REDACTED VERSION
EXHIBIT 10.28
TO
LIGHT SCIENCES ONCOLOGY, INC.'S
REGISTRATION STATEMENT ON FORM S-1
INITIALLY FILED
APRIL 21, 2006
REGISTRATION NO. 333-133474
"[ * ]" = omitted, confidential material, which material has been separately
filed with the Securities and Exchange Commission pursuant to a
request for confidential treatment.
INDIVIDUAL PROJECT AGREEMENT NO. 3
DATED AS OF MARCH 8, 2006
BETWEEN
LIGHT SCIENCES ONCOLOGY, INC.
AND
ERGOMED CLINICAL RESEARCH, LTD.
APPENDIX G
INDIVIDUAL PROJECT AGREEMENT #3
This Individual Project Agreement #3 ("IPA") is entered into pursuant to the
Master Services Agreement, effective February 27, 2004 by and between Light
Sciences Oncology, Inc., a corporation organized under the laws of the state of
Washington, USA, with its principal place of business at 0000 XX Xxxxxxx Xxxxxx,
Xxxxx 000, Xxxxxxxxxx, XX 00000 XXX ("LSO" or "Sponsor"), and Ergomed Clinical
Research, Ltd., a corporation organized under the laws of United Kingdom, with
its principal place of business at 0 Xxxxxxxxx Xxxxxx Xx., Xxxxxx Research Park,
Guildford, Surrey, GU2 7YD, U.K., ("Contractor").
RECITALS
Whereas Light Sciences Corporation assigned the Master Services Agreement,
effective February 27, 2004, to Light Sciences Oncology on October 5, 2005.
Whereas LSO and Contractor desire to enter into another IPA.
For good and valuable consideration, the receipt and sufficiency of which are
hereby acknowledged, the parties agree as follows:
A. PROJECT TITLE:
A Multicenter Multinational Phase 3 Randomized Study to Evaluate the Safety and
Efficacy of Treating Colorectal Cancer Patients with Recurrent Liver Metastases
using the Litx(TM) plus Chemotherapy as Compared to Chemotherapy Only (the
"Protocol"), attached hereto as Appendix G-1.
B. SCOPE OF WORK:
Contractor will perform clinical research organization Services in Austria,
Croatia ,Czech Republic, Germany, Hungary, Italy, Poland, Romania, Serbia,
Slovak Republic, Slovenia, Sweden, Ukraine and USA for the benefit of LSO as
described in this IPA, and all appendices hereto, to manage the clinical trials
conducted under the Protocol (as amended from time to time) as described by this
IPA.
C. TIMELINE AND DELIVERABLES:
The term of this IPA commences upon execution and continues until all Services
described by this IPA are completed, unless either the IPA or the Agreement is
terminated early in accordance with the terms and conditions of the Agreement.
LSO and Contractor will review the timeline, progress against deliverables at
least every [ * ] during the term of this IPA.
-------------
[ * ] Confidential Treatment Requested
D. PROJECT DESCRIPTION/TASKS:
Recruitment Strategies
Contractor will be responsible for pre-screening and qualifying potential Study
sites as requested by Sponsor.
Regulatory Approval/Permits
Contractor will file all appropriate documents with the applicable regulatory
authorities and secure approvals for conducting clinical studies in the
countries which will be selected upon completion of the feasibility assessment
with the approval of the Sponsor. Sponsor will provide any reasonable documents
required for these submissions in a timely manner. Contractor will secure
appropriate permits for the import of investigational drugs and devices to the
clinical sites.
Study Management
Contractor is responsible for the day to day management of the Study including
the project schedules, budgets, regulatory issues, and overall Study progress.
The Ergomed Project Manager, Dubnavka Xxxxx - Sladoljev will be the primary
contact point for Sponsor. The Ergomed Project Manager is responsible for the
management of the studies and will ensure that the studies are performed to the
highest quality and according to All Applicable Laws and Regulations and to the
timelines outlined below.
The Ergomed Project Manager will update the Light Sciences Project Manager,
Xxxxx Xxxxxx, during the set up phase on the status of the approval processes
and on the recruitment on a weekly basis in order to ensure that any issues are
highlighted and resolved quickly.
Clinical Site Study Agreements
Contractor shall enter into Clinical Study Agreements ("CSAs") with the
Institutions and / or Investigators, as applicable, as the contracting party,
with each site approved by LSC to conduct the Study. Contractor shall use the
template attached as Appendix G-2 as the form of the contract. Any contract with
the Institution and / or Investigator which substantially deviates from the
template from Appendix G-2 shall be pre-approved in writing by Sponsor before it
is executed. Contractor shall use commercially best efforts to negotiate the
lowest reasonable study budgets and contractual terms and conditions with all
Study sites and Investigators. Contractor will also be responsible for
administering payments to the study sites and Investigators during the course of
the study. The parties will treat investigator grants, as well as all direct
costs, as pass-through costs with no surcharges or fees applied.
Monitoring
Contractor will comply with the Contractor SOPs concerning site initiation,
routine Monitoring and Close Down visits in the provision of Services under this
IPA as well as All Applicable Laws and Regulations in the provision of services
under this IPA.
a. Patient Eligibility Confirmation. Contractor will carefully
review each patient's signed consent form and primary medical
records to confirm that the patient satisfies all of the
inclusion and exclusion criteria during the recruitment phase to
ensure patient eligibility of patients enrolled and that such
patients can be accurately evaluated. Sponsor will assign patient
identification numbers upon Contractor's request.
b. Case Report Forms ("CRFs"). Contractor will verify CRFs against
appropriate source documentation to ensure completion, accuracy
and consistency of the CRFs, retrieve completed CRFs from study
sites and forward the completed CRFs to the Sponsor or its
designate for data entry and analysis.
c. Request product shipment to study sites. Contractor will be
authorized to request product shipment to the individual study
sites after the required regulatory documents have been reviewed
by Contractor and Sponsor.
d. Adverse Event Reporting/Data Management. Contractor will assure
that all adverse experiences are being reported accurately and
appropriately according to Sponsor's direction and in compliance
with All Applicable Laws, Rules and Regulations. Contractor is
responsible for all data management and all Serious Adverse Event
reporting, including write-up of CIOMS and maintenance of the
safety database, as well as performing two interim analyses of
the data and writing a report for Sponsor.
e. Regulatory Compliance. Contractor will comply with all Applicable
Laws and Regulations in performance of Services under this IPA
f. Communication. Contractor will maintain regular, frequent
contact with all study sites and will maintain a communication
log. Contractor will transmit the communication log to Sponsor
weekly.
g. SDV. Contractor will perform one hundred percent (100%) Source
Document Verification (SDV) on all Study data, including patient
eligibility and all SAEs.
h. Proposed Monitoring Schedule. Contractor will comply with the
following Monitoring Schedule:
TASK TIMELINES
Frequency of monitoring/telephone contacts Weekly
Timelines for production and review of monitoring report 2 weeks
Timelines for close down visit following last patient's last
visit ("LPLV") 1 Week
i. Contractor will conduct the following Study site visits
(including all sites):
VISIT TYPE NUMBER OF VISITS
Feasibility Assessment 70
Qualification 60
Initiation 50
Monitoring 1200
Close Down 50
Total 1430
j. Quality Assurance. Contractor will utilize an Independent
Quality Assurance Manager to perform Study site audits where
required or upon Sponsor request. The audit report will be
forwarded to Sponsor for review and discussion prior to sign-off.
k. Contractor will provide a full list of all Contractor SOPs to
Sponsor and will make available for review in the Contractor's
offices specific SOPs to Sponsor upon request.
Communication/Project Tracking
Contractor shall send Sponsor regular email communication summarizing site
visits, patient enrollment status, CRF retrieval data and key issues and actions
to be taken. In addition, every month a report will be sent to Sponsor which
will include an updated Xxxxx chart, the contents of which shall be mutually
agreed upon, the budget, site status, patient enrollment activities, SAE
reconciliation, all visit and telephone contact reports.
Task Description
See Appendix G-3.
E. PROJECT BUDGET:
See Appendix G-3.
F. APPROVED EXPENSES:
See Appendix G-3.
G. MILESTONE PAYMENTS/PREPAYMENTS:
Four milestone payments will be made, in addition to the payment of regular
monthly invoices:
1. [ * ]
2. [ * ]
3. [ * ]
4. [ * ]
The total of these [ * ]. Payments 2.-4. will be made pursuant to the procedure
described in Section 7 of the Master Services Agreement.
H. EXPECTED STAFFING LEVEL REQUIREMENTS/SUBCONTRACTORS:
The Contractor's clinical operations team for this IPA include the following:
1. Project Director, Xxxxxxx Xxxxxxxx
2. Project Managers
3. Study Physicians
4. Regulatory Manager
5. Safety Manager
6. Medical Monitor
7. CRAs
8. CTAs
The Contractor will use the following subcontractors:
1. [ * ]
2. [ * ]
-------------
[ * ] Confidential Treatment Requested
I. KEY MEMBERS OF PROJECT TEAMS:
For LSO:
Project Director, XXX-XXX XXXX, PH.D.
