This document discusses adaptive clinical trial designs used by Merck for oncology studies. It provides examples of different types of adaptive designs including: 1) Dose-finding designs like modified toxicity profile interval designs that allow for dose escalation and de-escalation in a table-driven manner. 2) Single-arm response rate studies that can provide early access for patients and allow early interim analyses to discontinue biomarker-negative patient populations if no responses are found. 3) Comparative studies with dual primary endpoints of overall survival and progression-free survival that can adapt based on biomarker-selected patient populations at interim analyses. 4) Bayesian adaptive studies like I-SPY 2 that

1. Newell McElwee, PharmD, MSPH
Merck Research Labs
Center for Outcomes and Real World Evidence
14 April 2015
Adaptive Design in Merck
Oncology Studies

2. 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)

3. Extra-Corporeal Membrane Oxygenation
(ECMO)

4. 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)

5. 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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6. 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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7. 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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8. 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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9. 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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