Phase I/II adaptive design for drug combination oncology trials

Abstract

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose-toxicity and dose-efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents.

Keywords: adaptive randomization; continual reassessment method; dose finding; drug combination; phase II.

Figure 1

Operating characteristics of the proposed design and Yuan and Yin [19]. Each bar represents the proportion of times that each method recommended target combination(s) as the ODC at the conclusion of a simulated phase I/II trial with a maximum sample size of N = 80 patients.