Project Manager, XXXXX XXXXXX
For Contractor:
Project Director, XXXXXXX XXXXXXXX PH.D
Project Manager, XXXXXXXX XXXXX - XXXXXXXXX, MD
J. TRANSFER OF OBLIGATIONS FORM:
LSO transfers to Contractor certain requirements of the US Food and Drug
Administration, as described in Appendix G-4.
K. OTHER:
For purposes of this IPA only, the Master Services Agreement effective
February 27, 2004 is hereby amended, as follows:
Section 1. Definitions
Section 1., Definitions, definition of "All Applicable Laws and Regulations" is
deleted in its entirety and the following section is "Applicable Laws and
Regulations" definition is inserted:
"All Applicable Laws and Regulations" means applicable federal, state,
provincial and local laws, orders, ordinances, policies, regulations, rules and
guidelines of any countries (including but not limited to the United States and
the European Union) having authority over any clinical studies conducted
hereunder, the use or review of data obtained as a result of such clinical
studies, or the activities of Ergomed in providing Services under this
Agreement. For clinical studies conducted under an investigational new drug
application and investigational device exemption filed in the United States,
Applicable Laws include, without limitation, 21 CFR Pts. 312, 812, 50, 54, and
56, the FDA's Electronic Records and Electronic Signatures Guidance (21 CFR Pt.
11), and the Health Insurance Portability and Accountability Act of 1996 and its
implementing regulations (45 CFR Pts. 160 and 164) ("HIPAA"), as amended from
time to time. For studies conducted in, or for use in an application for
marketing in the European Union or in any Member State of the European Union,
Applicable Laws and Regulations include, but are not limited to the Clinical
Trials Directive (2001/20/EC), The Medical Device Directive (93/42/EEC), the EU
Good Clinical Practice Guideline (Directive 2005/28/EC), and the Personal Data
Directive (95/46/EC). Applicable Laws and Regulations also include all
conditions of approval imposed by the
reviewing IRB/Ethics Committees, FDA and other applicable authorities, ICH
guidelines (including the "Good Clinical Practice:
Consolidated Guideline") and the ethical principles contained in the Declaration
of Helsinki, as set forth in 21 CFR Section 312.120(c)(4), as amended from time
to time.
Section 10. Indemnification
Section 10., Indemnification, of the February 27, 2004 agreement between the
parties is amended, as follows:
The current Section 10 is renumbered to Section 10.1. and entitled, "LSO
Indemnification." and the following sentences are deleted: "The indemnifying
party will reimburse the indemnified party promptly upon invoicing for any
payment made by indemnified party in respect to any liability or claim to which
any indemnity obligation under this contract relates. The indemnified party will
give prompt notice to indemnifying party of any claim to which this paragraph
relates."
A new section 10.2, "Contractor Indemnification." is added:
Contractor will indemnify, pay the defense costs of, and hold harmless LSO and
its successors, officers, directors and employees and subcontractors from and
against any and all actions, causes of action, claims, demands, costs, losses,
liabilities, expenses, penalties, fines and damages (including, without
limitation, reasonable attorneys' fees) (collectively, "LSO Losses") arising out
of or in connection with any third party claim arising from (a) the actual or
alleged breach of any representations, warranties or obligations contained in
this Agreement; and (b) property damage or bodily injury (including death), if
and to the extent the same is attributable to the fault, negligence, gross
negligence, strict liability, willful misconduct, or intentional misconduct of
Contractor or any of its successors, officers, directors, employees, agents,
investigators, subcontractors or representatives, or the failure of Contractor
or any such person or entity to comply with this Agreement.
A new Section 10.3, "Procedure." is added:
Each party will give the indemnifying party (a) prompt written notice of any
claim for which it seeks indemnification hereunder; (b) all relevant facts in
its possession or control; (c) the right to control the defense and settlement
of any action unless the party being indemnified reasonably determines that a
conflict of interest exists with respect to such assumption of the defense due
to actual or potential differing interests between the parties or because of a
business relationship between the indemnifying party and the third party
claimant; and (d) cooperation in the defense and settlement of any such action
at the indemnifying party's expense. The indemnifying party will not settle any
third party claims without the prior written consent of the indemnified party,
not to be unreasonably withheld.
Section 14. Notices
The legal Notice information for LSO is deleted in its entirety and the
following is inserted:
For LSO:
Xxx Xxxxxxx, MD, FACP
Chief Operating Officer and Chief Medical Officer
0000 XX Xxxxxxx Xxxxxx, Xxxxx 000
Xxxxxxxxxx, XX 00000
XXX
Phone: 000.000.0000
Fax: 000.000.0000
(Note: This is for legal notice provisions under the Master Service Agreement,
NOT for the monitoring, adverse event reporting, and communication with LSO
described in Section D. of this IPA.)
Upon the date of the last signature, below, this IPA is fully incorporated into
the Master Services Agreement effective February 27, 2004, and all Services and
Deliverables created in connection with this IPA are subject to the conditions
of the Master Services Agreement.
ACKNOWLEDGED AND AGREED TO:
LIGHT SCIENCES ONCOLOGY INC.
/s/ Xxx Xxxxxxx, MD 3/1/01
-----------------------------------------
Xxx Xxxxxxx, MD, FACP
Chief Operating Officer, Chief Medical Officer
ERGOMED CLINICAL RESEARCH LTD.
/s/ Xxxxxxxx Xxxxxxxxx, MD 8th March, 2006
-------------------------------------------------
Xxxxxxxx Xxxxxxxxx, MD
CEO
APPENDIX G-1
--------------------------------------------------------------------------------
A MULTICENTER MULTINATIONAL PHASE 3 RANDOMIZED STUDY TO EVALUATE THE SAFETY AND
EFFICACY OF TREATING COLORECTAL CANCER PATIENTS WITH RECURRENT LIVER METASTASES
USING THE LITX(TM) PLUS CHEMOTHERAPY AS COMPARED TO CHEMOTHERAPY ALONE
--------------------------------------------------------------------------------
STUDY PRODUCT: Litx(TM) System
PROTOCOL NUMBER: LSO-OL006
IND NUMBER: 37,088
STUDY SPONSOR: Light Sciences Oncology
00000 XX Xxxxxxx Xx., Xxxxx 000
Xxxxxxxxxx, XX 00000
Original protocol: February 28, 2006
--------------------------------------------------------------------------------
THE INFORMATION CONTAINED HEREIN IS THE PROPERTY OF LIGHT SCIENCES ONCOLOGY AND
IS CONFIDENTIAL. IT MAY BE SUBMITTED TO A REGULATORY AUTHORITY OR AN
INSTITUTIONAL REVIEW BOARD/ETHICAL COMMITTEE FOR THE PURPOSES OF ASSESSMENT IN
RELATION TO REGISTRATION OF THE PRODUCT OR INITIATION OF A CLINICAL TRIAL.
REPRODUCTION OR DISCLOSURE OF THE INFORMATION, IN WHOLE OR IN PART, OTHER THAN
FOR THE SAID PURPOSE, IS FORBIDDEN UNLESS AT THE EXPRESS REQUEST OR WITH THE
WRITTEN CONSENT OF THE PROPRIETOR.
