Combining cytotoxic agents with continuous dose levels in seamless phase I-II clinical trials

TL;DR

This paper introduces a novel two-stage clinical trial design for combining cytotoxic agents with continuous dose levels, improving efficiency by utilizing all collected data across stages in a single patient population.

Contribution

It proposes a new adaptive design that integrates toxicity and efficacy data across stages, unlike traditional methods that discard efficacy data after stage I.

Findings

The design effectively identifies optimal dose combinations.

Simulation results demonstrate improved trial efficiency.

The method is validated with a real case study.

Abstract

Phase I-II cancer clinical trial designs are intended to accelerate drug development. In cases where efficacy cannot be ascertained in a short period of time, it is common to divide the study in two stages: i) a first stage in which dose is escalated based only on toxicity data and we look for the maximum tolerated dose (MTD) set and ii) a second stage in which we search for the most efficacious dose within the MTD set. Current available approaches in the area of continuous dose levels involve fixing the MTD after stage I and discarding all collected stage I efficacy data. However, this methodology is clearly inefficient when there is a unique patient population present across stages. In this article, we propose a two-stage design for the combination of two cytotoxic agents assuming a single patient population across the entire study. In stage I, conditional escalation with overdose control (EWOC) is used to allocate successive cohorts of patients. In stage II, we employ an adaptive randomization approach to allocate patients to drug combinations along the estimated MTD curve, which is constantly updated. The proposed methodology is assessed with extensive simulations in the context of a real case study.