of either the combined BEC2/BCG
vaccine or BEC2 alone (BEC2 may only be administered as a single agent to
patients who have experienced a grade 4 skin reaction to the BCG component of
the BEC2/BCG vaccine - see section 6.4).
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6.3 STORAGE
The BEC2/BCG vaccine package (containing 5 vials, 1 each of BEC2 for injection,
lyophilized BCG powder, BCG diluent, preservative-free PBS, and a sterile, empty
vial) must be stored under refrigeration at +2(degree)C to +8(degree)C
(+36(degree)F to +46(degree)F) and protected from light. Do not freeze the
BEC2/BCG vaccine package. The BEC2/BCG vaccine package must be kept in a secure,
limited access storage area under the recommended storage conditions.
6.4 POSSIBLE ADVERSE EVENTS
Allergic reactions may occur during or following the administration of BEC2 or
BEC2/BCG vaccine. As a routine precaution, patients treated with BEC2 or
BEC2/BCG vaccine will be observed for one hour after the injection of the
vaccine with resuscitation equipment and other agents (epinephrine, prednisone
equivalents, etc.) available. Should an allergic reaction to the BEC2 or
BEC2/BCG vaccine occur, the patient must be treated according to the best
available medical practices. Patients should be instructed to report any delayed
reactions to the investigator immediately.
NOTE - In the event that a patient experiences a grade 1 or 2 allergic reaction
to BEC2 or BEC2/BCG vaccine, the patient may be pre-medicated with an
antihistamine (i.e., Diphenhydramine HCL) prior to receiving the next injection
of BEC2 or BEC2/BCG vaccine. Patients who experience a grade 3 or 4 allergic
reaction to BEC2 or BEC2/BCG vaccine will have treatments terminated and be
discontinued from the study. Allergy to any component of BEC2, including murine
products or by-product, or to BCG, including monosodium glutamate or Tween 80,
or grade 4 anaphylactic reactions to the BEC2/BCG vaccine are contraindications
to vaccination.
PRECAUTION: - Concomitant use of antimicrobial or immunosuppressive agents may
interfere with the adjuvant activity of BCG. The concomitant use of steroids
with BEC2/BCG vaccine may cause a BCG related systemic infection which may be
treated with antituberculosis medication. Immunisation with BEC2/BCG vaccine
should be deferred during the course of a moderate or severe febrile illness or
acute infection.
Expected adverse event of BEC2/BCG for this study include injection side
reaction of pain, inflammation, hematoma, hemorrhageor grade 3 skin toxicities
of ulceration or scar formation, in addition to regional lymphadenopathy.
Adverse events reported for all indications of the BCG product include
lymphadenopathy, suppurative lymphadenitis, osteomyelitis, arthritis, lupoid
reactions, and rare occurrences of disseminated BCG infections, granulomatous
illness (e.g. mild fever to severe hepatitis or pneumonitis; single cases were
lethal in immunocompromised patients).
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6.5 PACKAGING AND LABELING OF STUDY MEDICATION
The study medication will be packaged and each vial will be labeled. Components
of the labels will be: Content, Volume, Lot Number, Expire date, storage
conditions, mentioning the investigational usage only, warnings.
6.6 CONCOMITANT TREATMENTS
No concomitant chemotherapy, immunotherapy, radiation therapy,
immune-suppressant therapy, systemic corticosteroids or chronic use of
anti-histamines will be allowed during secondary therapy. Analgesics, sedatives,
antibiotics, antihistamines or other medication as well as red blood cells,
platelet or fresh frozen plasma transfusions may be given to assist in the
management of pain, infection, and other complications of the malignancy.
All concomitant medications and any changes in these, will be recorded, from day
of randomization until last follow-up visit, on the case report forms and in the
patient's medical chart, noting the type of medication, the dose, duration, and
indication.
PRECAUTION: The concomitant use of steroids with BEC2/BCG may cause a BCG
related systemic infection. If necessary, the infection may be treated with
anti-tuberculosis drugs.
NOTE: Concomitant antimicrobial or immunosuppressive agents may interfere with
the adjuvant activity of BCG.
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7. CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP
The initial clinical examination, evaluation of the disease as well as blood
counts and serum chemistry should be performed within 14 days before the start
of treatment. All investigations performed before this date must be repeated.
7.1 AT REGISTRATION
- Relevant medical history of the patient will be recorded
- Pathological proven SCLC
- Karnofsky performance status
- Chest X-ray (in two projections)
- Chest CT-scan (including supraclavicular lymphnodes) and upper abdomen CT
(including adrenal glands)
- Brain CT- or MRI scan
- Bone scan and bone marrow examinations are strongly recommended
- Hematology including: Hb, WBC, differential, platelets
- Biochemistry including: serum creatinine, LDH, ASAT (GOT), sodium, potassium,
calcium and glucose
- Screening tests for active infections (and if applicable (beta) HCG for
fertile woman)
7.2 RESTAGING (WITHIN 6 WEEKS AFTER END OF INDUCTION THERAPY)
- Chest X-ray
- Chest CT-scan (including supraclavicular lymphnodes) and upper abdomen CT
(including adrenal glands)
- No clinical evidence of distant metastases by physical examination
--------------------------------------------------------------------------------
Patients who completed ADEQUATE chemo-radiotherapy treatment and having a PR or
CR at re-staging must be checked for randomization eligibility criteria.
--------------------------------------------------------------------------------
THE PPD SHOULD BE TESTED A.S.A.P. IN PATIENTS ELIGIBLE FOR RANDOMIZATION.
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7.3 AT RANDOMIZATION (WITHIN 6 WEEKS AFTER THE END OF INDUCTION THERAPY)
- Purified Protein Derivative - negative to >= 5 TU (Tuberculin Units)
- Clinical examination should include Karnofsky Performance Status, weight and
xxxxx xxxxx (temperature, pulse, blood pressure).
- Hematology including: Hb, WBC, differential, platelets
- Biochemistry including: serum creatinine, LDH, ASAT (GOT), sodium, potassium.
calcium and glucose
- Serum sample for humoral response
- ECG (three lead)
- Quality of Life assessment: QLQ-C30 version 2.0 complemented with the Lung
Module (QLQ-LC13) together with the EORTC Health Thermometer (see chapter 12)
- Economic evaluation assessment: concomitant medications and hospitalizations
(see chapter 13)
7.4 FIRST 12 WEEKS AFTER RANDOMIZATION
7.4.1 VACCINATION COHORT
Vaccination with BEC2/BCG is planned 5 times on day 1 of week 0, 2, 4, 6 and
week 10: every attempt is made to do this on schedule. Should that not be
possible for reasons other than toxicity, it should be accomplished not earlier
than 1 day before or 2 days after the scheduled time point. In case of severe
toxicity (NCIC-CTC grade 3 or 4) the administration of the next vaccination may
be postponed by a total of two weeks throughout the whole vaccination period
(Vaccination has to be completed within a total of 12 weeks). The decision if
the next vaccination is postponed for some days or the vaccination is ceased at
all, shall also incorporate the subjective perception of the individual patient.
Before each vaccination:
- Karnofsky performance status
- Clinical symptoms reporting
- Clinical signs of disease progression
- Serum sample for humoral response
At week 6: - Quality of Life assessment: QLQ-C30 version 2.0 complemented with
the Lung Module (QLQ-LC13) together with the EORTC Health
Thermometer
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Two weeks after last vaccination (week 12):
- Karnofsky performance status
- Clinical symptoms reporting
- Clinical signs of disease progression
- Serum sampling for humoral response
- Chest X-ray
- Hematology including: Hb, WBC, differential, platelets
- Biochemistry including: serum creatinine, LDH, ASAT (GOT), sodium,
potassium, calcium and glucose
- Quality of Life assessment: QLQ-C30 version 2.0 complemented with
the Lung Module (QLQ-LC13) together with the EORTC Health
Thermometer
- Economic evaluation assessment (concomitant medications and
hospitalizations)
7.4.2 OBSERVATION COHORT
6 weeks after randomization:
- Karnofsky performance status
- Clinical symptoms reporting
- Clinical signs of disease progression
- Serum sample for humoral response
- Quality of Life assessment: QLQ-C30 version 2.0 complemented with
the Lung Module (QLQ-LC13) together with the EORTC Health
Thermometer
12 weeks after randomization:
- Kamofsky performance status
- Clinical symptoms reporting
- Clinical signs of disease progression
- Serum sample for humoral response
- Chest X-ray
- Hematology including: Hb, WBC, differential, platelets
- Biochemistry including: serum creatinine, LDH, ASAT (GOT), sodium,
potassium, calcium and glucose
- Quality of Life assessment: QLQ-C30 version 2.0 complemented with
the Lung Module (QLQ-LC13) together with the EORTC Health
Thermometer
- Economic evaluation assessment (concomitant medications and
hospitalizations)
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7.5 DURING FOLLOW-UP
7.5.1 FIRST FU (6 MONTHS AFTER RANDOMIZATION)
- Karnofsky performance status
- Clinical symptoms reporting
- Clinical signs of disease progression
- Serum sample for humoral response
- Chest X-ray
- Hematology including: Hb. WBC, differential, platelets
- Biochemistry including: serum creatinine, LDH, ASAT (GOT), sodium,
potassium, calcium and glucose
- EORTC Health thermometer
- Economic evaluation assessment (concomitant medications and
hospitalizations)
7.5.2 FURTHER FU (starting 9 months after randomization till progression of
disease)
7.5.2.1 every 3 months
- Karnofsky performance status
- Clinical signs of disease progression
- Chest X-ray
- EORTC Health thermometer
- Economic evaluation assessment (concomitant medications and
hospitalizations)
7.5.2.2 every 6 months
- Hematology including: Hb, WBC, differential, platelets
- Quality of Life assessment: QLQ-C30 version 2.0 complemented with
the Lung Module (QLQ-LC13)
As soon as progression appears during disease evaluation, a new Chest CT-scan
(including supraclavicular lymphnodes) and upper abdomen CT (including adrenal
glands) should be done to confirm the progression of disease.
7.6 AFTER PROGRESSION OF THE DISEASE
The patient should be followed every 3 months for survival. Additional
anti-tumor therapy will be recorded together with the EORTC Health Thermometer
and Economic evaluation assessments.
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7.7 SUMMARY TABLE
-----------------------------------------------------------------------------------------------
At At At
registration restaging randominization
-----------------------------------------------------------------------------------------------
within 14 days for definition of timing within 14 days
prior to start ref. to chapter 7.2 prior to start
-----------------------------------------------------------------------------------------------
Informed consent o
-----------------------------------------------------------------------------------------------
Histology / Cytology o
-----------------------------------------------------------------------------------------------
Medical history o ###
-----------------------------------------------------------------------------------------------
Clinical examination* o
-----------------------------------------------------------------------------------------------
Performance status o o
-----------------------------------------------------------------------------------------------
ECG o
-----------------------------------------------------------------------------------------------
Screening tests** o
-----------------------------------------------------------------------------------------------
Clinical Evidence of o
Disease progression
-----------------------------------------------------------------------------------------------
Haematology*** o o
-----------------------------------------------------------------------------------------------
Serum chemistry**** o o
-----------------------------------------------------------------------------------------------
Blood sampling for o
Humoral Response
-----------------------------------------------------------------------------------------------
PPD results # o
-----------------------------------------------------------------------------------------------
Chest X-ray o o
-----------------------------------------------------------------------------------------------
Chest CT-scan o o
incl. upper abdomen
-----------------------------------------------------------------------------------------------
Quality of Life o
-----------------------------------------------------------------------------------------------
Health thermometer o
-----------------------------------------------------------------------------------------------
Economic evaluation o
-----------------------------------------------------------------------------------------------
Clinical symptoms o
-----------------------------------------------------------------------------------------------
Vaccination
-----------------------------------------------------------------------------------------------
First 12 weeks period After treatment
-----------------------------------------------------------------------------------------------------------------
week 0,2,4,6,10 week 6 and 12 first FU=6 until PD after PD
months after every 3 months every 3 months
random
-----------------------------------------------------------------------------------------------------------------
Informed consent
-----------------------------------------------------------------------------------------------------------------
Histology / Cytology
-----------------------------------------------------------------------------------------------------------------
Medical history
-----------------------------------------------------------------------------------------------------------------
Clinical examination*
-----------------------------------------------------------------------------------------------------------------
Performance status o o o o
-----------------------------------------------------------------------------------------------------------------
ECG
-----------------------------------------------------------------------------------------------------------------
Screening tests**
-----------------------------------------------------------------------------------------------------------------
Clinical Evidence of o o o o
Disease progression
-----------------------------------------------------------------------------------------------------------------
Haematology*** (carat) o +
-----------------------------------------------------------------------------------------------------------------
Serum chemistry**** (carat) o
-----------------------------------------------------------------------------------------------------------------
Blood sampling for o o o
Humoral Response
-----------------------------------------------------------------------------------------------------------------
PPD results #
-----------------------------------------------------------------------------------------------------------------
Chest X-ray (carat) o o
-----------------------------------------------------------------------------------------------------------------
Chest CT-scan @
incl. upper abdomen
-----------------------------------------------------------------------------------------------------------------
Quality of Life o #
-----------------------------------------------------------------------------------------------------------------
Health thermometer o o o o
-----------------------------------------------------------------------------------------------------------------
Economic evaluation (carat) o o o
-----------------------------------------------------------------------------------------------------------------
Clinical symptoms o o o
-----------------------------------------------------------------------------------------------------------------
Vaccination o
-----------------------------------------------------------------------------------------------------------------
## All inclusion and exclusion criteria should be fulfilled
* Clinical examination including weight and xxxxx xxxxx (temperature, pulse
blood pressure)
** Screening tests for active infections and if applicable also (beta)HCG
*** Hematology includes hemoglobin, white blood cells, differential and
platelets counts
**** Biochemistry includes serum creatinine, LDH, ASAT (GOT), sodium,
potassium, calcium and glucose
# PPD results of the PPD test using a commercially available standard test
(Appendix IX)
(carat) Examinations to be performed only at week 12
@ As soon as progression appears during disease evaluation, a new Chest
CT-scan (including supraclavicular lymphnodes) and upper abdomen CT
(including adrenal glands) should be done to confirm the progression of
disease.
+ Will be performed on a 6 monthly basis until progression of disease
--------------------------------------------------------------------------------
Only for vaccination cohort
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8. MONITORING AND REPORTING OF ADVERSE EVENTS AND ADVERSE DRUG REACTIONS
8.1 DEFINITIONS
Adverse Drug Reactions (ADR) (in the pre-marketing phase with new medicinal
products) are all noxious and unintended responses to a medicinal product
related to any dose.
An Adverse Event (AE) is any untoward medical occurrence or experience in a
patient or clinical investigation subject which occurs following the
administration of the trial medication regardless of the dose or causal
relationship. This can include any unfavorable and unintended signs (such as
rash or enlarged liver), or symptoms (such as nausea or chest pain), an abnormal
laboratory finding (including blood tests, x-rays or scans) or a disease
temporarily associated with the use of the study medication.
(Note: For the purpose of this trial, in an attempt to eliminate bias adverse
events will be reported in both treatment cohorts i.e. in the observation cohort
regardless of whether or not the patient received trial medication).
Serious Adverse Events (SAE) or Serious Adverse Drug Reactions (SADR) are
defined as any undesirable experience occurring to a patient, whether or not
considered related to the investigational drug. Adverse events and adverse drug
reactions which are considered as serious are those which result in:
o death (excluding SCLC related death)
o a life -threatening event (i.e. the patient was at immediate risk of death
at the time the reaction was observed)
o a permanently disabling event
o hospitalization or prolongation of hospitalization
o persistent or significant disability/incapacity
o a congenital anomaly/birth defect
8.2 REPORTING ADVERSE EVENTS
8.2.1 DOCUMENTATION OF ADVERSE EVENTS
Adverse events which occur during the induction therapy consisting of
non-investigational treatment regimens do not need to be reported.
All adverse events and serious adverse events will be monitored and reported in
all patients (vaccination cohort and observation cohort).
In this trial it was decided to define the AE observation period from
randomization to the second follow up visit (6 months after randomization) for
the following reasons. The investigational treatment is a vaccine and therefore
is expected to act much longer in the patients organism than a small molecule.
The vaccine can not be detected in the circulation by standard methods of
pharmacokinetics, however, toxicity relating to the administered vaccine has to
be monitored. From humoral response studies it is well known that all patients
receiving BEC2/BCG vaccination will develop anti-BEC2-antibodies (= human anti
murine antibodies [HAMA]) of the IgG-class within 6
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weeks after vaccination at the latest. When high titters of HAMA are established
there is rapid clearance of any protein molecule of murine origin. Thus, it has
to be assumed that no BEC2 will be present in the patient after the
establishment of HAMA, since it will be rapidly cleared.
As a consequence, monitoring and reporting of all adverse events and all serious
adverse events will be performed until 6 months after randomization.
Any AE that occurs in the course of clinical study, must principally be
monitored and followed until:
- it has receded
- pathological laboratory findings have returned to
normal
- steady state has been achieved or
- it has been shown to be unrelated to the study
medication
8.2.2 GENERAL EVALUATION OF SIDE-EFFECTS
All reported adverse events should be graded according to the "Common Toxicity
Criteria" defined by the NCI (US) and extended by the NCIC (Canada) (see
Appendix V).
Non hematological acute side effects will be assessed and reported separately
for each cycle of therapy, and graded according to the "Common Toxicity
Criteria" defined by the NCI (US) and extended by the NCIC (Canada) (see
Appendix V).
8.2.3 TOXIC DEATHS
Toxic death is defined as death due to toxicity. This must be reported on the
summary form: the cause of death must be reported as "toxicity".