--------------------------------------------------------------------------------
TABLE OF CONTENTS
1 INVESTIGATOR AGREEMENT
2 SYNOPSIS
3 STUDY OBJECTIVES
4 BACKGROUND
4.1 INTRODUCTION
4.2 HEPATOCELLULAR CARCINOMA
4.3 RATIONALE
5 PRODUCT INFORMATION
5.1 LS11 DESCRIPTION
5.2 LS11: CLINICAL USE AND HANDLING
5.3 LIGHT SOURCES
5.4 POWER CONTROLLER
6 ELIGIBILITY
6.1 ELIGIBILITY CRITERIA
7 TREATMENT SCHEDULE
8 STUDY PROCEDURES
8.1 SCREEN/BASELINE:
8.2 TREATMENT: DAY 0
8.3 [ * ]
8.4 [ * ]
8.5 [ * ]
8.6 [ * ]
8.7 [ * ]
8.8 [ * ]
8.9 [ * ]
8.10 [ * ]
8.11 [ * ]
8.12 CHANGE IN TREATMENT
8.13 RE-TREATMENT WEEKS
8.14 DATA SAFETY MONITORING COMMITTEE (DSMC)
8.15 SURVIVAL
8.16 SCHEDULE OF EVENTS FROM BASELINE TO STUDY COMPLETED
[ * ] Confidential Treatment Requested
9 CRITERIA FOR EVALUATION
9.1 STUDY ENDPOINTS
10 DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS
10.1 DATA COLLECTION MANAGEMENT AND ANALYSIS
11 PROTOCOL MANAGEMENT
11.1 PATIENT SCREENING
11.2 PATIENT REGISTRATION
11.3 PROTOCOL ADHERENCE
11.4 ACCURACY OF DATA COLLECTION
11.5 CASE REPORT FORMS AND DATA ANALYSIS
12 REPORTING REQUIREMENTS FOR ADVERSE EVENTS
12.1 DEFINITIONS
12.2 REPORTING REQUIREMENTS
12.3 CATEGORIES FOR RANKING SEVERITY OF AN ADVERSE EVENT
12.4 CATEGORIES FOR DETERMINING RELATIONSHIP TO THE INVESTIGATIONAL PRODUCT
12.5 REPORTING SERIOUS ADVERSE EVENTS
13 REGULATORY REQUIREMENTS
13.1 INVESTIGATOR OBLIGATIONS
13.2 INFORMED CONSENT
13.3 INSTITUTIONAL REVIEW BOARD
14 ADMINISTRATIVE CONSIDERATIONS
14.1 PRE-STUDY DOCUMENTATION
14.2 STUDY DOCUMENTATION
14.3 DATA COLLECTION
14.4 PROTOCOL INTERPRETATION AND COMPLIANCE
14.5 STUDY MONITORING
14.6 DISCLOSURE OF DATA / PUBLICATION
15 REFERENCES
16 APPENDIX 1
APPENDIX G-1
1 INVESTIGATOR AGREEMENT
I have read the proceeding protocol dated December 28, 2005:
"A Multicenter Multinational Phase 3 Randomized Study to Evaluate the Safety and
Efficacy of Treating Colorectal Cancer Patients with Recurrent Liver Metastases
using the Litx(TM) plus Chemotherapy as Compared to Chemotherapy Only" and agree
that it contains all necessary details for conducting the study.
I will conduct the study as outlined therein, in accordance with Good Clinical
Practices (GCPs) and the Declaration of Helsinki and comply with the obligations
and requirements of clinical investigators and all other requirements listed in
the International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) and Good Clinical Practice
(GCP). I will attempt to complete the planned enrollment of patients within
approximately one year of the receipt of clinical supplies.
I will provide copies of the protocol and all drug information relating to the
nonclinical and prior clinical experience, furnished to me by the Sponsor, to
all relevant staff/members. I will discuss this material with them to ensure
they are fully informed regarding the drug and the conduct of the study. I have
been explained the purpose of the Source Documentation Verification (SDV), and
fully understand this will be part of the monitoring process. I understand and
agree which items must be included in the source documents. All parties agree to
ensure direct access to examine, analyze, verify and reproduce source
data/documents, and reports from all trials related sites for the purpose of
monitoring and auditing by the Sponsor or the respective CRO that is managing
the site, and inspection by domestic and foreign regulatory authorities.
I agree to keep records on all patient information (Case Report Forms and
patient's informed consent statement), drug transportation and return forms, and
all other information collected during the study for a period of 2 years
following the date a marketing application is approved for the drug for the
indication for which it is being investigated; or, if no application is to be
filed or if the application is not approved for such indication, until 2 years
after the investigation is discontinued and the FDA or other regulatory
authorities are notified and I have received notification from Light Sciences
Oncology.
I agree not to publish all or any part of the results of the study carried out
under this protocol, without the prior written consent of Light Sciences
Oncology.
Investigator Name:
-------------------------
(Printed)
Signature: Date:
--------------------------------- ------------------
(dd/mm/yy)
APPENDIX G-1
2 SYNOPSIS
Title of Study A Multicenter Multinational Phase 3 Randomized
Study to Evaluate the Safety and Efficacy of
Treating Colorectal Cancer Patients with
Recurrent Liver Metastases using the Litx(TM)
plus Chemotherapy as Compared to Chemotherapy
Only
Protocol Number LSO-OL006
Investigator Countries United States, Europe, and Asia
Indication Colorectal Cancer with recurrent liver metastases
Study Centers [ * ]
Number of Patients [ * ]
Enrollment Duration [ * ]
Study Duration
Objectives [ * ]
Eligibility Criteria INCLUSION CRITERIA
1. Patients with recurrent metastatic
liver lesions from colorectal cancer
2. Biopsy proven evidence of colorectal
cancer
3. [ * ]
4. [ * ]
5. [ * ]
6. [ * ]
7. Understanding and ability to sign
written informed consent.
8. [ * ]
9. [ * ]
EXCLUSION CRITERIA
1. Patients who are candidates for
complete surgical resection
2. [ * ]
3. [ * ]
4. [ * ]
5. [ * ]
6. [ * ]
7. [ * ]
8. [ * ]
9. [ * ]
10. [ * ]
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[ * ] Confidential Treatment Requested
APPENDIX G-1
11. [ * ]
12. [ * ]
Stratification and Upon enrollment, patients will be stratified by
Randomization [ * ].
Light Source Placement Light Source placement will be conducted under
ultrasound or CT guidance. [ * ].
Study Drug, Dose LS11 (Talaporfin Sodium) presented as a
lyophilized powder for reconstitution. Each 10mL
vial contains 100 mg LS11 for reconstitution with
4 mL of 0.9% Sodium Chloride Injection USP to
give a solution at a concentration of 25 mg/mL.
[ * ].
Study Device Light Source was designed for percutaneous
placement under imaging guidance. [ * ].
Drug Light Interval [ * ]
Duration of Light Activation [ * ]
Imaging Independent radiologists will assess all CT
images. [ * ].
Chemotherapy for both groups The standard chemotherapy is FOLFOX 4 or FOLFIRI.
[ * ].
Treatment Plan Patients who provide Informed Consent and
satisfy the Eligibility Criteria will be placed
in an eligibility pool for randomization for
either, Litx(TM) plus chemotherapy treatment arm
or the chemotherapy arm. [ * ].
[ * ]. The following table is a guide to a
suggested treatment plan:
[ * ].
All Study Patients:
[ * ].
The Study Design is outlined below.
[ * ] (5 pages)
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[ * ] Confidential Treatment Requested
APPENDIX G-I
Change in Treatment for A change in treatment may be considered if in the
either Litx(TM)+chemo or investigators opinion there has been a treatment
chemo only group failure of either Litx(TM)+chemo or chemo only as
defined as disease progression. [ * ].
Disease Progression using Defined as [ * ].
modified RECIST criteria
Re-treatment Litx(TM)+chemo [ * ]
Group
Survival All patients will be monitored for survival from
the time of randomization [ * ].
Data Safety Monitoring Board [ * ]
(DSMB)
Criteria of Evaluation [ * ]
Statistical Methodology [ * ]
3 STUDY OBJECTIVES
Assess the time to progression in patients [ * ].
Demonstrate the safety of Litx(TM) therapy.
Assess the survival of patients [ * ].
4 BACKGROUND
4.1 INTRODUCTION
This protocol is for a research study in patients with liver metastases from
colorectal cancer. This study is to be conducted according to U.S. and
International Standards of Good Clinical Practice (FDA Title 21 CFR part 312 and
International Conference on Harmonization guidelines), applicable government
regulations, and Institutional research polices and procedures.
4.2 LIVER METASTASES FROM COLORECTAL CANCER
Colorectal cancer is one of the most common malignancies in the world and the
second leading cause of cancer death in Western countries(1). More than 300,000
new cases of colorectal cancer occur each year in Europe and the United
States(2,3). Liver metastases form the main cause of death in patients with
colorectal cancer. Already at the time of detection of the primary tumor 15-25%
of the patients present with liver metastases, another 20% will develop these
metastases following treatment of the colorectal primary(4). Without any
treatment median survival after detection of liver metastases is approximately 9
months, depending on the extent of the disease at the time of diagnosis(5). In
patients with metastatic disease confined to the liver, resection of the
metastases offers the best chance of cure. After resection a 5-year survival
rate can be achieved of 35% - 40% depending on the extent of liver
involvement(6-9). Only a
----------
[ * ] Confidential Treatment Requested
APPENDIX G-I
minority (10% - 15%) of patients with liver metastases is however, considered
candidate for resection. In the majority of patients the liver metastases prove
unresectable.
In general, large tumors are difficult to operate on and less responsive to
chemotherapy and radiotherapy. Consequently, palliation of symptoms related to
increasing tumor load, and/or delay of the onset of the symptoms as well as
survival, are major clinical objectives in management of patients with advanced
cancers. Recent chemotherapy schedules combining fluorouracil (FU) and
oxaliplatin or irinotecan have considerably improved the results of systemic
chemotherapy in the palliative treatment of patients with metastatic colorectal
cancer in terms of the response rate, progression-free survival,(10-14) and
overall survival(11, 12, 14).
The management of these patients with liver metastases from colorectal cancer is
a therapeutic challenge. The need for well-tolerated, active interventions for
locoregional disease is clear. Light Infusion Technology or "Litx(TM)" has the
potential to significantly contribute to the fulfillment of this medical need.
