Challenges and Innovations in Phase I Dose-Finding Designs for Molecularly Targeted Agents and Cancer Immunotherapies.

Jun Yin,Shihao Shen

doi:10.4172/2155-6180.1000324

Abstract

Phase I oncology trials are designed to identify a safe dose with an acceptable toxicity profile. In traditional phase I dose-finding design, the dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle. The recent development of molecularly targeted agents and cancer immunotherapies call for new innovations in phase I designs, because of prolonged treatment cycles often involved. Various phase I designs using toxicity and efficacy endpoints from multiple treatment cycles have been developed for these new treatment agents. Here, we will review the novel endpoints and designs for the phase I oncology clinical trials.

Highlights

Phase I clinical trials are designed to identify the recommended phase II dose (RP2D) for follow-up trials
Recent observations indicate that the majority of the dose-limiting toxicity (DLT) occurred after the first treatment cycle in multiple phase I oncology clinical trials
molecular targeted agents (MTAs) and cancer immunotherapies last for longer treatment cycles than the cytotoxic agents, so that it becomes more important to account for the late-cycle toxicity events and lasting effect of minor toxicity events

Summary

Introduction

Phase I clinical trials are designed to identify the recommended phase II dose (RP2D) for follow-up trials. Recent observations indicate that the majority of the DLT occurred after the first treatment cycle in multiple phase I oncology clinical trials This provides the rationale for a variety of dose-finding designs to take into account toxicities from subsequent cycles of treatment. To account for the minor toxicity events (¡ grade 3) over multiple treatment cycles, a Bayesian phase I design was developed [12] to incorporate the total toxicity profile (TTP), a quasi-continuous toxicity endpoint, in the dose estimation from toxicity data of multiple treatment cycles. New phase I oncology clinical trial designs are proposed to use both the toxicity and early efficacy endpoints in the dose-finding. A bivariate normal distribution is used as the joint model of toxicity and efficacy: In which, P is a bivariate normal distribution and Z is a continuous latent variable related to the binary toxicity endpoint

Findings

Discussion

Conclusion