A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints

Abstract

There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose-efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information-theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information-theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single-agent and dual-agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model-based alternative under scenarios with nonmonotonic dose/combination-efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.

Keywords: Phase I/II clinical trial; combination trial; continuous endpoint; nonmonotonic efficacy.

Figure 1

The logistic transformation (3) for (i) ${\alpha }^{\ast }=0,{\beta }^{\ast }=-1$ (dotted line), (ii) ${\alpha }^{\ast }=-4.6,{\beta }^{\ast }=-1$ (dashed line) and (iii) ${\alpha }^{\ast }=-4.6,{\beta }^{\ast }=-1.5$ (solid line)

Figure 2

Proportion of OBR selections under different combinations of toxicity and efficacy steps

Figure 3

The logistic transformation using the lowest efficacy bound $p_e=0.01$ (solid line) and the lowest efficacy bound $p_e=0.50$ (dashed line)