Litx(TM) is a locoregional cancer treatment in which a systemically administered
photosensitizer is activated locally by illuminating the diseased tissue with
light of a specific wavelength. The activated photosensitizer reacts with
endogenous oxygen to yield a highly reactive species of oxygen (singlet oxygen)
that cause peroxidation of the cellular structures such as mitochondria,
lysosomes, and cell walls, leading to irreversible cell damage and tissue
necrosis(15).
[ * ].
In clinical studies thus far, LS11 has demonstrated to be well tolerated when
administered by intravenous injection. For more information see the Investigator
Brochure.
4.3 RATIONALE
RATIONALE FOR LS11 DOSE:
All patients in the Litx(TM) group will receive a 1 mg/kg intravenous dose of
LS11 based on previous clinical experience and registration of this drug dose in
Japan for early endobronchial cancer using a laser as the light energy source.
RATIONALE FOR LIGHT DOSE:
[ * ].
RATIONALE FOR DRUG-LIGHT INTERVAL (DLI):
[ * ].
RATIONALE FOR POSITIONING OF MULTIPLE LIGHT SOURCES:
[ * ].
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[ * ] Confidential Treatment Requested
APPENDIX G-1
LESION SIZE AND KILL ZONE:
[ * ].
RATIONALE FOR CHEMOTHERAPY:
[ * ].
4.4 SUGGESTED DRUG REGIMEN:
FOLFOX4:
Oxaliplatin 85 mg/m(2)
Folinic Acid 200/100 mg/m(2)
Fluorouracil 400 mg/m(2) (IV Bolus)
Fluorouracil 600 mg/m(2)
Repeat every 14 days for a maximum total of 12 cycles or disease progression
Some of the frequently occurring adverse events include:
- Nausea
- Vomiting
- Diarrhea
- Stomatitis
- Neutropenia
- Thrombocytopenia
FOLFIRI
Irinotecan 180 mg/m(2)
Folinic Acid 400/200 mg/m(2)
Fluorouracil 400 - 500 mg/m(2) (IV Bolus)
Then
Fluorouracil 2400 - 3000 mg/m(2)
Repeat every 14 days until disease progression Some of the frequently occurring
adverse events include:
- Nausea
- Vomiting
- Diarrhea
- Stomatitis
- Myelosuppression
RATIONALE FOR RE-TREATMENT:
[ * ].
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[ * ] Confidential Treatment Requested
APPENDIX G-1
5 PRODUCT INFORMATION
5.1 LS11 DESCRIPTION
LS11 (mono-L-aspartyl chlorin e(6)) is a chemically synthesized photosensitizer
with a molecular weight of 799.69.
(MOLECULAR STRUCTURE)
LS11 appears as a dark blue-green powder. The absorption spectrum of LS11
exhibits a maximum peak at 664 nm in an UV-visible absorption spectrum when LS11
is incubated with PtK2 cells, or when it is mixed with bovine serum albumin at a
molar ratio of 1:1 in phosphate buffer solution of pH 7.4. LS11 has been shown
to be stable for a minimum of 2.5 years when stored in sealed containers at
2-8 degrees C protected from light.
Light Sciences Oncology supplies LS11 as a lyophilized powder in 10 mL clear
vials, each containing 100 mg drug product. Each vial is individually packaged
in a carton. For more information please refer to the Investigator Brochure.
5.2 LS11: CLINICAL USE AND HANDLING
5.2.1 VIAL LABELING
Each LS11 vial and single vial carton has a label containing the following
information:
For IV Use Only
100 mg/vial
Lot number and expiration date
Keep Refrigerated. Store between 2-8 degrees C
Protect from Light
Caution: New Drug - Limited by Federal Law to Investigational Use
Use within 8 hours of Reconstitution
5.2.2 SHIPPING TO CLINICAL SITES
[ * ].
5.2.3 STORAGE OF LS11
[ * ].
5.2.4 DOSE CALCULATION
[ * ].
5.2.5 PREPARATION OF THE SOLUTION
[ * ].
5.2.6 LS11 ADMINISTRATION
Since compatibility between LS11 and other drugs is not established, LS11 should
not be mixed with or physically added to other drugs.
[ * ].
5.2.7 POTENTIAL ADVERSE EVENTS
[ * ].
5.2.8 RETURN OF DRUG
All used vials will be retained in the institution's pharmacy until the Clinical
Research Associate performs a complete drug accountability audit. Following this
accounting used vials may be discarded according to hospital policy or may be
returned to an LSO designated vendor for destruction.
5.3 LIGHT SOURCES
5.3.1 DESCRIPTION
The Light Sciences Oncology Light Source consists of a Light Bar at the distal
end of the Light Source catheter and a Power Controller attached to the catheter
at the proximal end. The disposable Light Source is battery powered and emits a
broad band of wavelength, which peaks [ * ].
The Power Controller supplies an isolated low voltage power to the Light Source
and provides internal continuous monitoring of performance. It is designed and
tested to comply with IEC 60601-1 medical device safety standards.
Detailed specifications for the disposable Light Source(s) and Power Controller
are described in the Litx(TM) System Operator's Manual provided by Light
Sciences Oncology.
5.3.2 CLINICAL USE AND HANDLING
[ * ]. It is recommended that the Light Source be placed as follows: [ * ].
-------------
[ * ] Confidential Treatment Requested
5.3.3 LABELING
Light Source pouch including Power Controller labeling includes the
following information:
Investigational Device, Contents and Property of.
5.3.4 SHIPPING TO CLINICAL SITES
During manufacturing, the Light Sources are individually packed inside a
sterile pouch, which is then placed inside a protective box. Upon shipment
request from Light Sciences Oncology or its designated representative, the
distribution service provider will pull the appropriate number of boxes and
properly prepare them for shipment to the institution. The package will be
shipped via traceable means to arrive at the site within the time frame
requested.
5.3.5 STORAGE
[ * ].
5.3.6 DISPOSAL OF USED LIGHT SOURCES
Upon completion of each Litx(TM) treatment as outlined in Section 7 of this
protocol, the explanted disposable Light Source and Power Controller should be
disposed, as per the institutions standard operating procedures.
5.3.7 PRECAUTIONS OF LIGHT SOURCES
The Light Source should not be used with Magnetic Resonance Imaging (MRI), as
the system has not been verified to be MRI safe.
Follow universal infection control precautions when inserting and maintaining
the Light Source in the tumor.
The Light Sources and Power Controller are for one time use only. Do not attempt
to retreat the devices will not function.
5.4 INTRODUCER
5.4.1 DESCRIPTION
[ * ].
Detailed specifications for the Introducer are described in the LitxTM System
Operator's Manual provided by Light Sciences Oncology.
5.4.2 CLINICAL USE AND HANDLING
The Introducer is provided as a single use only device in a single barrier
sterile pouch. [ * ].
-------------
[ * ] Confidential Treatment Requested
5.4.3 LABELING
Introducer pouch labeling includes the following information:
Investigational Device, Contents and Property of.
5.4.4 SHIPPING TO CLINICAL SITES
[ * ].
5.4.5 STORAGE
[ * ].
5.4.6 DISPOSAL OF USED INTRODUCERS
Upon completion of each Litx(TM) treatment as outline in Section 7 of this
protocol, the explanted Introducer should be disposed of as specified per the
institutions standard operating procedures.
5.4.7 PRECAUTIONS OF INTRODUCERS
The Light Source should not be used with MRI due to the metallic nature of the
trocar. Follow universal infection control precautions when inserting and
maintaining the sheath in the tumor.
-------------
[ * ] Confidential Treatment Requested
6 ELIGIBILITY
6.1 INCLUSION CRITERIA
1. [ * ]
2. [ * ]
3. [ * ]
4. [ * ]
5. [ * ]
6. [ * ]
7. Understanding and ability to sign written informed consent
8. [ * ]
9. [ * ]
6.2 EXCLUSION CRITERIA
1. Patients who are candidates for complete surgical resection
[ * ]
-------------
[ * ] Confidential Treatment Requested
APPENDIX G-1
7 TREATMENT SCHEDULE
Eligible patients will be treated according to the schedule shown in Table
8.16-1.
[ * ].
7.1 SUGGESTED LITX(TM) TREATMENT PLAN
[ * ].
8 STUDY PROCEDURES
8.1 SCREEN/BASELINE:
[ * ].
8.2 TREATMENT: DAY 0
8.2.1 LITX(TM)+CHEMO GROUP:
[ * ].
8.2.2 CHEMO ONLY GROUP:
[ * ]. (4 pages)
8.2.13 CHANGE IN TREATMENT
[ * ].
8.2.14 RE-TREATMENT WEEKS
8.2.15 LITX(TM)+CHEMO GROUP
[ * ].
8.2.16 DATA SAFETY MONITORING COMMITTEE (DSMC)
[ * ].
8.2.17 SURVIVAL
All patients will be followed for survival [ * ].
----------
[ * ] Confidential Treatment Requested
APPENDIX G-1
8.2.18 SCHEDULE OF EVENTS FROM BASELINE TO STUDY COMPLETED
[ * ].