The evaluation of toxic deaths is independent of the evaluation of response
(patients can die from toxicity after a complete assessment of the response to
therapy)
8.2.4 EVALUATION OF TOXICITY
All patients who have been randomized will be included in overall toxicity
analyses.
8.3 REPORTING PROCEDURES
8.3.1 REPORTING SERIOUS ADVERSE EVENTS (SAE) OR SERIOUS ADVERSE DRUG REACTIONS
(SADR)
All Serious Adverse Events (SAE) and Serious Adverse Drug Reactions (SADR) must
be reported to the respective safety desk by fax within 24 hours of the initial
observation of the event. Details should be documented on the specified Serious
Adverse Event Form. Death related to SCLC is the primary end-point and therefore
will be excluded from reporting.
It should be recognized that Serious Adverse Events (SAE) and Serious Adverse
Drug Reactions (SADR) are subject to rapid reporting to Regulatory Authorities
by the sponsor (or any other party having taken over the sponsor's reporting
obligations) of the countries participating in the trial (as defined by the
national laws). This is not applicable to SAE or SADR which are considered
unrelated to the study product whether expected or not.
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In order to comply with regulatory reporting requirements, every possible effort
should be made to submit the completed documentation of any reported serious
adverse events or serious adverse drug reactions to the safety desk within 10
calendar days of the initial report of the event.
ALL FORMS MUST BE DATED AND SIGNED
BY THE RESPONSIBLE INVESTIGATOR.
The assessment of causality is made by the investigator using the following as a
guideline:
UNRELATED: There is no temporal coincidence between intake of study medication
and occurrence of the adverse event (e.g. no active medication was taken).
or
There is a temporal coincidence between the intake of study medication and
occurrence of the adverse event, but the adverse event can be attributed to
other obvious reasons (e.g. underlying disease, concomitant medication, other
causal factors). Contribution by the study medication is excluded.
REMOTE: There is a temporal coincidence between intake of study medication and
occurrence of the adverse event, but there are one or more obvious other reasons
which are known to explain the adverse event. A contribution of the study
medication is unlikely (according to present scientific knowledge no
pharmacological explanation is possible).
POSSIBLE :There is a temporal coincidence between intake of study medication and
occurrence of the adverse event. A contribution of the study medication is
possible (e.g. due to the pharmacological properties of the study medication),
but other explanations are also possible (e.g. underlying disease, concomitant
medication).
PROBABLE: There is a temporal coincidence between intake of study medication
and occurrence of the adverse event. A contribution of the study medication is
probable (e.g. due to the pharmacological properties of the study medication).
Improvement or recovery is noted after withdrawal of study medication. Specific
findings (e.g. positive allergy testing or antibodies against the study
medication) definitely indicate a contribution by the study medication.
NOT ASSESSABLE: The available information is insufficient to assess causality.
8.3.2 REPORTING NON-SERIOUS ADVERSE EVENTS (AE) AND NON-SERIOUS ADVERSE DRUG
REACTIONS (ADR)
All Adverse Events (AE) and Adverse Drug Reactions (ADR) will be recorded on the
toxicity forms. The investigator will decide if those events are related to the
medicinal product (i.e. unrelated, remote, possible, probable, and not
assessable) and the decision will be recorded on the toxicity forms.
PLEASE REPORT SERIOUS ADVERSE EVENTS BY FAX WITHIN 24 HOURS OF INITIAL
OBSERVATION TO THE LOCAL SAFETY DESK (REFERENCES SEE PAGE 2).
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9. REGISTRATION AND RANDOMIZATION PROCEDURES
9.1 PATIENT REGISTRATION
Registration should be done by calling the Local Data Center from 9.00 AM to
6.00 PM from Monday through Friday (please find phone numbers on page 2).
A patient will be registered by the Local Data Center after verification of
eligibility criteria through the EuroCODE or the INTERNET network.
Patient registration must be done within one month from start of induction
therapy.
A PATIENT WHO HAS NOT BEEN REGISTERED WILL NOT BE ACCEPTED FOR RANDOMIZATION.
A list of questions to be answered during the registration procedure is included
in the registration check-list, which is part of the case report forms. This
check-list should be completed by the responsible investigator before the
patient is registered.
o protocol number?
o institution number?
o callers name?
o name of the responsible investigator?
o patient's initials (maximum 4 letters)?
o patient's chart number (if available)?
o patient's birth date (day/month/year)?
o eligibility criteria:
- all eligibility criteria will be checked;
- actual values of the eligibility parameters will be requested
when applicable
o DATE foreseen for first line treatment?
At the end of the registration procedure, a number will be allocated to the
patient (patient sequential identification number). This number has to be
recorded on the registration check-list, along with the date of registration.
The sequential identification number attributed to the patient at the end of the
registration procedure identifies the patient and must be reported on all case
report forms.
AFTER FIRST LINE TREATMENT, PATIENTS NEED TO BE RE-STAGED. PATIENTS WITH CR OR
PR AT RE-STAGING MUST BE RANDOMIZED THROUGH THE FOLLOWING RANDOMIZATION
PROCEDURE:
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9.2 PATIENT RANDOMIZATION
Randomization should be done by calling the Local Data Center from 9.00 AM to
6.00 PM from Monday through Friday (please find phone numbers on page 2).
A patient will be randomized by the Local Data Center after verification of
eligibility criteria through the EuroCODE or the INTERNET network.
This must be done BEFORE the start of the investigational treatment
A list of questions to be answered during the randomization procedure is
included in the randomization check-list, which is part of the case report
forms. This check-list should be completed by the responsible investigator
before the patient is randomized.
o protocol number ?
o institution number ?
o callers name ?
o name of the responsible investigator ?
o registration or randomization ?
o patient's initials (maximum 4 letters) ?
o patient's birth date (day/month/year) ?
o eligibility criteria:
- all eligibility criteria will be checked;
- actual values of the eligibility parameters will be requested
when applicable
Allocation to the study arm will be automatically attributed.
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10. FORMS AND PROCEDURES FOR COLLECTING DATA
10.1 CASE REPORT FORMS AND SCHEDULE FOR COMPLETION
Data will be reported on the EORTC forms and faxed to the Local Data Center (see
page 2)
Original Case Report Forms will be collected at the end of the trial by the
local monitor.
Case report forms must be completed according to the following schedule:
A. Before registration:
o the patient must be registered by phone to the Local Data Center
(page 31).
o the following set of forms has to be completed and faxed to the
Local Data Center:
the registration check-list (form 1)
the on-study form (form 2)
a laboratory data form (form 3)
The optimal way to work is to complete the registration check-list and, if
possible, the above set of forms first, and to register the patient by
calling the Local Data Center as soon as data are complete; the date of
registration and patient sequential identification number are then
completed on the check-list, and the whole set can be faxed to the Local
Data Center within one week.
B. At time of re-staging:
o a re-staging form (form 4)
C. At randomization:
o the randomization check list (form 5)
o QLQ-C30 (version 2.0) with the QLQ-LC13
o the Health Thermometer
o Economic evaluation form (form 6)
o a laboratory data form (form 3)
o an clinical symptom form (form 7)
The optimal way to work is to complete the randomization check-list and,
if possible, the above set of forms first, and to randomize the patient by
calling the Local Data Center as soon as data are complete; the date of
randomization and patients treatment arm are then completed on the
check-list, and the whole set can be faxed to the Local Data Center within
one week.
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D. First 12 weeks after randomization
Vaccination cohort (week 0, 2, 4, 6, 10)
o a treatment form for each period of vaccination, every 2 weeks (form
8)
o an clinical symptom form for each period of vaccination, every 2
weeks (form 7)
o the Health Thermometer (only at week 6)
o QLQ-C30 (version 2.0) with the QLQ-LC13 (only at week 6)
Observation cohort (week 6)
o a "treatment" form (form 8)
o an "clinical symptom" form (form 7)
o the Health Thermometer
o QLQ-C30 (version 2.0) with the QLQ-LC13
E. Week 12 and week 24 after randomization (for all patients)
o an clinical symptom form (form 7)
o Economic evaluation form (form 6)
o a laboratory data form (form 3)
o a disease evaluation form (form 9)
o the Health Thermometer
o QLQ-C30 (version 2.0) with the QLQ-LC13 (only at week 12)
F. Further follow-up (starting 9 months after randomization till progression of
disease)
Every 3 months
o a disease evaluation form (form 9)
o the Health Thermometer
o Economic evaluation form (form 6)
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Every 6 months
o a laboratory data form (form 3)
o QLQ-C30 (version 2.0) with the QLQ-LC13
G. After disease progression and upon patient death
o a follow-up form (form 10)
o the Health Thermometer
o Economic evaluation form (form 6)
o a death report (form 99)
ALL FORMS MUST BE DATED AND SIGNED
BY THE RESPONSIBLE INVESTIGATOR.
10.2 PRACTICAL CONSIDERATIONS AND DATA FLOW
The investigator has to keep a written or electronic patient file for every
patient participating in the clinical study. In this file the available
demographic and medical information of a patient has to be documented (name,
date of birth, sex, patient history, concomitant diseases and medication,
examinations performed and clinical findings as mutually agreed upon xxxxxxxx
observed clinical symptoms (if applicable) etc.). It must be possible to
identify each patient by using this patient file. The period during which the
patient is participating in the clinical study must be clearly stated.
Additionally, any other documents with source data, especially original
print-outs of data that were generated by technical equipment have to be filed
(e.g. laboratory value listings, ECG recordings etc.). All these documents have
to bear at least patient initials, patient number and the printing date.
The main objective is to obtain a complete documentation from each patient.
The case report forms must be filled in completely and legibly (with either blue
or black ball-point pen, acceptable for use on official documents) and signed by
the investigator as soon as the requested information is available, according to
the above described schedule. It is the responsibility of the investigator to
check that all case report forms are FAXED to the Local Data Center and that
they are completely and correctly filled out. Any amendments and corrections
necessary shall be undertaken and countersigned by the investigator, stating the
date of the amendment/correction. Errors must remain legible and may not be
deleted with correction aids (e.g. Tipp.Ex). The investigator must state his/her
reason for the correction of important data. In the case of a missing
data/remarks, the entry spaces provided for in the CRF should be canceled out so
as to avoid
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unnecessary follow up inquiries. The CRF's are documents and must be suitable
for submission to authorities.
The original copy will be collected at the end of the study (when number of
events is reached) and they will be returned to the sponsors. A copy of these
final CRF's must be kept at the investigators site, at the local data center and
at the EORTC data center.
The EORTC Data Center will perform consistency checks on the CRF's and issue
Query Forms in case of inconsistent data. Those Query Forms must be answered
during the monitoring visits and signed by the investigator. The original must
stay at the investigators site together with the original, corrected CRF's and a
copy of both forms (CRF and Query) must be faxed back to the EORTC Data Center.
The original of the CRF's at the investigator's site may not be modified unless
modifications are reported on a Query From, and the Query Form reference is
indicated on the CRF.
The investigator shall insure that documents forwarded contain no mention of any
patient names. It shall be the duty of the investigator to ensure that the
patient-identification sheets are stored at least 15 years beyond the end of the
clinical study. All original patient files must be stored for the longest
possible time permitted by the regulations of the hospital, research institute,
or practice in question.
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11. STATISTICAL CONSIDERATIONS
11.1 PRIMARY AND SECONDARY ENDPOINTS
Primary endpoint is overall survival, calculated by the time interval (in days)
from randomization to death regardless of cause. The survival times for patients
who are alive at the end of the study are censored.
Secondary endpoints are progression-free survival, safety, QoL and Health
Economics.
Progression free survival is defined by the time interval from randomization to
disease progression or death (whichever occurs first). The progression free
survival time of patients who are alive at the end of the study with no disease
progression are censored.
Progression-free survival data are interval censored. Therefore the
determination of disease progression has to follow an exact time schedule, which
is the same for all patients.
Follow-up examinations will be done every 3 months until death
After progression the patient will be followed up for determination of survival.
QoL will be evaluated at randomization, at 12 weeks and then six monthly until
progression.
The Health Thermometer and resource utilization data will be collected at
randomization and then every 3 months until patients death.
11.2 SAMPLE SIZE DETERMINATION
The patients are recruited at diagnosis of LD SCLC. After completion of
induction therapy, patients with CR or PR (fulfilling all inclusion / exclusion
criteria) will be randomized. These two phases will be referred to as
"registration phase" and "randomization phase".
To detect a 40% increase in the median duration of survival in the BEC2/BCG arm,
376 deaths are necessary, using a two-sided (alpha) of 5% (Collet 1996) and a
power of 90% (allowing for one interim analysis as described in section 11.3.3)
Assuming a median survival in the observation group of 15 months (since
randomization), a randomization phase of 2 years and another 2 years of
follow-up after randomizing the last patient, an estimate of 10% for drop-outs,
570 patients should be randomized and a number of about 820 patients to be
registered (assuming that about 70% of enrolled patients will be eligible for
randomization). The analysis will be performed when 376 deaths have been
observed among the randomized patients. These figures allow for one interim
analysis as described in section 11.3.3.
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11.3 DESCRIPTION OF STATISTICAL ANALYSIS
Comparison at baseline will be assessed in a descriptive manner.
11.3.1 PRIMARY ANALYSIS
The primary analysis of efficacy will be performed on all randomized patients
according to the intention-to-treat principle. Differences in survival will be
assessed by the log-rank test. Survival curves are calculated for each treatment
group with Xxxxxx-Xxxxx estimates.
11.3.2 SUPPORTIVE ANALYSES
o Same as 11.3.1, based on all eligible patients (according to the inclusion /
exclusion criteria), irrespective of the compliance to protocol treatment.
o A multivariate Xxx proportional hazards model (Xxx, 1970) with a backward
variable selection procedure at the 5% level of significance will explore the
prognostic value of the following variables: age (as a continuous variable),
gender, Karnofsky performance status (60-70 vs. 80-100), induction therapy (VP16
in combination with Cis or Carbo vs. CDE), radiation (concomitant vs.
sequential), the continent (Europe vs. North America vs. Australia), LDH level,
Na level, Ca level, serum creatinine, WBC and WBC subsets count and thrombocytes
count. The treatment effect, adjusted for the significant factors in the Xxx
model, will also be estimated and reported. The assumption of proportional
hazards will be checked. This Xxx model will also explore the effect of the
interaction of these covariates with randomized treatment in order to assess
whether the treatment comparisons are consistent across different values of the
covariates.
o All explorative tests will be performed two-sided at a significance level
fixed at (alpha) = 5 %.
11.3.3 INTERIM ANALYSIS
The statistician of the trial will monitor the total number of deaths. One
interim analysis will be conducted when a total of 80 deaths are reported. The
analysis report will present all aspects of the trial. An alpha-spending
function (Lan and DeMets, 1983) (in order to be flexible with respect to the
timing of the analysis) with an X'Xxxxx-Xxxxxxx boundary (O'Brien and Xxxxxxx,
1979) will be used. For example, if the interim analysis is performed when a
total of exactly 80 deaths are reported, the P value should be less than
0.000021 in order to statistically conclude a difference between the two
treatment arms. In this case, the final analysis will be performed with a
significance value of 0.04999. The nominal significance levels, however, will be
calculated using the program EaST.
If the interim analysis shows statistically significant results, the IDMC will
advise the XXXXX Steering Committee to consider early disclosure of the results.
As for all other reports, besides the report which will be sent to the IDMC, no
efficacy data per treatment arm will be presented.
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11.3.4 SAFETY
Incidence and type of clinical symptoms and side effects will be summarized by
treatment groups. We anticipate an underestimation of adverse events in the
control arm because of difference in follow-up schedule during the first 12
weeks. A descriptive report of adverse events will be performed.
11.3.5 QUALITY OF LIFE ASSESSMENT
Data will be scored according to the algorithm described in the EORTC QLQ-C30
scoring manual. All scales and single items are scored on categorical scales and
linearly transformed to 0-100 scales where:
o A high score for a functional scale represents a high or healthy level of
functioning.
o A high score for the global health status/QoL represents high QoL.
o A high score for a symptom scale or item represents a high level of
symptomatology/problems
Data will be analyzed using descriptive statistics for the subscales and single
items for each study group at each of the assessment points. Compliance of
completing QoL questionnaires will be investigated at each time point.
The global health status/QoL scale (EORTC Scoring Procedures Manual) will be
used as an overall measure for QoL. Quality of Life between the two treatment
groups will be compared using the longitudinal mixed data model (PROC Mixed in
SAS). The model will allow the change of QoL in the two groups over time to be
investigated. The main effects for demographic and clinical factors will also be
analyzed (see factors mentioned in 11.3.2).
Mean group scores on the EORTC Health Thermometer will be transformed to a
utility Time Trade-Off score using a power function (Stiggelbout et al., 1996).
These adjusted scores will be used as the quality adjusted factor in the
cost-utility analysis.
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11.3.6 HEALTH ECONOMICS DATA ANALYSIS
Life years saved will be calculated either by non-parametric approach or by a
parametric approach depending on the shape of distribution.
The identified resource units and the effectiveness variables are the basis to
calculate incremental cost-effectiveness and cost-utility ratios. The robustness
of the results will be examined by extensive sensitivity analysis. In the light
of insufficient knowledge about the main sources of uncertainty in the data, one
approach to this will be to use threshold analysis, where critical values (i.e.
such that change the direction of the results) of the variables will be
determined. Another approach will be to use the endpoints of confidence
intervals for data collected in the clinical trial to identify the range of
values to test, combined with high and low boundary estimates for
"deterministic" data for variables taken from outside the trial (i.e. cost
data).
