Finding the Biologically Optimal Dose with Early Efficacy Biomarkers in Phase I Cancer Clinical Trials

• Activity Number: 407
• Type: Topic Contributed
• Date/Time: Tuesday, August 6, 2013 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Rui Qin*+
• Companies: Mayo Clinic
• Keywords: phase I clinical trial ; efficacy biomarker ; biologically optimal dose ; Bayesian design

Abstract

Toxicity remains the primary endpoint for dose escalation in phase I cancer clinical trials. However, the maximally tolerated dose (MTD) is not necessarily provide optimal efficacy with novel targeted and vaccine therapies. In comparison to cytotoxic agents, these novel therapies usually carry mild toxicity profile and the probability of efficacy does not always increase with dose escalation. Early efficacy biomarkers for these therapies shall be incorporated in the determination of the biologically optimal dose (BOD) in phase I cancer clinical trials.

Several novel dose-finding designs have been proposed in recent years to determine the BOD. We will discuss appropriate clinical scenarios for those novel designs to be implemented in cancer clinical trials. Statistical models and estimation will be unified in a Bayesian framework utilizing utility function of toxicity and efficacy. The operating characteristics of these novel dose-finding designs will be compared through simulations under various scenarios. We will explore the criteria for selecting an early efficacy biomarker and the practical challenges to incorporate it into dose escalation.