9. IMAGING RESPONSE
9.1 IMAGING DEFINITIONS
[ * ].
9.1.1 RESPONSE
[ * ].
9.1.2 COMPLETE RESPONSE
[ * ].
9.1.3 PARTIAL RESPONSE
[ * ].
9.1.4 STABLE DISEASE
[ * ].
9.1.5 DISEASE PROGRESSION
10 REPORTING REQUIREMENTS FOR ADVERSE EVENTS
10.1 DEFINITIONS
An adverse event is any undesirable experience concerning the health of a
patient occurring during a clinical trial. This is whether or not the adverse
event is considered related to the study treatments, such as events not reported
at baseline, intercurrent illnesses, hypersensitivity reactions, toxicity,
injuries, and clinically relevant laboratory abnormalities.
A Serious Adverse Event (SAE) is any adverse drug/device experience occurring at
any dose that results in any of the following outcomes:
Death;
Life-threatening adverse drug/device experience;
Inpatient hospitalization or prolongation of existing hospitalization;
A persistent or significant disability/incapacity;
A congenital anomaly/birth defect;
----------
[ * ] Confidential Treatment Requested
APPENDIX G-1
Important medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious adverse drug experience
when, based upon appropriate medical judgment, they may jeopardize the patient
and may require medical or surgical intervention to prevent one of the outcomes
listed in this definition.
10.2 REPORTING REQUIREMENTS
10.2.1 DEFINITION OF SERIOUS ADVERSE EVENTS (SAES)
All serious adverse events during the study period, whether or not considered to
be related to study treatment must be reported to the respective CRO that is
managing the site within 24 hours or, at the latest, on the following working
day.
At the time of the initial report, as much information as possible should be
provided: patient allocation number, treatment, study identifiers, the phase of
treatment during which the event occurred, a description of the event, its date
of onset and current status; the start date, the start time, whether this
treatment has been discontinued; the reason why the event is regarded as
serious; the current assessment of causality, investigator's name and address.
The investigator must fax the SAE form within the next 24 hours if it is not
provided at the time of the initial notification. Any other diagnostic
information, which will assist the understanding of the event, should be
provided at this time.
The study patient must be followed until the final outcome of the SAE is known,
including any which are still ongoing at the end of the study. Significant new
information on the SAE, and the final outcome, must be supplied promptly to the
respective CRO that is managing the site. This should be done in the same way
and time frame as for the original notification, using the SAE form and
identifying this as follow up information.
The investigator must report promptly any SAEs, which may be detected after the
study, and are suspected to be related to study treatment.
Investigators must report all SAEs to the IRB according to their institutional
policy.
10.2.2 NON-SERIOUS ADVERSE EVENTS
All non-serious adverse events reported or observed, and the remedial action
required will be recorded in the patient's Case Report Form. The Case Report
Form must have all relevant fields completed.
10.3 CATEGORIES FOR RANKING SEVERITY OF AN ADVERSE EVENT
National Cancer Institute Common Terminology Criteria for Adverse Events v3.0
(CTCAE) will be used to categorize adverse events and to score severity. A copy
of the criteria is presented in Appendix 1. The following definitions will
assist in scoring adverse events.
APPENDIX G-1
Grade 1 Mild, easily tolerated by the patient, causing minimal
discomfort and not interfering with everyday activities.
Grade 2 Moderate, sufficiently discomforting to interfere with
normal everyday activities.
Grade 3 Severe, prevents normal everyday activities.
Grade 4 Life threatening, places the patient at immediate risk of
death.
Grade 5 Death
10.4 CATEGORIES FOR DETERMINING RELATIONSHIP TO THE INVESTIGATIONAL PRODUCT
The causality assessment to be used to record the relationship between the study
treatment (drug related or device related) and the adverse event are as follows:
None: The temporal relationship of the clinical event to the study
treatment (drug related or device related) makes a causal
relationship unlikely, or
other drugs, therapeutic interventions or underlying conditions
provide a sufficient explanation for the observed event.
Probable: The temporal relationship of the clinical event to study
treatment (drug related or device related) makes a causal
relationship probable, and other drugs, therapeutic
interventions or underlying conditions do not provide a
definitive explanation for the observed event.
Definite: The temporal relationship of the clinical event to study
treatment (drug related or device related) makes a causal
relationship definite, and other drugs, therapeutic
interventions or underlying conditions can provide a definitive
explanation for the observed event.
10.5 REPORTING SERIOUS ADVERSE EVENTS
All serious adverse events during the study period, whether or not considered to
be related to study treatment must be reported to the respective CRO that is
managing the site within 24 hours or, at the latest, on the following working
day.
At the time of the initial report, as much information as possible should be
provided: patient allocation number, treatment, study identifiers, the phase of
treatment during which the event occurred, a description of the event, its date
of onset and current status; the start date, the start time, whether this
treatment has been discontinued; the reason why the event is regarded as
serious; the current assessment of causality, investigator's name and address.
The investigator must fax the SAE form within the next 24 hours if it is not
provided at the time of the initial notification. Any other diagnostic
information, which will assist the understanding of the event should be provided
at this time.
The study patient has to be followed until the final outcome of the SAE is
known, including any which are still ongoing at the end of the study.
Significant new information on the SAE, and the final outcome, must be supplied
promptly to the
APPENDIX G-1
respective CRO that is managing the site. This should be done in the same way
and time frame as for the original notification, using the SAE form and
identifying this as follow up information.
The investigator must report promptly any SAEs, which may be detected after the
study, and are suspected to be related to study treatment.
Investigators must report all SAEs to the IRB according to their institutional
policy.
11 REGULATORY REQUIREMENTS
11.1 INVESTIGATOR OBLIGATIONS
As indicated on FDA Form 1572, the Principal Investigator is responsible for
ensuring that all study site personnel, including Sub-Investigators and other
study staff members, adhere to all FDA regulations and guidelines regarding
clinical trials both during and after study completion.
11.2 INFORMED CONSENT
All patients will be informed of the nature of the program, its possible
hazards, and their right to withdraw at any time, and will sign a form
indicating their consent to participate. Each institution's Informed Consent
Form must be reviewed and approved by its designated Institutional Review Board
and by LSO clinical staff.
11.3 INSTITUTIONAL REVIEW BOARD
This protocol and relevant supporting data are to be submitted to the
appropriate Institutional Review Board (IRB) for review and approval before the
study can be initiated. Amendments to the protocol will also be submitted to the
IRB prior to implementation of the change. The Sponsor must receive a letter
documenting the IRB approval prior to initiation of the study. The Principal
Investigator is also responsible for informing the IRB of the progress of the
study and for obtaining annual IRB renewal. The IRB must be informed at the time
of completion of the study and should be provided with a summary of the results
of the study by the Principal Investigator. The Principal Investigator must
notify the IRB in writing of any serious adverse event or any unexpected adverse
event according to FDA guidelines.
12 ADMINISTRATIVE CONSIDERATIONS
12.1 PRE-STUDY DOCUMENTATION
Light Science Oncology must receive the following documentation prior to
initiation of the trial:
FDA form 1572 signed by the Principal Investigator (PI);
Curriculum vitae of the PI and all sub-investigators;
Signed protocol agreement;
Copy of the informed consent form that was reviewed and approved by the IRB;
Copy of IRB approval letter;
APPENDIX G-1
Financial disclosures of the PI and all sub-investigators;
Normal reference ranges and laboratory accreditation.
12.2 STUDY DOCUMENTATION
The Principal Investigator and study staff has the responsibility of maintaining
a comprehensive and centralized filing system containing all study related
documentation. These files must be suitable for inspection by LSO or the FDA at
any time, and should consist of the following elements:
Patient files, containing the completed medical records, laboratory data,
supporting source documentation, and the informed consent;
Study files, containing the protocol with all amendments, copies of all
regulatory documentation, and all correspondence between the IRB and Sponsor;
Drug accountability files, containing a complete account of the receipt and
disposition of the drug and device.
Records are to be available for two years after marketing application approval,
or if the application is not approved or never submitted, two years after the
last shipment and delivery of the material and the FDA is so notified. The files
should not be destroyed until the official termination letter from the Light
Science Oncology.
12.3 DATA COLLECTION
Case Report Forms (CRFs) are to be completed in a neat, legible manner, using a
black or blue pen, to ensure accurate interpretation of data. Any changes or
corrections made on the CRFs must be dated and initialed by the individual who
is authorized to make the change. When corrections are made, the original entry
should be crossed out using a single line. Do not erase or overwrite the
original entry. All blanks on the CRFs must be filled in.
12.4 PROTOCOL INTERPRETATION AND COMPLIANCE
The Principal Investigator and staff, prior to the time of study initiation, to
ensure accurate interpretation and implementation, will carefully review the
procedures defined in the protocol.