11.3.7 INDEPENDENT DATA MONITORING COMMITTEE
An Independent Data Monitoring Committee (IDMC) will be established comprising
of at least 5 independent experts (2 medical oncologists, two immunotherapists
and one statistician) who have no conflict of interest and agree with the
outline of the protocol. None of the members of the IDMC should be among the
participants in the trial. The committee will meet when the interim analysis has
been performed by the statistician of the trial. All possible aspects of the
trial will be the subject of the interim analysis (see section 11.3.3).
Following this meeting, the IDMC will report to the Steering Committee and may
recommend changes in the conduct of the trial.
The IDMC may call additional meetings if at any time there is concern about any
aspect of the trial. All data presented at the meetings will be considered
confidential.
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12. QUALITY OF LIFE EVALUATION
Reducing mortality and morbidity is still the most important factor in clinical
research. Nevertheless, issues such as reducing side effects, symptom relief and
patients satisfaction have also become relevant parameters in the evaluation of
medical strategies. Cancer treatments may produce adverse effects and diminish
the QoL even when survival is extended. Progress in the acceptance of new cancer
therapies is sometimes critically dependent on their QoL consequences. Thus,
formal assessment of QoL is important because mere extension of survival may not
be directly correlated with an improved QoL. Health related QoL is a
multidimensional concept which represents the physiological, psychological and
social influences of the disease and the therapeutic process from the patients
perspective (Xxxxxxxx 1990). It comprises four principal components: physical,
psychological and social well-being, and daily-life functioning.
12.1 OBJECTIVES
In this study QoL is a secondary endpoint. The main objective of QoL assessment
within this clinical trial is to determine the impact of vaccination on overall
health/QoL. The H(o) hypothesis will be tested that there is no difference
between patients in both arms during and after treatment. A secondary objective
is to evaluate the effect of vaccination on the various symptoms and functioning
scales as treatment related side-effects may have a (temporary) negative
influence on the health related domains of QoL of these patients. The aim of QoL
evaluation in this study is to get a better understanding of the effects of
vaccination in terms of frequency and degree of treatment related side-effects
from the perspective of the patients. For this purpose a detailed questionnaire
including symptoms and functioning will be used.
Since a cost-effectiveness analysis will also be performed in this study it is
relevant to combine the three outcome measures, i.e., length of life, QoL and
economic aspects of the two treatment arms in one overall outcome measure such
as quality and cost adjusted survival by using e.g. a Quality Adjusted Life
Years (QALY) model. In order to be able to do this, a valuation of the health
related QoL is needed. For this purpose the EORTC Health Thermometer will be
used, which is a single question.
12.2 QUESTIONNAIRE
The instruments used are the EORTC core questionnaire (QLQ-C30 version 2.0), the
lung cancer module QLQ-LC13) and the EORTC Health Thermometer.
The QLQ-C30 is a well-validated and accepted instrument to measure various
domains that constitute QoL. It is a self-administered questionnaire consisting
of 30 questions. It incorporates 5 functional scales, 3 symptom scales, and a
global health/QoL scale. The remaining single items assess additional symptoms
commonly reported by cancer patients, as well as the perceived financial impact
of disease and treatment. All scales and single items meet the standards for
reliability. The reliability and validity of the questionnaire is highly
consistent across different language-cultural groups (Xxxxxxxx et al., 1993;
1994).
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The QLQ-C30 will be complemented by the EORTC lung module (QLQ-LC13). This
13-item module (Xxxxxxxx et al., 1994) comprises one multi-item scale and a
series of single items assessing lung cancer-associated symptoms and side
effects from conventional therapy, which has been developed to assess disease
specific symptoms in lung cancer patients.
The EORTC Health Thermometer comprises a single question in which the patient is
asked to rate his/her current health related QoL on a 0 to 100 scale, where 100
stands for "perfect health" and 0 for "worst imaginable health".
All instruments can be found in Appendix III of this protocol.
12.3 DESIGN
QoL will be evaluated in a longitudinal design in all patients entered in this
study. Baseline assessment will be performed at or prior to randomization.
Subsequent assessments will take place at week 6 and 12 after randomization.
Subsequent assessments will be performed every 6 months until progression.
Since the EORTC Health Thermometer will be used to adjust survival taking into
account QoL, it is imperative that this is assessed on a more regular basis.
Therefore the EORTC Health Thermometer will be used during follow-up at all
timepoints in which clinical data will be collected (see Appendix III).
12.4 QOL DATA COLLECTION
QLQ-C30 questionnaires must be filled out at the hospital when the patients
comes to the hospital for a scheduled visit. The questionnaire will be handed
out to the patients by the investigator or a study nurse prior to seeing the
doctor for clinical evaluations. Patients will be asked to fill out the
questionnaires as completely and accurately as possible. The average time to
complete the entire questionnaire is approximately 10-15 minutes.
The compliance of the QoL assessments will be reviewed twice a year and will be
a part of the descriptive report by Data Center for the Group's plenary
sessions.
Mastercopies of the QoL questionnaires (EORTC QLQ-C30, the QLQ-LC13, and the
EORTC Health Thermometer) will be sent to the institution together with CRF's.
The clinical forms will include a question whether the QoL forms have been
filled in -and if not, the reason why.
Guidelines for the administration of QLQ-C30 and QLQ-LC13 questionnaires are
added in Appendix III.
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13. HEALTH ECONOMICS
Lung cancer is one of the leading causes of cancer deaths throughout the world,
particularly among people aged 60 and older. Small cell lung cancer (SCLC)
represents approximately 20-25% of all lung cancers (Xxxxx et al. 1996;
Xxxxxxxxx et al, 1992; Onkos 1995). Approximately 40% of patients who are
diagnosed with SCLC have limited-stage disease (Onkos 1995). The median survival
is short and long-term survivors are uncommon. In view of poor survival rates
between 13 and 16 months for patients with limited disease (Xxxxxxxxx et al,
1992), even with aggressive combined modality treatment, the cost/outcome
relation of potentially expensive therapies is an issue which needs to be
addressed.
Currently there are only few evaluations available on the costs of care in SCLC.
According to a Canadian study (Xxxxx et al, 1995), diagnosis and initial
treatment of limited disease SCLC incurred average direct costs of $18691 per
case (reported in 1988 Canadian dollars). Annual follow up costs after the first
year amount to $944. The costs to determine relapse are established to be $1590,
while palliative radiotherapy and terminal care account for $10544. That means,
about 40% of the overall costs are associated with end of life care. From the
governments or payers perspective in Canada the main cost driver in the
management of SCLC is hospitalization. According to an Australian analysis
(Xxxxxxxxx et al, 1992), the direct median overall cost per patient for limited
disease SCLC is $18234 (reported in 0000 Xxxxxxxxxx dollars), and again
hospitalization is identified to be the main cost component. In the Australian
setting, the relative proportions of overall costs for initial chemotherapy,
radiotherapy and bed-days are 16%, 19% and 38% respectively. The remaining
expenditures relate to investigations (7%), follow up and the management of
relapse (12%). The treatment costs of terminal care have not been considered in
this evaluation. Finally, in an North American study (Xxxxx et al, 1991) the
Continuous Medicare History Sample File is used to derive an estimate of the
lifetime direct medical expenses attributable to lung cancer without distinction
of cancer cell type and stage. In agreement with the other analyses, inpatient
hospital care constitutes anew the major source of expense.
13.1 OBJECTIVES
In the setting of this clinical trial, only data on the quantities of resources
consumed will be collected, without any attempt at attaching pecuniary values to
it. In a further step, however, the main costs of vaccination treatment versus
observation will be calculated from the payer's perspective. As unit costs for
the various types of resources there will be used official reimbursement rates,
fees or charges taken from official fee schedules for various procedures and
services, hospital acquisition prices for drugs, etc. Total average cost will be
calculated as the sum of the various resources multiplied with their unit costs.
If indicated by the outcomes of the clinical trial, cost-effectiveness and
cost-utility analysis will be performed by relating the incremental costs for
the treatment group compared to the observation group to the different outcomes.
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13.2 HEALTH ECONOMIC VARIABLES
Resource Utilization:
--------------------------------------------------------------------------------
Concomitant drugs - generic name
- galenic form at each visit after
- dose randomization
- duration of therapy
--------------------------------------------------------------------------------
Hospitalizations - number of hospitalizations at each visit after
- length of stay randomization
- xxxx
- reasons for admission
--------------------------------------------------------------------------------
Additional anti-tumor - type of therapy after progression
therapy - doses
- schedules
--------------------------------------------------------------------------------
Vaccination therapy starts only after completion of conventional treatment and
has no impact on the initial treatment phase. Therefore, the economic features
of chemotherapy and radiation are not considered in this study. Data collection
on resource consumption centers on medication, therapeutic measures, and
hospitalization, because
a) this information can be measured without any change of clinical study
design,
b) any outpatient resource utilization during the symptom free follow up
period is expected to be relatively low and irrespective of previous
therapy (the investigations are essentially protocol driven), and
c) in the course of the disease, hospitalization is the main cost component.
Effectiveness:
--------------------------------------------------------------------------------
Life years gained - comparison of overall to be described retrospec-
survival tively at the time of data
analysis
--------------------------------------------------------------------------------
Quality Adjusted Life - health state valuation Chapter 12
Years gained (QALY's) via rating scale
(Health Thermometer)
--------------------------------------------------------------------------------
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14. STEERING COMMITTEE
The steering committee will be composed of the Chairman of the trial, a
representative of each cooperative group, a representative of the EORTC Data
Center, the statistician of the trial, a representative of Merck KGaA and a
representative of ImClone Systems Inc. They will be responsible for the conduct
of the study at the operational level. This incorporates the review of the
progress of the trial, discussion of the safety reports and any other aspects of
the trial except of efficacy data. Also the writing and approval of amendments
based on mutual agreement is to be done by this group. The Steering Committee
will meet every 6 months. Telephone conferences shall be held if necessary. All
activities of the Steering committee shall be documented by minutes which have
to be approved by all members of the committee.
15. BIOLOGICAL EFFICACY GROUP
The biological efficacy group will be responsible for the set up and
coordination of the "ancillary studies". Centers which run such studies will be
represented in this group (active members) as well as permanent advisors. This
group shall meet on a regular basis.
16. QUALITY ASSURANCE
It is agreed that the course of the clinical study shall be followed up at
regular intervals by the responsible monitors. They, as well as the
representatives of Merck KGaA and Imclone Inc. or designees and the appropriate
regulatory authority, are permitted to inspect the study documents (study
protocol, CRF's, study medication, original study-relevant patient's records).
All patient data shall be treated confidentially.
16.1 CONTROL OF DATA CONSISTENCY
Data forms will be entered in the database of the EORTC Data Center by a double
data entry procedure.
Computerized and manual consistency checks will be performed on newly entered
forms; Query Forms will be issued in case of inconsistencies.
Consistent forms will be validated by the Data Manager to be entered on the
master database. Inconsistent forms will be kept "on-hold" until full resolution
of inconsistencies.
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16.2 EXTERNAL REVIEW OF RESPONSES
Two external boards will review the primary diagnosis. restaging and relapse
data.
Extra-mural review of radiology
Two independent radiologists shall review all CT scans from the following
time points:
o Primary Diagnosis
o Restaging
o Time of Relapse
If the extent of disease at relapse for one particular should suggest that
there might have been a progress of disease at earlier follow ups, X-rays
from all follow ups have to be reviewed from this case.
Extra-mural review of pathology
Two independent pathologists will review a set of representative slides
(histology or cytology) which the diagnosis SCLC was based upon. For this
reviewing original slides shall be sent to the reviewers and will be
returned to the institution.
Reviews will only be done of those patients who were randomized.
16.3 ON-SITE QUALITY CONTROL
On-site quality control will be performed.
The aim of these site visits will be:
o to assess the consistency of the data reported on the case report
forms with the source data
o to resolve all previous unanswered queries
This quality control will be carried out retrospectively, based on data already
available at the Data Center. All modifications, amendments and/or additions
will be reported on query forms. This will enable a complete documentation of
the modifications brought to the original case report forms, in accordance with
the GCP standards and the EORTC policy.
17. ETHICAL CONSIDERATIONS
Before the start of the study, the study protocol shall be submitted to a
recognized Ethics committee for approval/appraisal; the Ethics committee's
written approval/appraisal of the study shall be appended to the study
documents. Any serious reservations brought forward by the Ethics Committee
against the performance of the clinical study in the present form must be
resolved before the study is commenced. The membership of the Ethical committee
should follow local guidelines and possibly meet the ICH requirements.
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17.1 PATIENT PROTECTION
The responsible investigator will ensure that this study is conducted in
agreement with either the Declaration of Helsinki (Tokyo, Venice, Hong Kong and
South Africa amendments), or the laws and regulations of the country, whichever
provides the greatest protection of the patient.
The protocol has been written, and the study will, be conducted according to the
ICH-guidelines for Good Clinical Practice.
The protocol will be approved by the EORTC Protocol Review Committee and by the
Local, Regional or National Review Boards.
For all countries involved: The national regulatory authorities will be notified
of the clinical trial in accordance with the national laws and requirements.
17.2 SUBJECT IDENTIFICATION
A sequential identification number will be automatically attributed to each
patient registered in the trial. This number will identify the patient. However,
in order to avoid identification errors, patients initials (maximum of 4
letters), date of birth and local chart number will be reported on the case
report forms.
17.3 PATIENT INFORMATION
An unconditional prerequisite for participation of a patient in the clinical
study is his/her consent after having been informed about the following points:
- objectives of the study
- therapeutic effects of and potential adverse reactions to the study
medication
- potential benefit of participation in the study and therapeutic
alternatives
- risks and additional examinations that the study may entail
- for women, the warning that clinical studies may not be carried out in
pregnant women and that pregnancy should therefore be avoided. If
pregnancy occurs, the investigator must be notified immediately.
- possible risks upon discontinuation of the study
- procedure of the study, allocation to the individual treatment groups
- the expected duration of the patients participation in the trial
- the approximate number of patients involved in the trial
- permitted and non-permitted concomitant medication and dietary aspects
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- insurance coverage, mentioning that the patient may undertake additional
medical treatment during the time period of vaccination only after
consultation of the investigator
- voluntary nature of participation in the study and the possibility to
withdraw from the study at any time without stating reasons and without
any disadvantages
- opportunity for obtaining further information
- mention that the patient may not have taken part in any other clinical
study during the past 30 days
- mention that any change in any concomitant medication must be reported to
the investigator immediately
- consent for the forwarding of the anonymous case report forms to the
monitors of the CRO's and the EORTC Data Center and later to Merck
KGaA/Imclone Inc. and the possibility for the inspection of study-relevant
data by third parties (e. g. Merck KGaA supervisory or regulatory
agencies) in agreement with data-protection regulations
- permission from the patient for inspection of medical records in the
strictest confidence by personnel appointed by Merck KGaA and Imclone Inc.
and Regulatory Bodies.
The investigator must inform the patient verbally. The information should be
given both verbally as well as in writing. The wording must be chosen in such a
way as for the content to be fully and readily understandable for laypersons.
17.4 PATIENT CONSENT
For all countries:
The consent of the patient to participate in the clinical study has to be given
in writing prior to participation in the study. The consent shall be confirmed
in the CRF by the investigator. The signed and dated declaration of informed
consent shall remain at the investigator's site and must be stored in the
patient file.
This consent must be obtained in accordance with local governmental regulations
and must be approved by the IRB/Ethical committee of the investigational center.
A template of the patient information is enclosed in this protocol (Appendix
IV).
Documented informed consent must be obtained for all patients included in the
study before they are registered at the EORTC Data Center. This must be done in
accordance with the national and local regulatory requirements and the local
rules followed in the institution.
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18. INVESTIGATOR COMMITMENT STATEMENT
Investigators will only be authorized to register patients in this trial when
they have returned the following:
o a commitment statement, indicating that they will fully comply with
the protocol, including an estimation of their accrual, and a
statement of conflict of interest disclosure form
o a copy of the letter of acceptance of the protocol and informed
consent by their local ethical committee
o updated Curriculum Vitae
o the list of the institutional laboratory normal ranges (for labs
required by the protocol)
As soon as all the documents have been received, the new investigator will be
added to the "authorization list", and will be allowed to register patients in
the trial.
Patients registrations from centers not (yet) included on the authorization list
will not be accepted.
18.1 CONFIDENTIALITY STATEMENT
The investigator must agree to maintain the confidentiality of the study at all
times and must not reveal information relating to the Investigator's Brochure,
protocol, CRF's or associated documents without the express permission of both
sponsors.
19. ADMINISTRATIVE RESPONSIBILITIES
The Study Coordinator (in cooperation with the EORTC Data Center) will be
responsible for writing the protocol, reviewing all case report forms and
documenting his/her review on evaluation forms, discussing the contents of the
reports with the Data Manager and/or the Statistician, the sponsors, and
publishing the study results. He will also be generally responsible for
answering all clinical questions concerning eligibility, treatment, and
evaluation of the patients.
STUDY COORDINATOR: XXXX. X. XXXXXXXX
The EORTC Data Center will be responsible for reviewing the protocol, collecting
case report forms, controlling the quality of the reported data, and generating
reports and analyses in cooperation with the Study Coordinator. All
methodological questions should be addressed to the EORTC Data Center.
THE SPONSOR WILL BE RESPONSIBLE FOR DRUG DISTRIBUTION (SEE PAGE 3)
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19.1 PROTOCOL AMENDMENTS
Should any change be required to the signed, final protocol, a protocol
amendment must be prepared. Written approval must be obtained for all amendments
from the Steering Committee, the Protocol Review Committee at the EORTC and at
Merck and ImClone prior to implementation. Thereafter the amendment will be
distributed to the centers for signing by the investigator and submission to the
appropriate Ethics Committee before implementation at that center.
