Continual Reassessment Method for a First-In-Human Trial: From Design to Trial Implementation

• Activity Number: 30
• Type: Contributed
• Date/Time: Sunday, August 3, 2014 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Inna Perevozskaya*+ and Lixin Han and Kristen Pierce
• Companies: Pfizer and Infinity Pharmaceuticals and Pfizer
• Keywords: continual-reassessment method ; first-in-humans trials ; dose-limiting toxicity ; Maximum Tolerated Dose ; adaptive designs ; adaptive trial case study

Abstract

We present a case study of a Phase 1 oncology dose-escalation trial utilizing modified Continual Reassessment Method (CRM). Learning about the dose-toxicity relationship and choosing the correct Maximum Tolerated Dose (MTD) to take forward into Phase II is one of the most challenging research questions in Phase 1 oncology trials. CRM is a Bayesian adaptive design targeting a specific Dose Limiting Toxicity (DLT) rate, e.g. 25%. Similar to the traditional 3+3 designs used in oncology Phase 1 trials, learning about drug's toxicity profile with CRM occurs in real time. However, since CRM algorithm incorporates dose-toxicity modelling in the learning process, its ability to identify the correct Maximum Tolerated Dose is substantially improved, compared to the traditional 3+3 design.

This presentation will cover first CRM trial designed and executed within Pfizer. We present the whole "story" of the trial from beginning to end, including selection of study design, assessment of its operating characteristics via simulations, execution, study results and lessons learned.