Pembrolizumab Dose Sample Clauses

Pembrolizumab Dose. The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the totality of data generated in the Keytruda® development program, 200 mg Q3W is the appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type. As outlined below, this dose is justified by: • Clinical data from 8 randomized studies demonstrating flat dose- and exposure- efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), • Clinical data showing meaningful improvement in benefit-risk including overall survival at 200 mg Q3W across multiple indications, and • Pharmacology data showing full target saturation in both systemic circulation (inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 200 mg Q3W Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and exposure-response relationships across the doses studied representing an approximate 5- to 7.5 fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat dose-exposure- response relationships were also observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, and not via direct binding to cancer cells. Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expression. This evaluation concluded that pembroliz...
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  • Commercialization BMS, its Affiliates and Sublicensees shall be entitled to continue to sell (but not to actively promote after the effective date of termination) any existing inventory of Products in each terminated Region of the Territory for which Regulatory Approval and all pricing and reimbursement approvals therefor have been obtained (provided that such Products shall have launched in each such terminated country as of the applicable effective date of termination), in accordance with the terms and conditions of this Agreement, for a period not to exceed [***] from the effective date of such termination (the “Commercialization Wind-Down Period”). Any Products sold or disposed of by BMS, its Affiliates or Sublicensees during the Commercialization Wind-Down Period shall be subject to the same Total Compensation under Section 8.5 as would have applied had this Agreement otherwise remained in force and effect with respect to such terminated Product(s) and terminated Region(s). After the Commercialization Wind-Down Period, BMS, its Affiliates and Sublicensees shall not sell such terminated Products in such terminated Region(s) or make any representation regarding BMS’s status as a licensee of such Product in such Region(s). Either (i) at the request of BN at the end of the Commercialization Wind-Down Period or (ii) prior to the end of the Commercialization Wind-Down Period, if BN has assumed responsibilities for regulatory activities under the Regulatory Approval, has received all clearances and Regulatory Approvals needed to sell and import the terminated Product in a given terminated country, and provides written notice to BMS that it wishes to assume sale of the terminated Product in a terminated country, then, in either case (i) or (ii), at BN’s election, BMS shall sell and transfer to BN such portion of the terminated Product inventory then held by BMS or its Affiliates which is in a saleable condition (including that it is undamaged, has been stored in proper conditions and has no less than [***] shelf-life remaining) as had been allocated to the terminated Region(s) [***]. This Section 12.7(b) shall not apply in the case of termination by BMS under Section 12.2(b) based on Safety Reasons.

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