19.2 DEVIATIONS FROM THE PROTOCOL
Deviations from the protocol - especially the prescription of doses NOT
scheduled in the study protocol -, other modes of administration, other
indications, and longer treatment periods shall not be permissible and shall not
be covered by the statutory patient insurance scheme.
20. TRIAL SPONSORSHIP / FINANCING
In Europe, Australia, and New Zealand: In North America:
Merck KGaA. ImClone Systems Inc.
21. PATIENT INSURANCE COVERAGE
In Europe, Australia and New Zealand:
Merck KGaA has insurance cover for the clinical trial (Colonia Insurance,
Germany: policy numbers 60 22 60 10204 and 60 22 60 10209) which provides
compensation for subjects participating in the trial and indemnity to any person
connected with the performance of the trial arising out the negligence resulting
in bodily injury and/or property damage. It will be invalidated by:
o Failure of the investigator to comply with the terms of the protocol
o Negligence of the investigator and any person connected with the
performance of the trial.
The investigator will indemnify and hold Merck KGaA harmless from any claim
caused by the above exceptions.
The investigator will notify Merck KGaA whenever he becomes aware of a potential
claim.
In North America:
ImClone Systems Incorporated has insurance coverage for clinical trials
(Columbia Casualty Insurance Company, Chicago IL, USA: policy number ADT 102 863
8853 and provides coverage to clinical investigators conducting Human Clinical
Trials for ImClone in compliance with FDA procedures and the Federal Food, Drug,
and Cosmetic Act as set forth in the Code of Federal Regulations, Title 21. This
policy extends coverage to worldwide as long as the Human Clinical Trial is in
compliance with country/local ordinances, standards, filings, and regulatory
requirements and test subjects have provided written consent prior to the
commencement of the trial.
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22. PUBLICATION POLICY
After conclusion of the study, a report shall be written by the EORTC Data
Center and the Coordinating Investigator that will include a statistical
analysis and an appraisal of the results from a medical viewpoint. This report
shall be based on the items listed in this study protocol.
The final publication of the trial results will be written on the name of all
participating groups. None of the participating groups should present any of the
data before publication of the final results of the overall trial. A draft
manuscript will be completed within 6 months from the final report, which will
be produced 18-24 months after the last patient has completed treatment. After
review by the co-authors and the sponsors, this manuscript will be sent to a
major scientific journal.
Authors of the manuscript may include the Study Coordinator, the investigators
who have included more than 5% of the eligible patients in the trial (by order
of inclusion), investigators who contributed significant work on the biological
mechanism of action of the vaccine, and the Data Center coordinator and
statistician in charge of the trial.
Interim publication or presentation of the study may include demographic and
toxicity data, but no data on activity may be made publicly available before the
recruitment is discontinued.
All publications, abstracts or presentations including data from the present
trial will be submitted for review to the Steering Committee at least two weeks
prior to submission for abstracts, and four weeks prior to submission for
manuscripts and slides for presentation. However, the sponsors will not be able
to veto any publication.
An additional report for registration of the drug will be written by the
sponsors.
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23. ADMINISTRATIVE SIGNATURES
Dr G Xxxxxxxx --------------------------- ----------------------
Study Coordinator Date
EORTC LCCG
X. Xxxxxx --------------------------- ----------------------
Biostatistician Date
EORTC Data Center
Xx Xxxxxx X. Xxxxx --------------------------- ----------------------
For Merck KGaA Date
Xx Xxxxxx X. Xxxxxx --------------------------- ----------------------
For ImClone Systems Inc. Date
Xx Xxxxx Xxxxxxxxxx --------------------------- ----------------------
For Quintiles Inc. Date
Xx. X. Xxxxxxxx --------------------------- ----------------------
Director EORTC Data Center Date
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24. LIST OF PARTICIPATING COUNTRIES
EUROPE EORTC Lung Cancer Cooperative Group
Spanish Lung Group
Other individual centers in Europe
NORTH AMERICA Memorial Sloan Kettering Cancer Center
Individual centers of the Veterans'
Administration
Other individual centers in North America
AUSTRALIA/NEW-ZEALAND Australian / New-Zealand individual centers
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References for QoL
B Xxxxxxxx, XX Xxxxxxxx, S Ahmedzai, S Xxxxx, M Xxxxxxxx for the EORTC Study
Group on Quality of Life; Xxx XXXXX XXX-XX00: a modular supplement to the EORTC
core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical
trials. Eur J Cancer (1994) 30A(5): 635-642.
H Xxxxxxxx, J Clinch, V Xxxxxx; Definitions and conceptual issues; In Xxxxxxx B
(ed.) Quality of life assessment in clinical trials, pp. 00-00, Xxxxx Xxxxx,
Xxx Xxxx, 0000.
XX Xxxxxxxx et al.; The European Organization for Research and Treatment of
Cancer QLQ-C30: A Quality of Life instrument for use in international clinical
trials in onkology. J Natl Cancer Inst (1993) 85(5):365-376.
XX Xxxxxxxx, A Cull, S Xxxxx, XXX Xxxxxxxxx for the EORTC Study Group on Quality
of Life; The European Organization for Research and Treatment of Cancer (EORTC)
modular approach to quality of life assessment in oncology. Int. J. Ment. Health
(1994) 23(2): 75-96.
References for health economics
MA Xxxxxxxxx, XX Xxxxxxx, XX Xxxxxx, XX Xxxxxx-Xxxxxx, XX Xxxxxxxxx, J
Xxxxxxx;The cost of treating small cell lung cancer; The Medical Journal of
Australia (1992) 156:605-610
XX Xxxxx, XX Xxxxxxx, N Urban, XX Xxxxxxx; Estimating the treatment costs of
breast and lung cancer; Medical Care (1991) 29 No.1: 40-49
Onkos, Small Cell Lung Cancer; Decision0Resources,0Inc.; Waltham,
Massachussetts; October 1995
XX Xxxxx, BP Will, XX Xxxxxxxxx, XX Xxxxxxx; Diagnostic and therapeutic
approaches to lung cancer in Canada and their costs; British Journal of Cancer
(1995) 72: 1270-1277
XX Xxxxx, BP Will, XX Xxxxxxxxx, XX Xxxxxxx; The economics of lung cancer
management in Canada; Lung Cancer (1996) 14: 19-29
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26. APPENDICES
I. Performance Status Scale (Karnofsky / WHO)
II. Drug medication guidelines
III. EORTC Quality of Life evaluation
IV. Patient information / informed consent template
V. Common toxicity criteria (NCIC - CTC) scale
VI. Declaration of Helsinki
VII. Working procedure on data entry
VIII. Ancillary studies on biological efficacy
IX. PPD testing
X. Induction therapy flow chart
XI. Overall study flow chart
XII. Vaccination instructions
XIII. List of abbreviations
XIV. Study acknowledgment
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26.1 APPENDIX I: PERFORMANCE STATUS SCALES
--------------------------------------------------------------------------------
STATUS SCALES STATUS
--------------------------------------------------------------------------------
KARNOFSKY ZUBROD-ECOG-
% WHO
Normal, no complaints 100 0 normal activity
Able to carry on normal activities 90 1 Symptoms, but
fully ambulatory
Minor signs or symptoms of disease
Normal activity with effort 80
Cares for self. Unable to carry on 70 2 Symptomatic, but
normal activity or to do active work in bed <50% of the
day.
Requires occasional assistance, but 60
able to care for most of his needs
Requires considerable assistance 50 3 Needs to be in bed
and frequent medical care >50% of the day,
but not bedridden
Disabled. Requires special care and 40
assistance
Severely disabled. Hospitalization 30 4 Unable to get out
indicated though death non imminent of bed
Very sick. Hospitalization 20
necessary. Active supportive
treatment necessary
Moribund 10
Dead 0 5 Dead
--------------------------------------------------------------------------------
From: Minna X.X., Xxxxxxx G.A and Xxxxxxxxx X.X. Cancer of the lung. In: XxXxxx
V, Xxxxxxx S., Roxenberg S., (Eds.). Cancer: Principles and Practice of
Oncology, Lippincott, Philadelphia, 1984, p.536.
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26.2 APPENDIX II: DRUG MEDICATION GUIDELINES
26.2.1 DRUG SUPPLY
Study material will be supplied by the sponsors free of charge.
Distribution of the study medication will be conducted from three
different distributors in the particular regions involved in this
trial (see page 3):
In Europe: Study drug will be supplied to the centers by Merck KGaA
In North America: Study drug will be supplied to the centers by
ImClone Systems Inc.
In Australia and New Zealand: Study drug will be supplied to the
centers by Quintiles Pty. under the authority of Merck KGaA
Depending on the commitment of the individual centers with regard to
the expected inclusion rate, the centers will be pre-stocked with a
basic supply of study medication. All regional distributors will
receive on-line notice of randomization by EUROCODE. Re-supply will
be shipped to the centers automatically. In case that there were any
problems with regard to supply of the study medication or the study
medication itself the following institutions should be contacted:
26.2.2 DISPOSAL OF STUDY DRUGS
The study medication may not be used for any purpose other than the
study in question, since the insurance coverage shall otherwise
become null and void.
Opened containers of BEC2, BCG, used transfer vials, or any product,
equipment, supplies or receptacles that contact the BEC2, BCG, or
BEC2//BCG vaccine must be considered chemotherapy or biohazardous
waste and disposed of accord to the documented procedures of the
investigational center. The documented procedure must be available
for review and approved by the sponsors or their designees prior to
initiating the study. Unopened BEC2/BCG vaccine packages may be
returned to the sponsors or their designees at the completion of the
investigational study or as directed by the sponsors or their
designees.
26.22 BEC2/BCG VACCINE PATIENT DOSE KIT
1) one vial BCG, lyophilized (2 mL xxxxx xxxx, containing lyo powder
BCG)
2) BCG Diluent (2 mL clear glass vial, containing 1.5 mL clear
liquid)
3) BEC2 (2 mL clear glass vial, containing 1 mL clear liquid)
4) Sterile Empty Vial
5) Phosphate-buffered Saline
All vials will be in a single foam-inserted carton of approximate
size of 13 xx xxxx, 3.5 cm wide and 6 cm high with an outer label.
Each patient kit will contain all materials necessary to administer
one patient dose of therapy regardless of which dose in the regime
it may be.
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26.3 APPENDIX III: EORTC QUALITY OF LIFE EVALUATION
26.3.1 EORTC QUALITY OF LIFE EVALUATION: GUIDELINES FOR ADMINISTRATION OF
QUESTIONNAIRES
The instructions given below are intended to provide some general guidelines for
collecting quality of life (QoL) data in EORTC studies. These instructions apply
for all types of questionnaires.
1. Who is the responsible person (RP) for QoL data collection?
The overall-responsible person for QoL data collection is the study-coordinator
of the trial. However, for practical reasons it is strongly recommended that one
person is responsible for the organization of QoL data collection in each
institution. This can be a physician, data manager, (research) nurse or a
psychologist. Such a person should have the full protocol at his/her disposal as
well as the questionnaire. This person would also be the intermediate contact
point in case of any necessary clarification asked by the Data Center.
2. Who should fill out the questionnaire?
In principle it is the patient him/herself who has to fill out QoL forms and
preferably without help from others. In case a patient is too sick to fill out
the questionnaire or if the patient is not able to fill out the questionnaire
for reasons such as forgetting his/her glasses, another person could read the
questions without making any comments and report the answers on the forms. If a
patient received this type of help, please note this on the form.
3. What instructions should be given to the patient?
At entry in a study, the RP should give the patient an explanation of the
objective of the study and instructions for filling out questionnaires.
The patient should be informed that participation in the QoL protocol is
voluntary and that the information provided is confidential (identification is
only for administrative purposes and includes patient's initials, date of birth
and today's date).
The following issues should be explained to the patient:
* The schedule of assessments.
* The questionnaire is a self administered questionnaire that should
be filled out preferably by the patient him(her)self.
* The patient should (circle) the choice that best corresponds to
his/her situation.
* There is no right or wrong answer to any of these questions.
* All questions should be answered.
The RP should make sure that the patient understands the instructions.
At each subsequent assessment as defined by the protocol, the patient should
receive the questionnaire by the RP or by other appropriate staff if the RP is
not available.
4. Where should the patient fill out the questionnaire?
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The patient should complete the questionnaire in the clinic, and, ideally in a
quiet, private room. If this is not possible, the waiting room is an acceptable
alternative. In general it does not take more than 5 to 10 minutes to fill out a
questionnaire, but patients should be given the time they need to answer all
questions.
5. When should the patient fill out the questionnaire?
When a QoL assessment is planned, the questionnaire should be given to the
patient preferably before the meeting with the physician, ensuring that the
patient has enough time to complete the questionnaire. If the patient receives a
therapy, the questionnaire should be filled out before administration of the
treatment. The questionnaire should not be taken home and/or mailed.
6. Review of the completed questionnaire.
After the patient has filled out the questions, the person handling the
questionnaire should:
* Check the answers for omissions, for incorrectly completed questions and
for inconsistent answers;
If this is the case:
* Please ask the patient for the reason of omissions or incorrect answers.
If the patient prefers not to answer a question this should be noted on
the form;
* Additional explanation may be provided, but the questions should not be
rephrased;
* Any additional comments could be added by the person handling the
questionnaire (if possible in English) followed by his name and signature.
7. Missing forms.
If for some reason the patient is unable or does not wish to complete a quality
of life questionnaire the reason and the date of visit should be documented on
the questionnaire and returned to the person responsible for completing the
CRF's (case record forms).
8. Mailing to the Data Center.
The questionnaire should be faxed to the Data Center with the CRF's. As it is
not possible to retrospectively collect missing quality of life forms, please
make sure the patient completes the questionnaire at the time-point when he/she
is supposed to fill it out.
Thank you very much for your cooperation. If you have any remarks on this
leaflet or if you need further information, please contact:
Quality of Life Unit - EORTC Data Center:
Phone: x00 0 000 00 00
Fax: x00 0 000 00 00
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26.3.2 EORTC QLQ - C30 (VERSION 2.0.)
We are interested in some things about you and your health. Please answer all of
the questions yourself by circling the number that best applies to you. There
are no "right" or "wrong" answers. The information that you provide will remain
strictly confidential.
Please fill in your initials: _____________
Your birthdate (Day, Month, Year): __________________
Today's date (Day, Month, Year): __________________
NO Yes
1. Do you have any trouble doing strenuous activities,
like carrying a heavy shopping bag or a suitcase? 1 2
2. Do you have any trouble taking a long walk? 1 2
3. Do you have any trouble taking a short walk outside of the
house? 1 2
4. Do you have to stay in a bed or a chair for most of the day? 1 2
5. Do you need help with eating, dressing, washing yourself or
using the toilet? 1 2
During the past week: Not at A Quite Very
All Little a Bit Much
6. Were you limited in doing either your work or
other daily activities? 1 2 3 4
7. Were you limited in pursuing your hobbies or
other leisure time activities? 1 2 3 4
8. Were you short of breath? 1 2 3 4
9. Have you had pain? 1 2 3 4
10. Did you need to rest? 1 2 3 4
11. Have you had trouble sleeping? 1 2 3 4
12. Have you felt weak? 1 2 3 4
13. Have you lacked appetite? 1 2 3 4
14. Have you felt nauseated? 1 2 3 4
15. Have you vomited? 1 2 3 4
Please go on to the next
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During the past week:
Not at A Quite Very
All Little a Bit Much
16. Have you been constipated? 1 2 3 4
17. Have you had diarrhea? 1 2 3 4
18. Were you tired? 1 2 3 4
19. Did pain interfere with your daily
activities? 1 2 3 4
20. Have you had difficulty in concentrating on
things, like reading a newspaper or watching
television? 1 2 3 4
21. Did you feel tense? 1 2 3 4
22. Did you worry? 1 2 3 4
23. Did you feel irritable? 1 2 3 4
24. Did you feel depressed? 1 2 3 4
25. Have you had difficulty remembering things? 1 2 3 4
26. Has your physical condition or medical
treatment interfered with your family life? 1 2 3 4
27. Has your physical condition or medical
treatment interfered with your social
activities? 1 2 3 4
28. Has your physical condition or medical
treatment caused you financial difficulties? 1 2 3 4
For the following questions please circle the number between 1 and 7 that best
applies to you
29. How would you rate your overall health during the past week?
1 2 3 4 5 6 7
Very Poor Excellent
30. How would you rate your overall quality of life during the past week?
1 2 3 4 5 6 7
Very Poor Excellent
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26.3.3 EORTC QLQ - LCl3
Patients sometimes report that they have the following symptoms. Please indicate
the extent to which you have experienced these symptoms during the past week.
--------------------------------------------------------------------------------
During the past week: Not at A Quite Very
All Little a Bit Much
31. How much did you cough? 1 2 3 4
32. Did you cough blood? 1 2 3 4
33. Were you short of breath when you rested? 1 2 3 4
34. Were you short of breath when you walked? 1 2 3 4
35. Were you short of breath when you climbed
stairs? 1 2 3 4
36. Have you had a sore mouth or tongue? 1 2 3 4
37. Have you had trouble swallowing? 1 2 3 4
38. Have you had tingling hands or feet? 1 2 3 4
39. Have you had hair loss? 1 2 3 4
40. Have you had pain in your chest? 1 2 3 4
41. Have you had pain in your arm or shoulder? 1 2 3 4
42. Have you had pain in other parts of your body? 1 2 3 4
If yes, where _______________________________
43. Did you take any medicine for pain?
1 No 2 Yes
If yes, how much did it help? 1 2 3 4
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26.3.4 EORTC HEALTH THERMOMETER
Health can be defined as a state of physical, psychological, and social
well-being.