12.5 STUDY MONITORING
A representative from Light Sciences Oncology or designated CRO will visit the
study center periodically to monitor adherence to the protocol, adherence to
applicable FDA regulations, and the maintenance of adequate and accurate
clinical records. CRFs will be reviewed to ensure that key safety and efficacy
data are collected and recorded as specified by the protocol. The LSO or
designated CRO representative will be permitted to access patient medical
records, laboratory data, and other source documentation as needed to
appropriately monitor the trial. The Investigator should allocate adequate time
for these visits.
12.6 DISCLOSURE OF DATA / PUBLICATION
No part of the results of the study carried out under this protocol, or any of
the
APPENDIX G-1
information provided by Light Sciences Oncology to the investigator for the
purposes of performing the study, will be published, or passed on to a third
party, without prior review by Light Sciences Oncology. The Principal
Investigator or anyone else working on the study will submit all proposed
publications, papers, abstracts or other written materials related to the Study,
or an outline of any proposed oral presentation with respect, to Light Sciences
Oncology at least one month prior to (i) submission of such written materials
for publication, or (ii) any proposed oral disclosure to a third party. Light
Sciences Oncology shall have the right to comment on such written material or
outline; the Principal Investigator in determining the final form of disclosure
shall consider such comments in good faith. Notwithstanding any of the above,
the Principal Investigator or anyone else working on the Study may not include
any confidential information in any such publication or disclosure.
The Investigator is obliged to provide Light Sciences Oncology with complete
test results and all data derived from the study. Only LSO and its authorized
CRO may make information obtained during the study available to regulatory
agencies, except as required by regulation.
APPENDIX G-1
13 REFERENCES
1. Efficace, F., X. Xxxxxxxxx, X. Xxxxxxxxxx, and X. X. Blazeby. 2004.
Methodological issues in assessing health-related quality of life of
colorectal cancer patients in randomised controlled trials. Eur J Cancer
40:187-197.
2. Xxxxx, X. X., X. Xxxx, X. Xxxxxx, and X. X. Xxxxxx. 1997. Cancer incidence
and mortality in the European Union: cancer registry data and estimates of
national incidence for 1990. Eur J Cancer 33:1075-1107.
3. Xxxxxx, X. X., X. Xxxxxx, X. Xxxxxx, and P. A. Xxxxx. 1999. Cancer
statistics, 1999. CA Cancer J Clin 49:8-31, 31.
4. Xxxxxxx, X., X. Xxxxxx, and X. Xxxxxxxxx-Xxxxxxx. 1990. Hepatic metastases
from colorectal carcinoma: impact of surgical resection on the natural
history. Br J Surg 77:1241-1246.
5. Xxxxxx, X., X. Xxxxxxxxx-Xxxxxxx, X. X. Xxxxxxxx, and X. Xxxxxxx. 1994.
Factors influencing the natural history of colorectal liver metastases.
Lancet 343:1405-1410.
6. Xxxx, Y., A. M. Xxxxx, X. X. Xxxxxxx, X. X. Enker, A. D. Xxxxxxxx, X. X.
Xxxx, A. M. Xxxxxxx, X. Xxxxxx, X. X. Xxxxxxxx, and X. X. Xxxxxxx. 1997.
Liver resection for colorectal metastases. J Clin Oncol 15:938-946.
7. Xxxxxx, K. S., X. Xxxxx, X. Xxxxxxxxxxxx, M. A. Xxxxx, X. X. Xxxxxxx, X. X.
Xxxxxxx, X. X. Xxxxxxx, X. X. Xxxxxx, X. X. Xxxx, X. Xxxxxxxxxxx, and et
al. 1986. Resection of the liver for colorectal carcinoma metastases: a
multi-institutional study of patterns of recurrence. Surgery 100:278-284.
8. Xxxxxxxxxx, B., X. Xxxxxxx, X. X. Xxxxxxxx, X. Xxxxxxxx, X. Xxxxxxxx, X.
Xxxxxxxxxx, and X. Xxxxx. 1996. Surgical resection of colorectal carcinoma
metastases to the liver. A prognostic scoring system to improve case
selection, based on 1568 patients. Association Francaise de Chirurgie.
Cancer 77:1254-1262.
9. Xxxxxxx, X., X. Xxxxx, X. Xxxxxxxxx-Xxxxxxx, and X. Xxxx. 1995. Resection
of colorectal liver metastases. World J Surg 19:59-71.
10. xx Xxxxxxx, X., X. Xxxxx, X. Xxxxxxx, X. Xxxxxxx, X. Xxxxxx, X. Xxxxxxx, X.
Xxxx, X. Xxxxxx-Xxxxx, X. Xxxxxxxxx, X. Xxxxxx, X. Xxxxxxxxxxx, X. Xx Xxxx,
X. Xxxxxx, X. Xxxxxxx, X. xx Xxxxx, X. Xxxxxx, X. Xxxxxx, and X. Xxxxxxx.
2000. Leucovorin and fluorouracil with or without oxaliplatin as first-line
treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947.
11. Xxxxxxxxx, X. X., X. Xxxxxxxxxx, A. D. Xxxx, X. Xxxxxxx, X. X. Xxxxx, X.
Xxxxxxx, X. Xxxxxx, X. Xxxxxx, X. Xxxxxxxxxx, X. Xxxxx, X. Xxxxx, X. Xxxx,
and X. Xxxxxxx. 2000. Irinotecan combined with fluorouracil compared with
fluorouracil alone as first-line treatment for metastatic colorectal
cancer: a multicentre randomised trial. Lancet 355:1041-1047.
12. Xxxxx, X. X., X. X. Xxx, X. Xxxxxx, X. X. Xxxxx, X. Xxxxxxxxxxxx, X. X.
Xxxxx, X. X. Xxxxxx, X. X. Xxxxxxx, X. X. Xxxxxx, X. Xxxxxxx, X. X.
Xxxxxxx, and L. L. Xxxxxx. 2000. Irinotecan plus fluorouracil and
leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl
J Med 343:905-914.
13. Xxxxxxxxxx, C., X. Xxxxx, X. Xxxxxxx, X. Xxxxx, X. Xxxxx, X. Xxxx-Xxxxxxx,
X. Xxxxxxx, X. Xxxxxxx, X. Xxxxx, X. Xxxxx, X. Xxxxx, X. Xxxxx, X. Xxxxxx,
and X.
APPENDIX G-1
de Gramont. 2004. FOLFIRI followed by FOLFOX6 or the reverse sequence in
advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol
22:229-237.
14. Xxxxxxxx, X. X., X. X. Xxxxxxx, X. X. Xxxxxx, X. X. Xxxxx, X. X.
Xxxxxxxxxx, X. X. Xxxxxxxxxx, X. X. Xxxxxxx, X. X. Xxxxx, and S. R.
Xxxxxxx. 2004. A randomized controlled trial of fluorouracil plus
leucovorin, irinotecan, and oxaliplatin combinations in patients with
previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30.
15. Xxxxxxxxx, X. X., and X. X. Xxxxxxxxx. 1992. How does photodynamic therapy
work? Photochem Photobiol 55:145-157.
16. Xxxxxx, X. 1997. Pharmacokinetics of N-aspartyl chlorin e6 in cancer
patients. J Photochem Photobiol B 39:81-83.
17. Data on File. In Control Document # 810-0019. Light Sciences Oncology.
APPENDIX G-2
GENERAL TEMPLATE CLINICAL RESEARCH AGREEMENT
ERGOMED-INVESTIGATOR/INSTITUTION
This AGREEMENT is made on this __________________________________________
BETWEEN:
ERGOMED CLINICAL RESEARCH LTD.
0 Xxxxxxxxx Xxxxxx Xx.
Surrey Research Park
Guildford, Surrey, GU2 7YD,
U.K. (hereinafter referred to as ERGOMED)
AND
___________________________________ (full name of the Institution)
___________________________________ (full address)
___________________________________
___________________________________
(hereinafter referred to as the INSTITUTION)
___________________________________
AND
___________________________________ (name of the Investigator)
with business address at:
___________________________________
___________________________________
___________________________________
___________________________________
(hereinafter referred to as the INVESTIGATOR)
___________________________________
WHEREAS:
ERGOMED and _________________________________________ (hereinafter the
"Sponsor") have concluded a Clinical Trial Agreement by which ERGOMED undertook
to carry out the following clinical trial:
"_________________________________________________ (hereinafter: "the Clinical
Trial") and agreed to undertake other necessary activities for preparing the
Clinical Trial;
and
ERGOMED wishes to involve the INSTITUTION and INVESTIGATOR in the Clinical Trial
in the role referred to herein and the INSTITUTION and INVESTIGATOR accept such
involvement.
1
WHEREBY IT IS AGREED AS FOLLOWS:
ARTICLE 1.
