Using Continual Reassessment Method to Design an Intracerebral Hemorrhage Trial to Estimate Maximum Tolerated Dose

• Activity Number: 615
• Type: Contributed
• Date/Time: Wednesday, August 12, 2015 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Harry Shi and Inna Perevozskaya* and Gerry Li
• Companies: Pfizer Inc. and Pfizer Inc. and Pfizer Inc.
• Keywords: Continual Reassessment Method ; Intracerebral Hemorrhage ; Thromboembolic and Ischemic Event ; Maximum Tolerated Dose ; Modified Toxicity Probability Interval ; 3+3 design

Abstract

Continual Reassessment Method (CRM) and its various modifications are Bayesian adaptive designs used in early-phase oncology drug development to estimate the Maximum Tolerated Dose (MTD) of the experimental drug. CRM incorporates dose-toxicity modeling to guide dose-escalation as trial progresses. Compared to more traditional algorithmic designs (e.g. 3+3), CRM provide more flexibility and precision in dose escalation/de-escalation, resulting in more desirable properties in estimating the MTD. Most examples of CRM application are seen in oncology area, but its use began to spread to other therapeutic areas. In this presentation, we discuss a case study of applying CRM to a Phase 1b dose-escalation trial in Intracerebral Hemorrhage (ICH) population. The unique challenges associated with this therapeutic area include vague definition of MTD (based on thromboembolic and ischemic events), narrow range of doses to be explored and dose-toxicity profiles different from those typically seen in oncology. We illustrate how CRM can be adapted from oncology applications to accommodate ICH population unique challenges. Other dose-escalation schemes (3+3, mTPI) are also considered.