We would like to ask you to indicate on the scale below, how good or bad
you consider your overall health state during the past week. Please draw a
horizontal line at the most appropriate point on the scale somewhere
between 100 and 0, where 100 stands for 'Perfect health' and 0 means
'Worst imaginable health'.
-------------------------------------
Example: if during the past week your
overall health state has been almost
perfect, your xxxx on the thermometer
would be close to 100.
[GRAPHIC OMITTED]
-------------------------------------
-------------------------------------
During the past week: how do you rate
your overall health state?
-------------------------------------
[GRAPHIC OMITTED]
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26.4 APPENDIX IV: PATIENT INFORMATION/INFORMED CONSENT TEMPLATE
PROPOSAL FOR PATIENT INFORMED CONSENT FOR CLINICAL RESEARCH
You are being asked to participate in a clinical research study. In order to
decide whether or not you should agree to be part of this research study, you
should understand enough about its risks and benefits to make an informed
consent. This process is known as informed consent.
This consent form gives detailed information about the research study which the
doctor will discuss with you. Once you understand the study, you will be asked
to sign this form if you wish to participate. You will receive a copy to keep as
a record.
The research study being proposed to you is: SURVIVAL IN AN INTERNATIONAL PHASE
III PROSPECTIVE RANDOMIZED LD SMALL CELL LUNG CANCER VACCINATION STUDY WITH
ADJUVANT BEC2 AND BCG
PURPOSE OF RESEARCH STUDY
The purpose of this study is to determine whether immunization with the antibody
BEC2 in combination with BCG can stimulate your immune system to make antibodies
against small-cell lung cancer cells that might still remain in your body.
Antibodies are substances made by the immune system to target foreign invaders
such as bacteria. BEC2 is a mouse antibody containing a portion that resembles
G(D3) ganglioside. G(D3) is a substance found on the majority of small cell lung
cancers. BCG is a strain of the microbe Mycobacterium bovis and has been used to
immunize against tuberculosis. BCG has been used for many years with vaccines to
boost the effects of these vaccines. We are adding BCG to BEC2 in an attempt to
improve the ability of BEC2 to stimulate your immune system. When BEC2 is
injected into the body, the immune system will recognize BEC2 as foreign, since
it was made in a mouse, and produce antibodies against BEC2. It is expected that
some of these antibodies will be against the portion of BEC2 that resembles
G(D3) and that these antibodies will also react with G(D3) on any small-cell
lung cancer that might still be present in your body. We hope that these
antibodies will kill any remaining small-cell lung cancer cells in your body and
prevent the tumor from coming back.
The overall study design will consist of the following three parts:
Diagnosis, Standard Induction Therapy, and Restaging
First of all your doctor has to establish the diagnosis of limited disease small
cell lung cancer. Subsequently, a standard induction therapy will be given to
you, consisting of a combination of 2 or 3 anticancer drugs, for 4 or 5 cycles.
In addition, you will receive radiation therapy to your chest. You may also
undergo radiation therapy to the brain, if your physician recommends this
additional treatment.
The success of the induction therapy will be evaluated within a period of 6-8
weeks after administration of the last chemotherapy or radiation therapy. Even
if your tumor responds (decreases significantly in size or resolves completely
following chemotherapy), the cancer may
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recur. The clinical research study can only be offered to you if the induction
therapy results in a complete or partial remission. This means that the tumor as
found at initial diagnosis has to be reduced by a minimum of 50% at restaging by
chest-X-ray, clinical examination, and computed tomography of the thorax and
upper abdomen.
DESCRIPTION OF RESEARCH PROCEDURES
The aim of a clinical study is to prove or disprove that the new treatment is
superior to established treatment modalities and has acceptable side effects. In
this controlled clinical trial half of the patients will be treated with the
investigational treatment and half will not receive any farther treatment after
completion of standard induction therapy. This controlled clinical research
study can only offered to you if the standard induction therapy results in
complete or partial remission. This means that the tumor as found at initial
diagnosis has been reduced by a minimum of 50% at restaging by chest X-ray,
computed tomography of the thorax and upper abdomen and clinical examination. To
achieve a proper assignment of patients to both patients groups a procedure
called randomization will be performed. This is an assignment by chance. You
will be randomized to either the observation or experimental arm. If you are
assigned to the observation arm, you will receive no cancer specific therapy
until you have documented progression of disease. If you are assigned to the
experimental arm, you will receive 5 injections of BEC2 with BCG as an
outpatient over the course of ten weeks. BEC2 and BCG will be mixed together and
injected into the skin in your arms and legs. The first four injections will be
given two weeks apart; 1 month later you will be given the fifth injection.
Treatment will be stopped if you show progression of disease or if you refuse
further treatment. Approx. 60 ml blood will be drawn prior to each injection.
Additional blood samples may be requested after completing the course of
vaccinations. These blood tests are designed to detect whether your immune
system is producing antibodies against G(D3) ganglioside. In addition, these
blood tests can help detect side effects that might be caused by BEC2 and/or
BCG. You will be followed, starting 6 months after randomisation until you have
progression of disease. The total duration of the study, beginning from
induction therapy through vaccination and follow-up, is approx. 24 months.
Approximately 820 patients will be registered at time point of diagnosis in
order to be able to randomize 570 responding patients.
RISKS of the investigational treatment
Injection of BCG into the skin will result in inflammation, redness, swelling,
itching and crusting at the sites of injection. A low-grade fever, lasting 4-24
hours after each immunization, may occur. The inflamed injections sites may
drain a small amount of fluid for up to several weeks. The inflammation will
resolve and heal, and can leave a scar. BCG is a live but weakened bacteria, and
there is a small chance that a generalized infection could develop although this
is very unlikely. If a generalized infection were to develop it would be treated
with antibiotics. After receiving immunization with BCG certain tests for
tuberculosis will become positive, however this does not mean that you have
tuberculosis.
Side effects previously observed with the combination BEC2/BCG vaccine include:
fever, muscle aches, fatigue/general body weakness, elevated blood glucose
levels, flu-like symptoms, dry mouth, increased liver enzyme levels, and pain,
inflammation and scarring at the injection site.
G(D3) is found in a few normal tissues in addition to small cell lung cancer
cells. Therefore, if immunization with BEC2 induces antibodies against G(D3), it
is theoretically possible that these
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antibodies might also attack normal tissue and cause damage. For example,
inflammation of the adrenal gland could result in blood pressure changes.
Since BEC2 is a mouse protein, allergic reactions are possible. Generalized
allergic reactions, such as hives and itching, may occur. When very high doses
of mouse monoclonal antibodies (higher than we intend to use in this study) have
been injected intravenously into patients, more pronounced allergic reactions
were seen, such as wheezing, chest discomfort, fever, diarrhea, and nausea.
Life-threatening allergic reactions (anaphylactic shock) or death can
theoretically occur but are considered unlikely. Since BEC2 is a mouse
monoclonal antibody, you might not be eligible for future treatment with other
mouse monoclonal antibodies, as a result of your participation in this trial. In
the initial studies with BEC2, no significant allergic reactions or deaths due
to BEC2/BCG were observed. BEC2 is a mouse monoclonal antibody. BEC2 has no
known effect on the thyroid gland but may interfere with the results of
laboratory tests to evaluate thyroid function. The antibody may also interfere
with certain other laboratory tests.
RISKS of the standard induction therapy.
Side effects of chemotherapy and radiotherapy are well known, and will be in
detail explained to you by your doctor. They may slightly vary depending on the
drugs used, the schedule and the timing. Side effects of chemotherapy usually
consist of nausea and vomiting, hairloss, reduction of white blood cells and
platelets. Side effects of radiation therapy may include pain with swallowing
and fatigue.
General RISKS and considerations
Treatment under this protocol may involve unforeseeable risks to an unborn child
if a woman should become pregnant during the course of these immunizations. For
this reason, women of childbearing age must use effective contraceptive during
participation in this study. In addition, male patients should take the
necessary precautions to prevent pregnancy.
You will be informed of any new findings which might affect your willingness to
participate. If you are injured as a results of your participation in this
research study, emergency care, hospitalization and outpatient care will be made
available by the hospital. If you seek additional help whilst you are taking
part in this study, for what ever reason, your doctor must be informed.
BENEFITS
Although we hope that this research study will be of benefit to you, or that it
will help others, we cannot guarantee that it will help you directly.
FINANCIAL COST
You are responsible for the costs of routine physician visits and the usual
laboratory tests. There will be no charge to you for the BEC2 vaccine or for
tests performed to measure your immunity. If you are injured as a result of your
participation in this research study, care will be provided to you.
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INSURANCE
There is a possibility that unforeseen adverse events can occur with any
medication however you will be protected by an insurance policy against such
risk. (Colonia Insurance Germany, Policy Number: 60 20 60 10204). This is in
accordance with the laws of your country and will be available for all patients
taking part in this study.
PRIVACY
Your research and hospital records are confidential. Your name or any other
personally identifying information will not be used in reports or publications
resulting from this study. A record of your progress in this study will be
passed on to the EORTC data center and finally to the sponsors of this trial,
Merck KGaA and ImClone Systems Inc.. All documents received by the sponsors and
other parties acting in the name of the sponsors will be strictly confidential
and will be only identified by a trial number and your initials. A copy of this
documents will be held with your patient files. Moreover, your progress in the
study will be checked against your clinical records by sponsors or firms acting
in the names of the sponsor's employees. By signing this informend consent form
you authorize representatives of the The Food and Drug Administration, the EMEA,
or other authorized agents and the sponsors to inspect your medical records.
RIGHT TO REFUSE OR WITHDRAW
The choice to enter or not to enter this study is yours. You are in a position
to make a decision if you understand what the doctor has explained and what you
have read about the research study and other possible forms of care. If you
decide not to participate, you will be offered other treatment based on your
needs and your cancer. If you begin the study, you still have a right to
withdraw at any time. If you should withdraw, you will be offered other
available care which suits your needs and medical condition.
TERMINATION OF STUDY
Treatment with the investigational drug may be ended if your small cell lung
cancer recurs, if the doctors treating you see side effects that they consider
dangerous, if you refuse to have the treatments as recommended by your doctor or
if you refuse to have the tests needed to determine whether the treatment is
safe and effective, or if you become pregnant.
This research study has been reviewed by INSTITUTION'S Institutional Review
Board. This Board is legally responsable for making sure that research with
patients is appropriate and that the patient's rights and welfare are protected.
The physician in charge of this research study is ______________, telephone
number _____________ If you need more information about this study before you
decide to join, or at any other time, you may wish to contact him. In the event
that you do decide to participate, he should also be called if there are side
effects from the treatment. A non-physician whom you may call for information
about the consent process, research patient's rights, or research-related injury
is _______________, telephone number _________
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PATIENT INFORMED CONSENT FOR CLINICAL RESEARCH
Title: SURVIVAL IN AN INTERNATIONAL PHASE III PROSPECTIVE RANDOMIZED LD SMALL
CELL LUNG CANCER VACCINATION STUDY WITH ADJUVANT BEC2 AND BCG
Purpose: To determine whether immunization with BEC2 in combination with BCG
following chemotherapy in patients with limited disease small-cell lung cancer
results in longer survival than chemotherapy alone. The study will also study
the "progression free survival" in the two separate treatment groups, toxicities
associated with the study agents BEC2 and BCG, and the effect of these agents on
the patients quality of life.
STATEMENT OF PHYSICIAN OBTAINING INFORMED CONSENT
I have fully explained this research study to the patient ______________ In my
judgment, and the patient's, there was sufficient access to information,
including risks and benefits, to make an informed decision.
DATE:_________________
PHYSICIAN'S SIGNATURE:___________________
PHYSICIAN'S NAME:________________________
PATIENTS STATEMENT
I have read the description of the clinical research study or have had it
translated into a language I understand. I have also talked it over with the
doctor to my satisfaction. I understand that my participation is voluntary. I
know enough about the purpose, methods, risks, and benefits of the research
study to judge that I want to take part in it.
PATIENTS NAME:___________________________
PATIENTS SIGNATURE:______________________
DATE:_________________
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26.5 APPENDIX V: COMMON TOXICITY CRITERIA (NCIC - CTC) SCALE
====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
ALLERGY
====================================================================================================================================
AL LER Allergy none transient rash, fever urticaria, fever = serum sickness, anaphylaxis
< 38(degrees)C, 38(degrees)C, bronchospasm, req
100.4(degrees)F 100.4(degrees)F, mild parenteral meds
bronchospasm
-----------------------------------------------------------------------------------------------------------
Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non allergic drug fever (e.g.
as from biologics) should be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection, code
INFECTION only (IN FEC or IN NEU). NB: Protocols requiring detailed reporting of hypersensitivity
reactions, will include a Hypersensitivity Reaction module.
------------------------------------------------------------------------------------------------------------------------------------
AL OTH other * none mild moderate severe life threatening
====================================================================================================================================
====================================================================================================================================
BLOOT/BONE MARROW (SI UNITS)
====================================================================================================================================
BL WBC White >=4.0 10(caret)9/1 3.0 - 3.9 2.0 - 2.9 1.0 - 1.9 < 1.0
Blood Count
(WBC)
------------------------------------------------------------------------------------------------------------------------------------
BL PLT Platelets WNL 10(caret)9/1 75.0 - normal 50.0 - 74.9 25.0 - 49.9 < 25.0
------------------------------------------------------------------------------------------------------------------------------------
BL HGB WNL g/1 100 - normal 80 - 99 65 - 79 < 65
Hemoglobin (Hgb)
------------------------------------------------------------------------------------------------------------------------------------
BL GRA >= 2.0 10(caret)9/1 1.5 - 1.9 1.0 - 1.4 0.5 - 0.9 < 0.5
granulocytes (i.e.
neuts + bands)
------------------------------------------------------------------------------------------------------------------------------------
XX XXX >= 2.0 10(caret)9/1 1.5 - 1.9 1.0 - 1.4 0.5 - 0.9 < 0.5
Lymphocytes
------------------------------------------------------------------------------------------------------------------------------------
BL HEM none mild, no transfusion gross, 1-2 units gross, 3-4 units massive, > 4
Hemorrhage (includes transfusion per transfusion per units transfusion
resulting from bruise/hematoma, episode episode per episode
thrombocytopenia petechiae)
(clinical)
------------------------------------------------------------------------------------------------------------------------------------
BL OTH Other * none mild moderate severe life threatening
====================================================================================================================================
====================================================================================================================================
CANCER RELATED SYMPTOMS
====================================================================================================================================
CA DEA Death - - - - -
from malignant
disease within 30
days of treatment *
(grade 5)
------------------------------------------------------------------------------------------------------------------------------------
CA PAI Cancer none pain, but no treatment pain controlled with pain controlled uncontrollable pain
pain * req non-opioids with opioids
------------------------------------------------------------------------------------------------------------------------------------
CA SEC Second none - - present -
malignancy *
------------------------------------------------------------------------------------------------------------------------------------
CA OTH Other * none mild moderate severe life threatening
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
CARDIOVASCULAR
====================================================================================================================================
CD ART Arterial * none - - transient events (e.g. permanent event
(non myocardial) transient ischemic (e.g. cerebral
attack) vascular accident)
------------------------------------------------------------------------------------------------------------------------------------
CD VEN Venous * none superficial (excludes deep vein thrombosis deep vein thrombosis pulmonary embolism
IV site not req anticoagulant req anticoagulant
reaction -> code therapy therapy
SK LTO)
------------------------------------------------------------------------------------------------------------------------------------
CD DYS none asymptomatic, recurrent or req therapy req monitoring, or
Dysrhythmias transient, req no persistent, hypotension, or
therapy req no therapy ventricular tachy-
cardia, or
fibrillation
------------------------------------------------------------------------------------------------------------------------------------
CD EDE Edema * none 1+ or dependent in 2+ or dependent 3+ 4+, generalized
(eg. peripheral evening only throughout day anasarca
edema)
====================================================================================================================================
====================================================================================================================================
CD FUN Function none asymptomatic, decline asymptomatic, decline mild CHF, responsive severe or refractory
of resting ejection of resting ejection to therapy CHF
fraction of >=10% but fraction by >20% of
< 20% of baseline baseline value
value
------------------------------------------------------------------------------------------------------------------------------------
CD HBP none or no change asymptomatic, transient recurrent or persistent req therapy hypertensive crisis
Hypertension increase by > 20mm increase by
Hg (D)or to > 150/100 > 20mm Hg (D) or to
if previously WNL. > 150/100 if previously
No therapy req WNL.