DEFINITIONS
1.1. For the purpose of this Agreement, the following expressions shall have the
meanings attributed to them below:
the "Clinical Trial" the clinical trial referred to and described in the
Protocol
the "Product" (state the full name of the substance /product to be used
in research)
the "Protocol" (state the full name of Protocol) (alternative: name of
the Protocol, as attached herein as Schedule 1 and as
approved and amended from time to time by the Sponsor)
"Recruitment Period" (in studies where this is a relevant element -- state the
date(s) during which or by which the recruitment is to be
fully completed or refer to the Recruitment Plan, if
there is such Plan)
the "Services" the services of research and other similar services to be
performed by the INVESTIGATOR at the INSTITUTION with a
primary purpose of testing the Product pursuant to the
Protocol.
ARTICLE 2.
RIGHTS AND OBLIGATIONS OF THE PARTIES
2.1. Pursuant to the terms and conditions of this Agreement, INSTITUTION,
through the efforts of INVESTIGATOR, agrees to conduct the Clinical Trial
in __________ patients according to the Protocol. By signing the Agreement
INVESTIGATOR acknowledges that (s)he has received and reviewed the full
text of Protocol (as herein attached).
2.2. INSTITUTION and INVESTIGATOR agree to perform the work required under the
Protocol and this Agreement and to conduct the Clinical Trial with
reasonable care and skill and in accordance with the Protocol, agreed
Standard Operating Procedures and the GCP regulations (see Note for
Guidance Good Clinical Practice [CPMP/ICH/135/95] and Guideline for Good
Clinical Practice [ICHE6] Step 4, Consolidated Guideline, 1.05.96, in its
then valid version, respectively.
2.3. INVESTIGATOR shall obtain any and all licenses, permits, approvals, and
patient informed consent documents required for conducting of the relevant
part of the Clinical Trial from the INSTITUTION and/or any other authorized
body and ICH and GCP guidelines.
2.4. INSTITUTION and INVESTIGATOR will arrange for any other relevant personnel
required to carry out the Protocol and shall ensure that at all times
during the Clinical Trial there is enough personnel to support the Clinical
Trial.
2.5. ERGOMED may, at its sole option, arrange for the availability of a study
coordinator, duly qualified by training and / or experience, to manage some
administrative functions at the site.
2
2.6. INSTITUTION and INVESTIGATOR shall perform the Clinical Trial efficiently
and within the time frames set out in this Agreement and the Protocol.
INSTITUTION and INVESTIGATOR agree that the time is of essence for the
purposes of this Agreement.
2.7. INVESTIGATOR shall personally conduct the Clinical Trial and supervise the
work of all the involved personnel. INVESTIGATOR shall not delegate his/her
obligations from this Agreement to any third party without the prior
written approval of ERGOMED.
2.8. The parties understand and agree that any alteration or amendment to either
the attached Protocol or this Agreement must be approved in writing by the
Sponsor prior to such alteration or amendment becoming effective.
ARTICLE 3.
COMPENSATION AND EXPENSES
3.1. As compensation for the conduct of the Clinical Trial as referred to in
this Agreement ERGOMED shall pay to the INSTITUTION the gross fee indicated
in Schedule II (Schedule I if no Protocol is attached) herein attached and
made an integral part of this Agreement. This gross fee includes any and
all taxes that may be applicable anywhere anytime and it is specifically
agreed that any such taxes shall be the sole responsibility of the
INSTITUTION.
3.2. It is agreed that payment of the sums due under this Agreement shall be
payable by ERGOMED by an international check or by wire transfer at the
bank account indicated in the INSTITUTION's invoice.
3.3. Unless otherwise agreed in writing and approved by Sponsor, payments of the
sums due under this Agreement shall be made according to the attached
Schedule II (Schedule I if no Protocol is attached).
3.4. In undertaking to perform professional services for ERGOMED, it is
understood that INVESTIGATOR is doing so as an employee of the INSTITUTION
and not as an employee of ERGOMED.
ARTICLE 4.
INTELLECTUAL PROPERTY
4.1. The parties hereby agree that ERGOMED and/or the Sponsor shall at all times
retain ownership of all intellectual property resulting from the Clinical
Trial or the Clinical Trial and the INSTITUTION and INVESTIGATOR have no
rights to any such intellectual property. For the avoidance of doubt, the
INSTITUTION and INVESTIGATOR hereby grant to Sponsor any and all right,
title and interest in any and to any invention, discovery or improvement
conceived or reduced to practice in connection with the Clinical Trial or
the Clinical Trial.
4.2. The parties agree the INSTITUTION and INVESTIGATOR assert no claim to
rights in technology and materials owned by ERGOMED or the Sponsor.
4.3. INSTITUTION or INVESTIGATOR may be allowed to present and publish data
resulting from the Clinical Trial pursuant to the Sponsor's publication
policies and upon obtaining prior written approval from the Sponsor for any
such presentation or publication. In case of presentation or publication of
such data INSTITUTION and INVESTIGATOR shall be bound by the
confidentiality clause from Article 5. of this Agreement and subject to
preserving Sponsor's
3
rights in Sections 4.1 and 4.2. The provisions of this Article 4 shall
survive termination or expiration of this Agreement.
ARTICLE 5.
CONFIDENTIALITY
5.1. INSTITUTION and INVESTIGATOR shall hold in strict confidence any and all
information acquired by the INSTITUTION and/or INVESTIGATOR from ERGOMED
and/or the Sponsor in reference to this Agreement or the Clinical Trial or
developed by him/her with regard to the Clinical Trial or the Product.
5.2. INSTITUTION and / or INVESTIGATOR undertake to permit access to the
Confidential Information only to those employees of the INSTITUTION or
members of the INVESTIGATOR'S team who reasonably need access to such
information for the carrying out of the duties under this Agreement.
Furthermore, such access to Confidential Information shall be permitted
only on condition that such employees have entered into legally binding
confidentiality agreement with terms equivalent to those stipulated herein
and have been instructed to treat the confidential information as such in
accordance with the provisions of this Agreement.
5.3. This Clause shall not apply to information:
a) which was known to INSTITUTION or INVESTIGATOR prior to its receipt
from ERGOMED or the Sponsor, and INSTITUTION or INVESTIGATOR is able
to so demonstrate through bona fide written records of such receipt,
b) which is or lawfully becomes generally available to the public as
evidenced by objective public record,
c) which is lawfully acquired from third parties who have a right to
disclose such information, or
d) which INSTITUTION or INVESTIGATOR is required by law to release,
provided that INSTITUTION or INVESTIGATOR gives advance written notice
of such requirement so that Sponsor has the opportunity to object to
such disclosure.
5.4. Nothing herein shall be construed as prohibiting the Sponsor from reporting
on this Clinical Trial to a governmental agency or from exercising its
publication rights as stated in Section 4.3.
5.5. The terms of this Article 5. and the parties' obligations hereunder shall
survive termination or expiration of this Agreement.
ARTICLE 6.
TERM AND TERMINATION
6.1. This Agreement shall become effective on the date first written above and
shall remain in full force and effect until the full and satisfactory
completion of the Services by the INSTITUTION and INVESTIGATOR.
6.2. ERGOMED may terminate this Agreement prior to the full and satisfactory
completion of the Services by the INSTITUTION and INVESTIGATOR by written
notice and immediate effect for
4
any of the following reasons:
A. Notice received by ERGOMED that the Sponsor has terminated the
relevant Agreement with ERGOMED and / or has ceased any further
activity on the Clinical Trial regardless of the reason given to
ERGOMED by the Sponsor;
B. Notification received by the Sponsor from Regulatory Authorities to
terminate the Clinical Trial;
C. Continuous and / or repetitive and /or material breach of any of the
INSTITUTIONS and / or INVESTIGATOR's obligations stipulated herein;
D. In case INVESTIGATOR does not recruit any patient within _____ days
from the day of the initial visit;
E. In case INVESTIGATOR delegates any of his/her obligations from this
Agreement without the prior written approval by ERGOMED in breach of
Article 2.7. herein;
F. Determination by ERGOMED and/or the Sponsor that the INVESTIGATOR,
after a reasonable opportunity, is unable, for any reason, to
satisfactorily perform the Clinical Trial as required by the Protocol
and a suitable replacement is not made;
G. Case Report Forms, to be completed by the INVESTIGATOR pursuant to
ERGOMED's and/or the Sponsor's request, have not been legibly
completed and / or forwarded by the INVESTIGATOR to ERGOMED or to its
designated representative, as appropriate, within 60 days of each
patient's completion date;
H. INVESTIGATOR and/or INSTITUTION prevent access to ERGOMED's employees
or contractors or any third persons authorized by ERGOMED and / or the
Sponsor to any and all original medical records necessary to verify
entries on Clinical Trial Case Report Forms;
I. INVESTIGATOR, his/her associates, or any other person engaged in this
Clinical Trial (excluding patients) are unavailable upon reasonable
notice by ERGOMED and/or the Sponsor, to meet with an ERGOMED's and/or
the Sponsor's representative during the course of the Clinical Trial,
as necessary, to discuss information relevant to the Clinical Trial;
J. Determination by the Sponsor that business or scientific
considerations require termination of the Clinical Trial;
K. INSTITUTION and/or INVESTIGATOR do not comply with all regulatory
requirements;
L. INVESTIGATOR ceases to be employed with the INSTITUTION.
6.3. In the event that ERGOMED chooses to exercise its right to terminate this
Agreement in line with Article 6.2. of this Agreement, the INVESTIGATOR
shall, immediately upon receipt of ERGOMED's notice to terminate, cease
enrolling patients into the Clinical Trial and shall discontinue conducting
Clinical Trial procedures, to the extent medically possible.
