Newell McElwee, PharmD, MSPH

Merck Research Labs

Center for Outcomes and Real World Evidence

14 April 2015

Adaptive Design in MerckOncology Studies

Adaptive designs are not new …

• Thompson WR. Biometrika 1944; 25: 285-294

• Ellenberg SS. Statis Med 2012; 31:2798-2804

• Adaptive design methodology in RCTs evolved starting in the 1950’s … but adoption was slow until the 1990’s when the FDA created an adaptive trial pathway for devices. (Ellenberg)

Extra-Corporeal Membrane Oxygenation (ECMO)

Acknowledgements

Many people within Merck have contributed to the planning, design, and execution of the adaptive trials used in our pembrolizumab program. These include:

• Keaven Anderson, Ph.D. (Biostatistics)• Cong Chen, Ph.D. (Biostatistics)• Christine Gause, Ph.D. (Biostatistics)• Eric Rubin, M.D. (Clinical Research)

Outline

• Types of designs– Dose-finding– Single-arm response rate studies– Comparative studies– Bayesian study design

• Driving theme: Biomarker-selected patient populations

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Dose-Finding Designs

• Modified TPI (toxicity profile interval) designs– Very specific Bayesian design– Dose escalation and de-escalation are table-driven

• No need for computer interaction like CRM designs

– Preferred of traditional 3+3 designs• Start similarly• Allow confirmation of dose with further

adaptation beyond 6 patients• Simple execution

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Single-arm Response Rate Studies

• Very high response rates allow possible early access for patients– Single arm studies where no effective therapy exists– Biomarker-selected population

• Evaluate in both biomarker-positive and biomarker-negative patients

• Designs allow evaluation of effectiveness in biomarker-positive and all-comer populations

• Early interim analysis to discontinue biomarker-negative patients if no responses

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Comparative Studies

• Dual primary endpoints:– Overall survival (OS)– Progression-free survival

• Multiple populations evaluated (depending on study)– Overall– Biomarker positive– Biomarker strong-positive

• Possible early adaptation– Discontinue biomarker negative– Interim filing for PFS– Early stop for both PFS and OS (e.g., Keynote-006)

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Bayesian Adaptive Studies

• I-SPY 2 (ispy2.org)– “..an innovative public-private collaboration that

combines Personalized Medicine & Novel Trial Design to develop new cancer treatments much faster and for much less cost.”

• Neoadjuvant phase 2 breast cancer study– Accelerated development– Adaptive biomarker and drug selection to generate

high probability of success in Phase 3

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