No therapy req
------------------------------------------------------------------------------------------------------------------------------------
CD LBP none or no change changes req no therapy req fluid replacement req therapy + req therapy +
Hypotension (incl. transient or other hospitalization: hospitalization for
orthostatic therapy but no resolves within 48hrs > 48hrs after stopping
hypotension) hospitalization of stopping agent agent
------------------------------------------------------------------------------------------------------------------------------------
CD ISC Ischemia none non-specific T wave asymptomatic, ST + T angina without acute myocardial
(myocardial) flattening wave changes evidence for infarction infarction
suggesting ischemia
------------------------------------------------------------------------------------------------------------------------------------
CD PAI none pain, but no treatment pain controlled with pain controlled with uncontrollable pain
Pain (chest) * req non-opioids opioids
------------------------------------------------------------------------------------------------------------------------------------
CD PER none asymptomatic effusion pericarditis (rub, symptomatic effusion tamponade, drainage
Pericardial no intervention req chest pain, drainage req urgently req; or
ECG changes) constrictive
pericarditis
req surgery
------------------------------------------------------------------------------------------------------------------------------------
CD TAC none mild moderate severe life threatening
Sinus tachycardia *
------------------------------------------------------------------------------------------------------------------------------------
CD OTH Other * none mild moderate severe life threatening
====================================================================================================================================
====================================================================================================================================
COAGULATION
====================================================================================================================================
CG FIB Fibrinogen WNL 0.99-0.75 x N 0.74-0.50 x N 0.49-0.25 x N <= 0.24 x N
------------------------------------------------------------------------------------------------------------------------------------
CG PT WNL 1.01-1.25 x N 1.26-1.50 x N 1.51-2.00 x N > 2.00 x N
Prothrombin time
------------------------------------------------------------------------------------------------------------------------------------
CG PTT Partial WNL 1.01-1.66 x N 1.67-2.33 x N 2.34-3.00 x N > 3.00 x N
thromboplastin
time
------------------------------------------------------------------------------------------------------------------------------------
CG OTH Other * none mild moderate severe life threatening
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
DENTITION (TEETH)
====================================================================================================================================
DE DEC none mild moderate severe -
Tooth decay*
------------------------------------------------------------------------------------------------------------------------------------
DE PAI none pain, but no treatment pain controlled with pain controlled with uncontrollable pain
Toothache* non-opioids opioids
------------------------------------------------------------------------------------------------------------------------------------
DE OTH Other * none mild moderate severe life threatening
====================================================================================================================================
====================================================================================================================================
ENDOCRINE*
====================================================================================================================================
EN AME no irregular menses >= 3 months - -
Amenorrhea
------------------------------------------------------------------------------------------------------------------------------------
EN CUS normal mild pronounced - -
Cushingoid
------------------------------------------------------------------------------------------------------------------------------------
EN FLA none mild or < 1/day moderate & >= 1/day frequent & interferes -
Hot flashes with normal function
------------------------------------------------------------------------------------------------------------------------------------
EN GYN normal mild pronounced or painful - -
Gynecomastia
------------------------------------------------------------------------------------------------------------------------------------
EN IMP normal decrease in normal - absense of function -
Impotence/Libido function
------------------------------------------------------------------------------------------------------------------------------------
EN OTH Other none mild moderate severe life threatening
====================================================================================================================================
====================================================================================================================================
FLU-LIKE SYMPTOMS
====================================================================================================================================
FL FEV fever in none 37.1 - 38.0(degrees)C 38.1 - 40.0(degrees)C > 40.0(degrees)C > 40.0(degrees)C
absence of infect.* 98.7 - 100.4(degrees)F 100.5 - 104.4(degrees)F > 104.0(degrees)F (104.0(degrees)F)
(incl. drug fever) for < 24 hrs for > 24 hrs or fever
accompanied by
hypotension
---------------------------------------------------------------------------------------------------------
Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non allergic drug fever
(e.g. as from biologics) should be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection,
code INFECTION only (IN FEC or IN NEU).
------------------------------------------------------------------------------------------------------------------------------------
FL HAY Hayfever* none mild moderate severe -
(includes sneezing,
nasal stuffiness,
post-nasal drip)
------------------------------------------------------------------------------------------------------------------------------------
FL JOI Arthralgia* none mild moderate severe -
(joint pain)
------------------------------------------------------------------------------------------------------------------------------------
FL LET Lethargy* none mild, fall of 1 level in moderate, fall of 2 severe, fall of 3 -
(fatigue, malaise) perf. status level in perf. status levels in perf.
status
------------------------------------------------------------------------------------------------------------------------------------
FL MYA Myalgia* none mild moderate severe -
(muscle ache)
------------------------------------------------------------------------------------------------------------------------------------
FL RIG none mild or brief pronounced or/and cyanosis -
Rigors/Chills* prolonged
(Gr 3 incl cyanosis)
------------------------------------------------------------------------------------------------------------------------------------
FL SWE Sweating* none mild moderate severe -
(diaphoresis)
------------------------------------------------------------------------------------------------------------------------------------
FL OTH Other* none mild moderate severe life threatening
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
GASTROINTESTINAL
====================================================================================================================================
GI ANO Anorexia* none mild moderate severe dehydration
------------------------------------------------------------------------------------------------------------------------------------
GI APP none mild moderate - -
Appetite increased*
------------------------------------------------------------------------------------------------------------------------------------
GI ASC Ascites none mild moderate severe life threatening
(non malignant)*
------------------------------------------------------------------------------------------------------------------------------------
GI DIA Diarrhea none increase of 2-3 stools increase of 4-6 stools increase of 7-9 stools increase of >= 10 stools
per day; or mild per day, or nocturnal per day, or per day, or grossly
increase of loose stools; or moderate incontinence, bloody diarrhea, or
watery colostomy increase in loose malabsorption, or grossly bloody
output compared to watery colostomy severe increase in loose clostomy output or
pre-trt output compared to watery colostomy loose watery colostomy
pre-trt output compared with output req parenteral
pre-trt support; dehydration
------------------------------------------------------------------------------------------------------------------------------------
GI DPH none dys.or odyn. not req dys. or odyn. req trt dys. or odyn. lasting dys. or odyn. with
Esophagitis/ trt, or painless ulcers > 14 days despite trt 10% loss of body wt,
dysphagia/ on esophagoscopy dehydration, hosp. req
odynophagia* (incl
recall reaction)
------------------------------------------------------------------------------------------------------------------------------------
GI DRY Mouth, none mild moderate severe -
nose dryness*
------------------------------------------------------------------------------------------------------------------------------------
GI FIS Fistula* none - - req intervention req operation
(intestinal,
esophageal, rectal)
------------------------------------------------------------------------------------------------------------------------------------
GI GAS none mild moderate severe -
Flatulence*
------------------------------------------------------------------------------------------------------------------------------------
GI HEA none mild moderate severe -
Heartburn*
(incl. dyspepsia)
------------------------------------------------------------------------------------------------------------------------------------
GI HEM none mild, no transfusion gross, 1-2 units gross, 3-4 units massive > 4 units
Gastrointestinal transfusion per transfusion per episode transfusion per episode
bleeding* episode
-----------------------------------------------------------------------------------------------------------
Bleeding resulting from thrombocytopenia should be coded under BL HEM, not GI
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
GI NAU Nausea none able to eat reasonable intake significantly no significant intake -
intake decreased but can eat
------------------------------------------------------------------------------------------------------------------------------------
GI OBS Small no - intermittent, no req intervention req operation
bowel obstruction* intervention
------------------------------------------------------------------------------------------------------------------------------------
GI PAI none pain, but no treatment pain controlled with pain controlled with uncontrollable pain
Gastrointestinal req non-opioids opioids
pain/cramping*
(incl. rectal pain)
------------------------------------------------------------------------------------------------------------------------------------
GI PRO Proctitis none perianal itch, tenesmus or ulcerations tenesmus or ulcerations mucosal necrosis with
(rectal) hemorrhoids relieved with therapy, or other symptoms not hemorrhage or other
anal fissure relieved with therapy life threatening
proctosis
------------------------------------------------------------------------------------------------------------------------------------
GI STO Stomatitis/ none painless ulcers, painful erythema, painful erythema, mucosal necrosis
oral erythema, or mild edema, or ulcers, edema, or ulcers, and and/or req parenteral
soreness but can eat cannot eat or enteral support,
dehydration
------------------------------------------------------------------------------------------------------------------------------------
GI TAS Taste, none mild moderate severe -
sense of smell
altered*
------------------------------------------------------------------------------------------------------------------------------------
GI ULC none antacid req vigourous medical uncontrolled by perforation or bleeding
Gastritis/ulcer* management or non- medical management;
surgical art req surgery for GI
ulceration
------------------------------------------------------------------------------------------------------------------------------------
GI VOM Vomiting none 1 episode in 24hrs 2-5 episodes in 24 hrs 6-10 episodes in > 10 episodes in 24hrs
24hrs or req parenteral
support, dehydration
------------------------------------------------------------------------------------------------------------------------------------
GI OTH Other* none mild moderate severe life threatening
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
GENITO-URINARY
====================================================================================================================================
GU BLA none light epithelial generalized severe generalized necrosis, or contracted
Bladder changes* atrophy, or minor telangiectasia telangiectasia (often bladder (capacity < 100
telangiectasia with petechiae) or ml), or fibrosis
reduction in bladder
capacity (< 15 ml)
------------------------------------------------------------------------------------------------------------------------------------
GU CRE WNL < 1.5 x N 1.5 - 3.0 x N 3.1 - 6.0 x N > 6.0 x N
Creatinine
------------------------------------------------------------------------------------------------------------------------------------
GU CYS Cystitis* none mild symptoms, req no symptoms relieved symptoms not relieved severe (life threatening)
(non bacterial) intervention completely with ther. despite therapy cystitis
--------------------------------------------------------------------------------------------------------------
Urinary tract infection should be coded under infection not GU
------------------------------------------------------------------------------------------------------------------------------------
GU FIS Fistula* none - - req intervention req operation
(vaginal,
vesicovaginal)
------------------------------------------------------------------------------------------------------------------------------------
GU FRE none freq of urination or freq of urination or freq with urgency and -
Frequency* nocturia twice pre-trt nocturia < hourly nocturia >= hourly
habit
------------------------------------------------------------------------------------------------------------------------------------
GU HEM negative micro only gross, no clots gross + clots req transfusion
Hematuria,
bleeding per vagina
--------------------------------------------------------------------------------------------------------------
Bleeding resulting from thrombocytopenia should be coded under BL HEM not GU.
------------------------------------------------------------------------------------------------------------------------------------
GU INC none mild moderate severe -
Incontinence*
------------------------------------------------------------------------------------------------------------------------------------
GU OBS Ureteral none unilateral, no surgery bilateral, no surgery not complete bilateral, complete bilateral
obstruction* req but stents, obstruction
nephrostomy tubes or
surgery req
------------------------------------------------------------------------------------------------------------------------------------
GU PAI Genito- none pain, but no treatment pain controlled with pain controlled with uncontrollable pain
urinary pain * (eg : req non-opioids opioids
dysuria,
dysmenorrhea,
dyspareunia)
====================================================================================================================================
====================================================================================================================================
GU PRT no change 1 + 2-3 + 4 + nephrotic syndrome
Proteinuria or < 0.3 g/% or 0.3-1.0 g/% or > 1.0 g/%
or < 3 g/l or 3-10 g/l or > 10 g/l
------------------------------------------------------------------------------------------------------------------------------------
GU VAG Vaginitis* none mild, no trt req moderate, relieved severe, not relieved life threatening
(+/- vaginal with trt with trt
discharge)
(non-infectious)
------------------------------------------------------------------------------------------------------------------------------------
GU OTH Other* none mild moderate severe life-threatening
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
HEPATIC
====================================================================================================================================
HP ALK Alk. within normal <= 2.5 x N (Normal) 2.6 - 5.0 x N 5.1 - 20.0 x N > 20 x N
Phos or limits (WNL)
5'nucleotidase
------------------------------------------------------------------------------------------------------------------------------------
HP ALT WNL <= 2.5 x N (Normal) 2.6 - 5.0 x N 5.1 - 20.O x N > 20 x N
Transaminase
SGPT (ALT)
------------------------------------------------------------------------------------------------------------------------------------
HP AST WNL <= 2.5 x N (Normal) 2.6 - 5.0 x N 5.1 - 20.0 x N > 20 x N
Transaminase
SGOT (AST)
------------------------------------------------------------------------------------------------------------------------------------
HP BIL WNL - < 1.5 x N 1.5 - 3.0 x N > 3.0 x N
Bilirubin
------------------------------------------------------------------------------------------------------------------------------------
HP CLI Liver no change from - - precoma hepatic coma
(clinical) baseline
------------------------------------------------------------------------------------------------------------------------------------
HP LDH LDH* WNL <= 2.5 x N (Normal) 2.6 - 5.0 x N 5.1 - 20.0 x N > 20 x N
------------------------------------------------------------------------------------------------------------------------------------
HP OTH none mild moderate severe life-threatening
Other*
------------------------------------------------------------------------------------------------------------------------------------
Viral Hepatitis should be coded as infection rather than liver toxicity.
====================================================================================================================================
====================================================================================================================================
INFECTION
====================================================================================================================================
IN FEC none mild, no active therapy moderate, localized sever systemic life threatening
Infection infection, active infection, req sepsis, specify
therapy req parenteral trt, site
specify site
------------------------------------------------------------------------------------------------------------------------------------
IN NEU Febrile none - - present -
Neutropenia*
-------------------------------------------------------------------------------------------------------------------
Absolute Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non-allergy drug fever (eg. as from
granulocyt biologics) should be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection, code INFECTION only
count < 1.0 x (IN FEC or IN NEU).
10(caret)9/1,
fever >= 38.5
(degrees)C
treated with
(or ought to
have been
treated with)
IV antibiotics
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
METABOLIC (SI UNITS)
====================================================================================================================================
MT XXX Amylase WNL < 1.5 x N 1.5 - 2.0 x N 2.1 - 5.0 x N > 5.1 x N
------------------------------------------------------------------------------------------------------------------------------------
MT HCA < 2.64 mmol/l 2.64 - 2.88 2.89 - 3.12 3.13 - 3.37 > 3.37
Hypercalcemia
------------------------------------------------------------------------------------------------------------------------------------
MT LCA > 2.10 mmol/l 2.10 - 1.93 1.92 - 1.74 1.73 - 1.51 <= 1.50
Hypocalcemia
------------------------------------------------------------------------------------------------------------------------------------
MT HGL < 6.44 mmol/l 6.44 - 8.90 8.91 - 13.8 13.9 - 27.8 > 27.8 or
Hyperglycemia ketoacidosis
------------------------------------------------------------------------------------------------------------------------------------
MT LGL > 3.55 mmol/l 3.03 - 3.55 2.19 - 3.02 1.66 - 2.18 < 1.66
hypoglycemia
------------------------------------------------------------------------------------------------------------------------------------
MT LKA no change or > 3.5 3.1 - 3.5 2.6 - 3.0 2.1 - 2.5 <= 2.0
Hypokalemia* mmol/l
------------------------------------------------------------------------------------------------------------------------------------
MT LMA > 0.70 mmol/l 0.70 - 0.58 0.57 - 0.38 0.37 - 0.30 <= 0.29
Hypomagnesemia
------------------------------------------------------------------------------------------------------------------------------------
MT LNA no change or > 135 131 - 135 126 - 130 121 - 125 <= 120
Hyponatremia* mmol/l
------------------------------------------------------------------------------------------------------------------------------------
MT 0TH Other* none mild moderate severe life threatening
====================================================================================================================================
====================================================================================================================================
METABOLIC (SI UNITS)
====================================================================================================================================
MT XXX Amylase WNL < 1.5 x N 1.5 - 2.0 x N 2.1 - 5.0 x N > 5.1 x N
------------------------------------------------------------------------------------------------------------------------------------
MT HCA < 2.64 mmol/l 2.64 - 2.88 2.89 - 3.12 3.13 - 3.37 > 3.37
Hypercalcemia
------------------------------------------------------------------------------------------------------------------------------------
MT LCA > 2.10 mmol/l 2.10 - 1.93 1.92 - 1.74 1.73 - 1.51 <= 1.50
Hypocalcemia
------------------------------------------------------------------------------------------------------------------------------------
MT HGL < 6.44 mmol/l 6.44 - 8.90 8.91 - 13.8 13.9 - 27.8 > 27.8 or
Hyperglycemia ketoacidosis
------------------------------------------------------------------------------------------------------------------------------------
MT LGL > 3.55 mmol/l 3.03 - 3.55 2.19 - 3.02 1.66 - 2.18 < 1.66
hypoglycemia
------------------------------------------------------------------------------------------------------------------------------------
MT LKA no change or > 3.5 3.1 - 3.5 2.6 - 3.0 2.1 - 2.5 <= 2.0
Hypokalemia* mmol/l
------------------------------------------------------------------------------------------------------------------------------------
MT LMA > 0.70 mmol/l 0.70 - 0.58 0.57 - 0.38 0.37 - 0.30 <= 0.29
Hypomagnesemia
------------------------------------------------------------------------------------------------------------------------------------
MT LNA no change or > 135 131 - 135 126 - 130 121 - 125 <= 120
Hyponatremia* mmol/l
------------------------------------------------------------------------------------------------------------------------------------
MT 0TH Other* none mild moderate severe life threatening
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
NEUROLOGIC
====================================================================================================================================
NE CER none slight incoordination, intention tremor, locomotor ataxia cerebellar necrosis
Cerebellar dysdiadochokinesis dysmetria, slurred
speech, nystagmus
------------------------------------------------------------------------------------------------------------------------------------
NE CON none or no change mild moderate severe, ileus > 96 hrs
Constipation obstipation
------------------------------------------------------------------------------------------------------------------------------------
NE COR Cortical none mild somnolence moderate somnolence severe somnolence, coma, seizures,
(includes confusion, toxic psychosis
drowsiness) disorientation,
hallucinations
------------------------------------------------------------------------------------------------------------------------------------
NE DIZ none mild moderate severe -
Dizziness* (includes fainting)
(includes
lightheadedness)
------------------------------------------------------------------------------------------------------------------------------------
NE EXT none mild agitation moderate agitation torticollis, -
Extrapyramidal/ (includes restlessness) oculogyric crisis
Involuntary severe agitation
movement*
------------------------------------------------------------------------------------------------------------------------------------
NE HED Headache none mild moderate or severe unrelenting and -
but transient severe
------------------------------------------------------------------------------------------------------------------------------------
NE HER none or no change asymptomatic hearing tinnitus, symptomatic hearing loss hearing changes or
Altered hearing loss on audiometry hearing changes not interfering with deafness not
only req hearing aid or trt function but correctable
correctable with
hearing aid or trt
------------------------------------------------------------------------------------------------------------------------------------
NE INS Insomnia* none mild moderate severe -
------------------------------------------------------------------------------------------------------------------------------------
NE MOO Mood no change mild anxiety or moderate anxiety or severe anxiety or suicidal ideation
depression depression depression
------------------------------------------------------------------------------------------------------------------------------------
NE MOT Motor none or no change subjective weakness, mild objective objective weakness paralysis
no objective findings weakness without with impairment of
significant impairment function
of function
------------------------------------------------------------------------------------------------------------------------------------
NE PAI none pain, but no treatment pain controlled with pain controlled uncontrollable pain
Neurologic pain* req non-opioids with opioids
(eg : jaw pain)
------------------------------------------------------------------------------------------------------------------------------------
NE PER no change change, not disruptive disruptive to patient harmful to others psychosis
Personality to patient or family or family or self
change*
------------------------------------------------------------------------------------------------------------------------------------
NE SEN Sensory none or no change mild paresthesias of deep mild or moderate sensory loss or -
tendon reflexes (including objective sensory paresthesias that
tingling) loss, moderate interfere with
paresthesias function
------------------------------------------------------------------------------------------------------------------------------------
NE VIS Vision none or no change blurred vision - symptomatic blindness
subtotal
loss of vision
------------------------------------------------------------------------------------------------------------------------------------
NE 0TH Other* none mild moderate severe life-threatening
(includes pain)
------------------------------------------------------------------------------------------------------------------
Code chest vain CD PAI, muscle aches (myalgia) FL MYA, abdominal pain GI PAI, and local pain at IV site SK LTO.