6.4. Any rights that any party might have obtained during the term of this
Agreement will survive such termination until the complete fulfillment of
such rights, or as otherwise provided.
6.5. In the event of early termination, the sum payable under this Agreement
shall be limited to pro-rated fees based on actual work performed pursuant
to the Protocol.
5
6.6. The INSTITUTION and INVESTIGATOR shall return to ERGOMED the Product and
all Clinical Trial materials immediately upon termination but in any case
no later than within one month from the termination of the Agreement.
ARTICLE 7.
FINAL PROVISIONS
7.1. None of the parties may delegate their obligations or assign their rights
hereunder without the prior written consent of the Sponsor.
7.2. Any and all additions and/or amendments to this Agreement shall be in
writing, numbered, dated and signed by the authorized representatives of
both parties.
7.3. Any and all disputes arising out of or in connection with the Agreement
shall be settled by an amicable effort of the parties.
7.4. Any dispute, which is not amicably settled by such efforts of the Parties,
shall be finally resolved under the Rules of the Chartered Institute of
International Arbitration in London, England, UK, by 1 (one) arbitrator
appointed pursuant to such Rules. The seat of such arbitration shall be in
London, UK.
7.5. This Agreement and all disputes thereof shall be governed by and construed
in accordance with the substantive laws of England.
7.6. If any provision of this Agreement should be deemed invalid or legally
unenforceable, such provision shall not affect the validity and/or
enforceability of any other provision(s) of this Agreement or the Agreement
as a whole. The parties shall, in such case, replace the invalid provision
with a valid one that best expresses their original intent.
7.7. This Agreement is being executed in 3 (three) identical copies, of which
each party shall keep 1 (one) copy.
SIGNED on behalf of ERGOMED:
------------------------------------- ----------------------------------------
Date
SIGNED by the INSTITUTION:
------------------------------------- ----------------------------------------
Date
SIGNED by the INVESTIGATOR:
------------------------------------- ----------------------------------------
Date
6
SCHEDULE I - THE PROTOCOL (IF APPLICABLE)
7
SCHEDULE II - BUDGET AND TIMING
8
SCHEDULE III - RECRUITMENT PLAN (WHEN APPLICABLE)
APPENDIX G-3
(ERGOMED LOGO)
REVISED BUDGET FOR MCRC TRIAL, [ * ].
Unit
Unit Cost Total
Activity Description (EUR) # Units (EUR)
-------- ----------- ----- ------- -----
Preparation
[ * ]
Subtotal Preparation [ * ]
Set up & Pre-Trial activity
[ * ]
Subtotal Set up & Pre-Trial activity [ * ]
Study Conduct
[ * ]
Subtotal Study Conduct [ * ]
Training
[ * ]
Subtotal Training [ * ]
Pharmacovigilance
[ * ]
Subtotal Pharmacovigilance [ * ]
Regulatory
[ * ]
----------
[ * ] Confidential Treatment Requested
Page 1
[ * ]
Subtotal Regulatory
Data Management
[ * ]
Subtotal Data Management [ * ]
Study Physician
[ * ]
Subtotal Study Physician [ * ]
Project Management
[ * ]
Subtotal Project Management [ * ]
Administrative support
[ * ]
Subtotal Project Management [ * ]
TOTAL EURO [ * ]
Unit Cost Total
Other costs (EUR) # Units (EUR)
----------- --------- ------- ----------
Site Payments
[ * ]
Other
[ * ]
TOTAL EURO [ * ]
10.154.328
22565,1722
----------
[ * ] Confidential Treatment Requested
Page 2
APPENDIX G-4
MARCH 9, 2006
XX. XXXXXXX XXXXXX, MD
DIRECTOR, DIVISION OF ONCOLOGY PRODUCTS
U.S. FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
5901-B AMMENDALE RD.
BELTSVILLE, MD. 20705-1266
RE: TRANSFER OF SPONSOR OBLIGATIONS TO A CONTRACT RESEARCH ORGANIZATION,
EUROPEAN AND USA SITES, IND NO. 37,088, LS11, FORMERLY NPE6 (TAPORFIN SODIUM)
Dear Xx. Xxxxxx,
In accordance with 21 CFR Part 312.52, Light Sciences Oncology, holder of the
above referenced IND, doing business at 34931 X.X. Xxxxxxx Street, Xxxxx 000,
Xxxxxxxxxx, XX 00000 is notifying you that certain sponsor obligations related
to IND 37,088 for the conduct of the study entitled:
"A MUTICENTER MULTINATIONAL PHASE 3 RANDOMIZED STUDY TO EVALUATE THE SAFETY
AND EFFICACY OF TREATING COLORECTAL CANCER PATIENTS WITH RECURRENT LIVER
METASTASES USING THE LITX(TM) PLUS CHEMOTHERAPY AS COMPARED TO CHEMOTHERAPY
ALONE"
have been transferred to:
ERGOMED CLINICAL RESEARCH, LTD.
0 XXXXXXXXX XXXXXX XX.
SURREY RESEARCH PARK
GUILDFORD, SURREY, GU2 7YD
U.K.
The specific sponsor obligations hereby transferred for the conduct of the above
referenced study at European sites to ERGOMED CLINICAL RESEARCH, LTD. are as
follows:
Selection of investigators in Europe and the USA
- Control of Drug in Europe and the USA
1
- Before permitting an investigator to begin participation in an
investigation, ERGOMED CLINICAL RESEARCH, LTD. shall obtain the
following information
(1) A signed investigator statement (FDA form FD-1572)
(2) Curriculum vitae(s) of all European investigators and
sub-investigators
(3) Financial disclosure information
- Selection of Monitors in Europe and USA
- Prior to the start of any investigation, ERGOMED CLINICAL RESEARCH,
LTD. will give each participating European and USA clinical
investigator a copy of the investigator Brochure (IB) containing
information required under 21 CFR Part 312.23(a)(5).
- ERGOMED CLINICAL RESEARCH, LTD. will keep each participating European
and USA investigator informed during the course of the investigation
of new observations discovered by or reported to the sponsor about the
drug, particularly with respect to adverse drug effects and safe use.
- ERGOMED CLINICAL RESEARCH, LTD. will monitor all Adverse Drug
Experiences (ADRs) occurring in Europe and USA and submit to FDA all
reports of such Adverse Drug Experiences.
- ERGOMED CLINICAL RESEARCH, LTD. will monitor the progress of all
clinical investigations in Europe and USA being conducted under IND
37,088.
- If ERGOMED CLINICAL RESEARCH, LTD. discovers that a European or USA
investigator is not in compliance with the signed agreement (FDA form
FD-1572), the investigational plan or the requirements of the
applicable regulations, ERGOMED CLINICAL RESEARCH, LTD. will promptly
attempt to secure the investigator's compliance or discontinue
European or USA shipments of the investigational drug and device
products to the European or American investigator and end the
participation of the investigator in the study. If the investigator's
participation is ended, ERGOMED CLINICAL RESEARCH, LTD. will secure
the disposition of all unused European or USA investigational products
and return the investigational product in compliance to 21 CFR Part
312.59 and also notify FDA.
- ERGOMED CLINICAL RESEARCH, LTD. will maintain adequate records showing
the receipt, shipment, and all other dispositions of the European and
USA investigational products. The records will include the name of the
European and USA investigator to whom the products are shipped
including the date, quantity and batch or identifying code number/mark
of each shipment.
- ERGOMED CLINICAL RESEARCH, LTD. will retain records for the
transferred responsibilities for at least 2 years as required under
the regulations after the application is approved or, if the
application is not approved until 2 years after the
2
last shipment of the investigational items is discontinued and upon
FDA notification.
- ERGOMED CLINICAL RESEARCH, LTD. will ensure the return of all unused
European clinical supplies of investigational products from each
European and USA investigator whose participation in the study is
discontinued. ERGOMED CLINICAL RESEARCH, LTD. may authorize
alternative disposition of unused European or USA supplies provided
the alternative does not expose humans to risks from the drug.
- ERGOMED CLINICAL RESEARCH, LTD. will maintain written records of any
European or USA disposition of the drug in accordance with 21 CFR Part
312.57
If you have any questions, please contact me at your earliest convenience.
Sincerely,
Xxxxx Xxxx Xxxxxxxxx, DDS, XX
Xx. Director, Legal and Regulatory Affairs
3