For all other types of pain (eg. bone pain), code NE 0TH.
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
OCULAR
====================================================================================================================================
OC CAT Cataract* none mild moderate severe -
------------------------------------------------------------------------------------------------------------------------------------
OC CJN none erythema or chemosis req trt steroids or corneal ulceration -
Conjunctivis/ not req steroids or antibiotics or visible
Keratitis antibiotics opacification
------------------------------------------------------------------------------------------------------------------------------------
OC DRY Dry eye normal mild req artificial tears severe req enucleation
------------------------------------------------------------------------------------------------------------------------------------
OC GLA no change - - yes -
Glaucoma
------------------------------------------------------------------------------------------------------------------------------------
OC PAI Eye none pain, but no treatment pain controlled with pain controlled uncontrollable pain
pain * req non-opioids with opioids
------------------------------------------------------------------------------------------------------------------------------------
OC TEA Tearing * none mild moderate severe -
(watery eyes)
------------------------------------------------------------------------------------------------------------------------------------
OC 0TH Other none mild moderate severe life threatening
====================================================================================================================================
====================================================================================================================================
OSSEOUS (BONE)
====================================================================================================================================
OS PAI Bone none pain, but no treatment pain controlled with pain controlled uncontrollable pain
pain * req non-opioids with opioids
------------------------------------------------------------------------------------------------------------------------------------
OS 0TH Other none mild moderate severe life threatening
(eg. avascular
necrosis)
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
PULMONARY
====================================================================================================================================
PU CMD Carbon > 90% decrease to 76 - 90% decrease to 51 - 75% decrease to 26 - 50% decrease to <= 25%
Monoxide Diffusion of pretreatment of pre-trt of pre-trt of pre-trt of pre-trt
Capacity (DLCO)* value
------------------------------------------------------------------------------------------------------------------------------------
PU COU Cough* norm mild moderate severe -
------------------------------------------------------------------------------------------------------------------------------------
PU EDE none - out-patient management in-patient management req incubation
Pulmonary edema*
------------------------------------------------------------------------------------------------------------------------------------
PU EFF none mild moderate severe life threatening
Pleural effusion*
(non-malignant)
------------------------------------------------------------------------------------------------------------------------------------
PU FIB Pulmonary normal radiographic changes, - changes with -
fibrosis* no symptoms symptoms
------------------------------------------------------------------------------------------------------------------------------------
PU HEM none mild, no transfusion gross, 1 - 2 units gross, 3 - 4 units massive, > 4 units
Hemoptysis* transfusion per transfusion per transfusion per
episode episode episode
---------------------------------------------------------------------------------------------------------------
Bleeding resulting from thrombocytopenia should be coded under BL HEM, not PU
------------------------------------------------------------------------------------------------------------------------------------
PU HIC none mild moderate severe -
Hiccoughs*
------------------------------------------------------------------------------------------------------------------------------------
PU PAI none pain, but not treatment pain controlled pain controlles uncontrollable pain
Pulmonary pain* req non-opioids with opioids
------------------------------------------------------------------------------------------------------------------------------------
PU PNE normal radiographic changes, steriods req oxygen req req assisted
Pneumonitis* symptoms do not req ventilation
(non-infectious) steriods
------------------------------------------------------------------------------------------------------------------------------------
PU SOB Shortness none or no change asymptomatic, with dyspnea on significant dyspnea at normal dyspnea at rest,
of breath (dyspnea) abnormality in PFT's exertion level of activity, apnea with cyanosis
(incl wheezing) apnea without
cyanosis
------------------------------------------------------------------------------------------------------------------------------------
PU VOI Voice none mild moderate severe -
changes* (incl.
hoarseness, loss
of voice)
------------------------------------------------------------------------------------------------------------------------------------
PU 0TH Other* none mild moderate severe life-threatening
------------------------------------------------------------------------------------------------------------------------------------
Pneumonia should be considered infection and not graded as pulmonary toxicity unless felt to be
resultant from pulmonary changes directly induced by treatment
====================================================================================================================================
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====================================================================================================================================
GRADE 0 1 2 3 4
====================================================================================================================================
====================================================================================================================================
SKIN
====================================================================================================================================
XX XXX Alopecia no loss mild hair loss pronounced or total total body hair -
head hair loss loss
------------------------------------------------------------------------------------------------------------------------------------
XX XXX none localized pigmentation generalized subcut.fibrosis or generalized
Skin changes* (eg. changes pigmentation changes localized shallow ulcerations or
photosensitivity) or atrophy ulceration necrosis
------------------------------------------------------------------------------------------------------------------------------------
SK DES none dry desquamation moist desquamation confluent moist -
Desquamation* desquamation
------------------------------------------------------------------------------------------------------------------------------------
SK DRY Dry skin* none mild moderate severe -
------------------------------------------------------------------------------------------------------------------------------------
SK FAC Flushing* none mild moderate severe -
(eg:-facial)
------------------------------------------------------------------------------------------------------------------------------------
SK HEM none mild, not transfusion gross, 1 - 2 units gross, 3 - 4 units massive, > 4 units
Bruising/bleeding transfusion per transfusion per transfusion per
episode episode episode
---------------------------------------------------------------------------------------------------------------
Bleeding from thrombocytopenia should be coded under BL HEM, not SK
------------------------------------------------------------------------------------------------------------------------------------
SK LTO none pain pain and swelling, ulceration plastic surgery
Local toxicity with inflammation or indicated
(reaction at IV site) phlebitis
------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------
SK NAI none mild moderate severe -
Nail changes*
------------------------------------------------------------------------------------------------------------------------------------
XX XXX Skin pain* none pain, but no treatment pain controlled with pain controlled with uncontrollable pain
(include sclap non-opioids opioids
pain)
------------------------------------------------------------------------------------------------------------------------------------
SK RAS Rash/Itch* none or no change scattered macular or scattered macular or generalized exfoliative
(not to due to papular eruption or papular eruption or symptomatic macular, dermatitis or
allergy) (includes) erythema that is erythema with pruritus papular, or ulcerating
recall reaction) asymptomatic or other associated vesicular eruption dermatitis
symptoma
------------------------------------------------------------------------------------------------------------------------------------
SK 0TH Other* none mild moderate severe life threatening
====================================================================================================================================
====================================================================================================================================
WEIGHT
====================================================================================================================================
WT GAI < 5.0% 5.0 - 9.9% 10.0 - 19.9% >= 20.0% -
Weight Gain
------------------------------------------------------------------------------------------------------------------------------------
WT LOS < 5.0% 5.0 - 9.9% 10.0 - 19.9% >= 20.0% -
Weight Loss
====================================================================================================================================
====================================================================================================================================
OTHER
====================================================================================================================================
OT 0TH Other* none mild moderate severe life-threatening
---------------------------------------------------------------------------------------------------------------
For toxicity which do not have an existing code, but do fit into an existing toxicity category, use "other"
variable in the appropriate toxicity category (eg. code sinus tachycardia CARDIOVASCULAR OTHER (CD 0TH). Only
toxicities which do not fit into existing categories should be coded OTHER OTHER (OT 0TH).
====================================================================================================================================
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26.6 APPENDIX VI: DECLARATION OF HELSINKI
WORLD MEDICAL ASSOCIATION DECLARATION
OF HELSINKI
Recommendations guiding physicians in
biomedical research involving human subjects
Adopted by the 18th World Medical Assembly
Helsinki, Finland, June 1964
and amended by the
29th World Medical Assembly
Tokyo, Japan, October 1975
35th World Medical Assembly
Venice, Italy, October 1983
and the
41st World Medical Assembly
Hong Kong, September 1989
and the
48th General Assembly
Somerset West, Republic of South Africa, October 1996
Introduction
It is the mission of the physician to safeguard the health of the people. His or
her knowledge and conscience are dedicated to the fulfilment of this mission.
The Declaration of Geneva of the World Medical Association binds the physician
with the words, "The health of my patient will be my first consideration," and
the International Code of Medical Ethics declares that, "A physician shall act
only in the patient's interest when providing medical care which might have the
effect of weakening the physical and mental condition of the patient."
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The purpose of biomedical research involving human subjects must be to improve
diagnostic, therapeutic and prophylactic procedures and the understanding of the
etiology and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic
procedures involve hazards. This applies especially to biomedical research.
Medical progress is based on research which ultimately must rest in part on
experimentation involving human subjects.
In the field of biomedical research a fundamental distinction must be recognised
between medical research in which the aim is essentially diagnostic or
therapeutic for a patient, and medical research, the essential object of which
is purely scientific and without the implication of direct diagnostic or
therapeutic value to the person subjected to the research.
Special caution must be exercised in the conduct of research which may effect
the environment, and the welfare of animals used for research must be respected.
Because it is essential that the results of laboratory experiments be applied to
human beings to further scientific knowledge and to help suffering humanity, the
World Medical Association has prepared the following recommendations as a guide
to every physician in biomedical research involving human subjects. They should
be kept under review in the future. It must be stressed that the standards as
drafted are only a guide to physicians all over the world. Physicians are not
relieved from criminal, civil and ethical responsibilities under the laws of
their own countries.
I. Basic principles
1. Biomedical research involving human subjects must conform to generally
accepted scientific principles and should be based on adequately performed
laboratory and animal experimentation and on a thorough knowledge of the
scientific literature.
2. The design and performance of each experimental procedure involving human
subjects should be clearly formulated in an experimental protocol which
should be transmitted for consideration, comment and guidance to a
specially appointed committee independent of the investigator and the
sponsor provided that this independent committee is in conformity with the
laws and regulations of the country in which the research experiment is
performed.
3. Biomedical research involving human subjects should be conducted only by
scientifically qualified persons and under the supervision of a clinically
competent medical person. The responsibility for the human subject must
always rest with a medically qualified person and never rest on the
subject of the research, even though the subject has given his or her
consent.
4. Biomedical research involving human subjects cannot legitimately be
carried out unless the importance of the objective is in proportion to the
inherent risk to the subject.
5. Every biomedical research project involving human subjects should be
preceded by careful assessment of predictable risks in comparison with
foreseeable benefits to the subject or to others. Concern for the
interests of the subject must always prevail over the interests of science
and society.
6. The right of the research subject to safeguard his or her integrity must
always be respected. Every precaution should be taken to respect the
privacy of the subject and to minimize the impact of the study on the
subject's physical and mental integrity and on the personality of the
subject.
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7. Physicians should abstain from engaging in research projects involving
human subjects unless they are satisfied that the hazards involved are
believed to be predictable. Physicians should cease any investigation if
the hazards are found to outweigh the potential benefits.
8. In publication of the results of his or her research, the physician is
obliged to preserve the accuracy of the results. Reports of
experimentation not in accordance with the principles laid down in this
Declaration should not be accepted for publication.
9. In any research on human beings, each potential subject must be adequately
informed of the aims, methods, anticipated benefits and potential hazards
of the study and the discomfort it may entail. He or she should be
informed that he or she is at liberty to abstain from participation in the
study and that he or she is free to withdraw his or her consent to
participation at any time. The physician should then obtain the subject's
freely-given informed consent, preferably in writing.
10. When obtaining informed consent for the research project the physician
should be particularly cautious if the subject is in a dependent
relationship to him or her or may consent under duress. In that case the
informed consent should be obtained by a physician who is not engaged in
the investigation and who is completely independent of this official
relationship.
11. In case of legal incompetence, informed consent should be obtained from
the legal guardian in accordance with national legislation. Where physical
or mental incapacity makes it impossible to obtain informed consent, or
when the subject is a minor, permission from the responsible relative
replaces that of the subject in accordance with national legislation.
Whenever the minor child is in fact able to give consent, the minor's
consent must be obtained in addition to the consent of the minor's legal
guardian.
12. The research protocol should always contain a statement of the ethical
considerations involved and should indicate that the principles enunciated
in the present Declaration are complied with.
II. Medical research combined with professional care (Clinical research)
1. In the treatment of the sick person, the physician must be free to use a
new diagnostic and therapeutic measure, if in his or her judgement it
offers hope of saving life, re-establishing health or alleviating
suffering.
2. The potential benefits, hazards and discomfort of a new method should be
weighed against the advantages of the best current diagnostic and
therapeutic methods.
3. In any medical study, every patient - including those of a control group,
if any - should be assured of the best proven diagnostic and therapeutic
method. This does not exclude the use of inert placebo in studies where no
proven diagnostic or therapeutic method exist.
4. The refusal of the patient to participate in a study must never interfere
with the physician-patient relationship.
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5. If the physician considers it essential not to obtain informed consent.
the specific reasons for this proposal should be stated in the
experimental protocol for transmission to the independent committee (I, 2)
6. The physician can combine medical research with professional care, the
objective being the acquisition of new medical knowledge, only to the
extent that medical research is justified by its potential diagnostic or
therapeutic value for the patient.
III. Non-therapeutic biomedical research involving human subjects (Non-clinical
biomedical research)
1. In the purely scientific application of medical research carried out on a
human being, it is the duty of the physician to remain the protector of
the life and health of that person on whom biomedical research is being
carried out.
2. The subjects should be volunteers - either healthy persons or patients for
whom the experimental design is not related to the patient's illness.
3. The investigator or the investigating team should discontinue the research
if in his/her or their judgement it may, if continued, be harmful to the
individual.
4. In research on man, the interest of science and society should never take
precedence over considerations related to the wellbeing of the subject.
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26.7 APPENDIX VII: WORKING PROCEDURE ON DATA ENTRY
--------------------------------
Working Procedure on Data Entry:
--------------------------------
---------- -------------- ----------
US Centers AUS/NZ Centers EU centers
---------- -------------- ----------
| | |
| fax of CRF-page | fax of CRF-page |
| | |
| | |
------------- ------------- -----------------
Quintiles RTP Quintiles Pty EORTC data center
------------- -------------
| |
| |
| |
| |----------> Check on the Fax:
| PlausiChecks,
|-------------------------------> List of Questions
------------------
----------------------------------------| | |
| | |
| | |
------------- ------------- | |
Quintiles RTP Quintiles Pty <------------| |
------------- ------------- |
| | |
| | |
----------------------------------------------------------
first visit of the monitor to the study site:
* let change original CRF pages based on queries
* collect new copies of CRF
----------------------------------------------------------
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26.8 APPENDIX VIII: ANCILLARY STUDIES ON BIOLOGICAL EFFICACY
Besides the clinical end points of this trial ancillary studies will investigate
the biological mechanism of action in which a vaccination with BEC2/BCG acts in
humans.
26.8.1 GENERAL CONSIDERATIONS
The BEC2/BCG combination therapy is designed not to be a direct interventional
therapy or to be directly cytotoxic to tumor cells. The therapy is designed as a
vaccine or immunotherapy that, upon administration, would induce cancer patients
to generate immune responses that would potentially have an anti-tumor effect.
Therefore, study of the mechanism of action of a BEC2/BCG therapy would be a
study of the immune responses to the therapy and potential effects of those
responses.
BEC2/BCG may be acting through immunologic mechanisms resulting in the targeting
of residual tumor cells and by that prevent re-growth of tumor load which may be
later present as clinical relapse of metachronous metastasis. The target antigen
of BEC2/BCG is the tumor-associated antigen GD3, a glycosphingolipid. In order
to evaluate the possibility that BEC2/BCG may elicit a specific immunologic
response to the GD3 antigen, select patient populations will be evaluated for
the development of B cell and T cell responses. However, there is a potential
that the specific immune-response induced by BEC2/BCG may act as a starting
point for subsequent immune reactions which, while not being necessarily
6D3-specific, will be specific for the individual patients tumor. Thus,
ancillary biological assays will not only focus on the specific anti-GD3
response but also try to evaluate both humoral and cellular immune reactions
induced by BEC2/BCG. For statistical analysis it is desired to incorporate as
many patients as possible both from the vaccination and from the follow up
cohort into these ancillary study. Nevertheless, the assays on T-cell function,
Th1/Th2-shift, and minimal residual disease are very sophisticated demanding
elaborate structures and capabilities from the participating centers such as
cell culture capability, expedited sample shipment, liquid nitrogen freezing and
storage equipment. As a consequence ancillary studies except of the
anti-GD3-humoral response monitoring may not be done in all centers.
Furthermore, not all centers which meet the prerequisites to undertake those
studies may do the whole panel of them because of the high demands on logistics
and personnel.
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26.8.2 HUMORAL RESPONSE
The anti-BEC2 / GD3-specific B cell responses will be determined through the
evaluation of serial serum samples from individuals immunized with BEC2/BCG.
Serum of all vaccinated patients will be evaluated for the development of
antibodies to BEC2 and to GD3 (anti-GD3) following immunization. In addition, a
quantitative assessment of the titer of anti-GD3 antibodies, the temporal
relationship of immunization with BEC2/BCG to the time of anti-GD3 response
development, and the correlation of antibody response to patient survival will
be evaluated.
The demand on blood sampling is the following:
10 ml per sample point, samples at registration, restaging, vaccination
visits, first and second follow up visit, every three months during
subsequent follow up
total volume to be drawn during this trial: 110 ml
Additionally, circulating cytokines may be measured if the results from "Th1 /
Th2" data should indicate that doing so may be useful. For details see below.
26.8.3 OTHER ANCILLARY STUDIES WHICH WILL BE PERFORMED IN SELECTED CENTERS
26.8.3.1 Minimal residual disease
Recurrence of SCLC is believed to be due to minimal residual disease in patients
following treatment with conventional therapy. BEC2/BCG may act to induce an
immune response that eliminates these residual tumor cells. An assay using
nested PCR-detection of Gastrin-related peptide-messenger-RNA isolated from
mononuclear cell fractions prepared from full blood will be used to assay the
prevalence of circulating SCLC-cells in patients treated in this trial. For
these studies a separate informed consent form will be given to the patient.
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26.8.3.2 TH1 / TH2 shift
It has been recently found that SCLC tumors not only secrete growth factors that
induced anergy, but also that a certain proportion of SCLC-patients are and
remain anergic defined by their cytokine response regardless of chemotherapy.
Subsequent to induction chemotherapy these patients relapse significantly faster
than immune-competent patients. Thus, it is significant to analyze if adjuvant
vaccination with BEC2/BCG induces circumvention of this anergy and to evaluate
longitudinal if clinical characteristics, such as time to relapse and survival,
correlate with the patients immune status. For these studies a separate informed
consent form will be given to the patient.
26.83.3 Cellular Immunity
Cytotoxic T cell responses generated through BEC2/BCG therapy may also play a
role in reducing or eliminating residual tumor in patients. A set of assays on
isolated T-cells will focus on the immune-reactivity (cytokine release, mitosis)
to SCLC-tumor antigens (SCLC-cell preps, specific antigens, GD3) and the
Adjuvant BCG. Again, for these studies a separate informed consent form will be
given to the patient.
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26.9 APPENDIX IX: PPD TESTING
26.9.1 TEST KITS
Commercially available test kits shall be used for PPD testing. All
approved test kits are acceptable.
26.9.2 GENERAL REMARKS
All Patients to be randomized must be free from a history of previous
Tuberculosis and negative to 5 IU purified protein derivative (PPD) of
tuberculin . The purpose of the PPD-testing procedure is to identify individuals
who do not have a history of known Tuberculosis but show a strong reaction to
Tuberculin when exposed to that antigen. Similarly, these patients are very
likely to react to the BCG component of the BEC2/BCG-vaccination with grade III
or IV skin toxicity right after the first vaccination. This would be both an
intolerable burden to the patient and second it is likely to hamper the
biological efficacy of the vaccination at all. As a consequence, patients who
already react with a strong skin reaction to as little as 5 IU PPD shall be
excluded from vaccination.
For tuberculin testing intracutaneous tuberculin testing by intradermal
injection of the test dose is mandated. Tine or stamp type of tests may not be
used in this study.
26.93 PPD TESTING
The reaction to intracutaneously injected tuberculin is a delayed (cellular)
hypersensitivity reaction. The reaction which characteristically shows a delayed
course, reaching its peak more than 24 hours after administration, consists of
induration due to cell infiltration and occasionally vesiculation and necrosis.
Clinically, a delayed hypersensitivity reaction to tuberculin is a manifestation
of previous infection with M. Tuberculosis or a variety of non-tuberculosis
bacteria. In most cases sensitization is induced by natural mycobacterial
infection or by vaccination with BCG Vaccine.
The sensitization following infection with mycobacteria occurs primarily in the
regional lymph nodes. Small lymphocytes (T lymphocytes) proliferate in response
to the antigenic stimulus to give rise to specifically sensitized lymphocytes.
After several weeks, these lymphocytes enter the blood stream and circulate for
long periods of time. Subsequent re-stimulation of these sensitized lymphocytes
with the same or a similar antigen, such as the intradermal injection of
tuberculin, evokes a local reaction mediated by these cells. The tuberculin
reaction is characterized by the early predominance of mononuclear cells (small
and medium sized lymphocytes and monocytes). Only a small proportion of these
cells appear to be lymphocytes sensitized to tuberculin. Most cells are brought
into the reaction through the release of biologically active substances by
sensitized lymphocytes. An increase in vascular permeability leading to erythema
and edema also occurs in tuberculin reactions.
Characteristically, delayed hypersensitivity reactions to tuberculin begin at 5
to 6 hours, are maximal at 48 to 72 hours and subside over a period of days. In
those who are elderly or those who
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are being tested for the first time reactions may develop slowly and may not
peak until after 72 hours. Immediate hypersensitivity reactions to tuberculin or
to constituents of the diluent can also occur.
Not all infected persons will have a delayed hypersensitivity reaction to a
tuberculin test. A large number of factors has been reported to cause a
decreased ability to respond to the tuberculin test in the presence of
tuberculous infection including viral infections (measles, mumps, chickenpox),
live virus vaccinations (measles, mumps, polio), overwhelming tuberculosis,
other bacterial infections, drugs (corticosteroids and many other
immunosuppressive agents), and malignancy
26.9.3.1 Usage
For the initial intracutaneous (Mantoux) tuberculin test it is customary to use
5 U. S. unites (TU) per test dose of 0.1 ml.
26.9.3.2 Contraindications
PPD-Tests should not be administered to known tuberculin positive reactors
because of the severity of reactions (e. g., vesiculation, ulceration or
necrosis) that may occur at the test site in highly sensitive persons.
26.9.3.3 Warnings
Avoid injecting PPD subcutaneously. If this occurs, no local reaction will
develop, but a general febrile reaction and/or acute inflammation around old
tuberculosis lesions may occur in highly sensitive individuals.
26.9.3.4 Precautions
a) General
A separate STERILE syringe and needle must be used for each individual injection
to prevent possibility of transmission of viral hepatitis or other infectious
agents from one person to another.
The possibility of allergic reactions in individuals sensitive to the components
of the product should be borne in mind. Epinephrine Hydrochloride Solution
(1:1000) should be readily available for use in case an anaphylactic or acute
hypersensitivity reaction occurs.
Failure to store and handle PPD-Testing reagents as recommended will result in a
loss of potency and inaccurate test results.
b) Information for patients
Reactivity to the test may be depressed or suppressed for as long as 5 to 6
weeks in individuals who have received concurrent or recent immunization with
certain virus vaccines (measles, influenza), who have had viral infections
(rubeola, influenza, mumps and probably others) or who are receiving
corticosteroids or immunosuppressive agents.
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In those who are elderly or being tested for the first time reactions may
develop slowly and may not peak until after 72 hours. Vesiculation, ulceration
or necrosis may appear at the test site in highly sensitive persons. Pain,
pruritus and discomfort at the test site may also occur.
Positive reactions are 10 mm or more to 5 TU. Doubtful tuberculin reactions are
5 to 9 mm to 5 TU.
c) Drug interactions
Reactivity to the test may be depressed or suppressed in individuals who are
receiving corticosteroids or immunosuppressive agents. Reactivity to PPD may be
temporarily depressed by certain live virus vaccines (measles, mumps, rubeola).
Therefore, if a tuberculin test is to be performed, it should be administered
either before or simultaneously with the injection of measles, mumps and rubella
vaccines in combined form or as separate antigens.
d) Carcinogenesis, mutagenesis, impairment of fertility
The product is not used for extended treatment over a long period of time.
26.9.3.5 Drug Interactions
Reactivity to the test may be depressed or suppressed in individuals who are
receiving corticosteroids or immunosuppressive agents. Reactivity to PPD may be
temporarily depressed by certain live virus vaccines (measles, mumps, rubeola).
Therefore, if a tuberculin test is to be performed, it should be administered
either before or simultaneously with the injection of measles, mumps and rubeola
vaccines in combined form or as separate antigens (see also PRECAUTIONS).
Adverse Reactions
In highly sensitized individuals, strongly positive reactions including
vesiculation, ulceration or necrosis may occur at the test site. Cold packs or
topical steroid preparations may be employed for symptomatic relief of the
associated pain, pruritus and discomfort.
Strongly positive reactions may result in scarring at the test site.
Immediate erythematous or other reactions may occur at the injection site. The
reason(s) for these infrequent occurrences are presently unknown.
26.9.3.6 Dosage and Administration
THE TEST: The PPD test is performed by intracutaneously injecting, with a
syringe and needle, 0.1 ml of PPD solution. 5 TU per test dose shall be used.
The result is read 48 to 72 hours after administration and induration only is
considered in interpreting the test.
26.9.3.6.1 Method of administration:
The following procedure is recommended for performing the PPD test:
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1. The site of the test is the flexor surface of the forearm about 4 inches
below the bend of the elbow.
2. The skin of the forearm is first cleansed with alcohol and allowed to dry.
3. The test dose (0.1 ml) of Tuberculin PPD is administered with a 1 ml
syringe calibrated in tenths and fitted with a short, one-half inch, 26 or
27 gauge needle.
4. Disposable sterile syringes and needles may be used.
5. The rubber cap of the vial should be wiped with a sterile piece of cotton
moistened with alcohol and allowed to dry. The needle is then inserted
gently through the cap and the required amount of the Tuberculin PPD is
drawn into the syringe.
6. The point of the needle is inserted into the most superficial layers of
the skin with the needle bevel pointing upward. If the intracutaneous
injection is performed properly, a definite white bleb will rise at the
needle point, about 10 mm (3/8") in diameter. This will disappear within
minutes. No dressing is required.
In the event of a subcutaneous injection (i. e., no bleb formed), the test
should be repeated immediately at another site.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solutions and container permit.
26.9.3.6.2 Interpretation of the test:
The test should be read 48 to 72 hours after administration. Sensitivity is
indicated by induration, usually accompanied by erythema. The widest diameter of
distinctly palpable induration should be recorded in millimeters (mm). Presence
of edema and necrosis should also be recorded.
A positive reaction indicates a sensitivity to tuberculin, which may be the
result of a previous infection with mycobacteria. This infection, likely due to
Mycobacterium Tuberculosis, may have occurred years ago or may be of recent
origin.
Reactions should be interpreted as follows:
POSITIVE REACTION -- Any palpable induration measuring 10 mm or more is
considered a positive reaction. In the case of tuberculosis suspects or close
contacts of individuals with tuberculosis an induration of 5 mm or even smaller
should be interpreted as a positive reaction and appropriate additional
follow-up measures initiated.
DOUBTFUL REACTION -- Induration measuring 5 to 9 mm indicated a doubtful
reaction.
NEGATIVE REACTION -- Induration of less than 5 mm is considered negative.
Patients with a doubtful or negative reaction may be randomized, given a
negative history of typical or atypical Tuberculosis.
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26.10 APPENDIX X: INDUCTION THERAPY FLOW CHART
Treatment Flow Chart
Dx Restaging
| |
| | -------------------
Vaccine / Control
------------------- ----- -------------------
4 * ETO/Pt Rad.
------------------- -----
--------------------------------------------------------------------------------
------
Rad.
------------------- -------------------
4 * ETO/Pt Vaccine / Control
------------------- -------------------
--------------------------------------------------------------------------------
------------------- ----- -------------------
5 * CDE Rad. Vaccine / Control
------------------- ----- -------------------
--------------------------------------------------------------------------------
===================================================== ===========
|
=========== ============================= |
| | | |
| | max 20 weeks | | 10 weeks
| max. | | max 6 weeks |
| | | |
| 2 weeks | | |
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26.11 APPENDIX XI: OVERALL STUDY FLOW CHART
Diagnosis |
|
----------------------- | Registration
|
Induction Therapy | within
| 1 month after start
Chemo + Radiation | of induction
|
----------|------------ |
| |
| |
--------------------------------------- | ------------------
Restaging |
|
PR / CR NC / Progression | 5-7 months
-----|-------------------|------------- | from diagnosis
| | |
| | |
----------- pre-randomization | ------------------
Xxxxx- drop out |
mization |
----|------| | 12 weeks
| | |
| ----------| |
---------- | | ------------------
Control ---------------------------- |
Group Vaccination Group |
n = 285 n = 285 | ------------------
---------- BEC2/BCG 5X (10 weeks) |
---------------------------- | ~ 2 year
|
|
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26.12 APPENDIX XII: VACCINATION INSTRUCTIONS
The vaccination shall be done strictly intradermal. Both subcutaneous and
intravasal injection has to be avoided under all circumstances. The area to
vaccination shall be disinfected with a skin-disinfectant before vaccination.
Please make absolutely sure, that the disinfecting liquid has completely dried
before the administration is done!
Every single dose (1.2 ml) shall be given in eight (8) intradermal injections.
Injections shall be administered as a grid made of two columns and four rows.
Space between two injections shall be -- one (1) cm. For the first dose the
right upper arm shall be used (in left handed persons start with the left upper
arm). Second shall be given to the opposite upper arm. Third dose shall be given
to the left upper limb, fourth to the right upper limb and fifth again to the
left thigh. Please refer to the following sketches for illustration:
[GRAPHIC]
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26.13 APPENDIX XIII: LIST OF ABBREVIATIONS
(degree)C centigrade
AE/AE's adverse event/s
ASAT aspartate-amino-transferase = GOT
ASCO American Society of Clinical Oncology
anti-ids anti-idiotypic antibodies
AUC 5 Carboplatin
AUS Australia
BCG Bacille Xxxxxxxx-Xxxxxx
CDE Cyclophosphamide, Doxorubicin, Etoposide regimen
CET Central European time
CFU Colony forming unit
CIS Carcinoma in situ
CR Complete Remission
CT computed tomography
CRF case report form
D day
Dx Diagnosis
EaST Early stopping Rule
ECG Electrocardiogram
ED extensive disease
EORTC European Organization for the Research and Treatment of Cancer
F Fahrenheit
FDA Food and Drug Administration
GCP good clinical practice
GD3 ganglioside fraction GD3
GMP good manufacturing practice
GOT glutamine oxalacetic transferase
h hour(s)
HAMA human anti-mouse antibodies
HBsAg hepatitis B virus surface antigen
BHCG beta-human chorionic gonadotropin
HIV human immune deficiency virus
HE health economics
HMW-MAA high molecular weight melanoma associated antigen
HR heart rate
IDMC Independent Data Monitoring Committee
i.d. intradermally
i. v. intravenous
IgG immunoglobulin gamma
LD limited disease
LDH lactate dehydrogenase
LPS lipopolysaccharide
MAb monoclonal antibody
NCI National Cancer Institute (of the United States of America)
NCIC-CTC National Cancer Institute Canada-common tox. criteria
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NSAID non-steroidal anti-inflammatory drugs
NY New York
NZ New Zealand
PBS phosphate buffered saline
PCR polymerase chain reaction
PD progressive disease
PPD purified protein derivative
PR partial remission
PT prothrombin time
PTT partial thromboplastin time
QALY quality adjusted life years
QoL Quality of Life
SAE serious adverse event
SCLC small cell lung cancer
SGOT serum GOT
TU tuberculin units
USA The United States of America
V visit
VA Veterans Administration
VP Etoposide (VP-16)
vs. versus
W week
WBC white blood count
WHO World Health Organization
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26.14 APPENDIX XIV: STUDY ACKNOWLEDGMENT
STUDY ACKNOWLEDGMENT
I have read the protocol and agree that it contains all necessary details for
carrying out the study as described.
I will conduct this protocol as outlined therein and will make a reasonable
effort to complete the study within the time designated.
I will provide copies of the protocol and access to all information furnished by
the EORTC Data Center to study personnel under my supervision. I will discuss
this material with them to ensure that they are fully informed about the drug
and the study.
----------------------------------------------------------
Investigator's printed name and signature Date
----------------------------------------------------------
Monitor Date
Protocol Number: EORTC 08971
Site: ____________________________
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-19-
Exhibit "B" (Section 2(a), ImClone's labelling requirements)
to Agreement among PMC, ImClone and Merck effective as of January 1, 1997
--------------------------------------------------------------------------------
121
Exhibit B
BCG (lyophilized) 1.5 mg
(An Active Immunizing Agent)
For Intracutaneous Injection Only
Dose as per Clinical Protocol
Lot:
Exp.:
For Investigational Use Only
MUST NOT BE ADMINISTERED AS A SINGLE AGENT
Mfg.: Connaught Laboratories Limited
North York, ONT Canada
122
-20-
Exhibit "C" (Section 2(a), Merck's labelling requirements)
to Agreement among PMC, ImClone and Merck effective as of January 1, 1997
--------------------------------------------------------------------------------
123
Exhibit C
BCG (lyophilized) 1.5 mg
(An Active Immunizing Agent)
For Intracutaneous Injection Only
Use according to study protocol EORTC 08971 only
Lot:
Exp.:
For Clinical Trial Use Only
MUST NOT BE ADMINISTERED AS A SINGLE AGENT
Mfg.: Connaught Laboratories Limited, North York, ONT Canada
Sponsor: Merck XXxX, 00000 Xxxxxxxxx, Xxxxxxx
