Dual-criterion Dose Finding Designs Based on Dose-Limiting Toxicity and Tolerability

TL;DR

This paper introduces dual-criterion dose finding designs for Phase I oncology trials that incorporate both dose-limiting toxicity and tolerability to better identify safe and effective doses for targeted therapies.

Contribution

It proposes novel model-based and model-assisted dual-criterion designs that improve dose-finding accuracy by considering both toxicity and tolerability, especially for therapies with delayed or low-grade toxicities.

Findings

Dual-criterion designs outperform traditional DLT-based methods when intolerance drives dose decisions.

The proposed methods perform comparably to traditional methods when DLT is the primary concern.

Real-time decision-making is facilitated despite pending data in long assessment windows.

Abstract

The primary objective of Phase I oncology trials is to assess the safety and tolerability of novel therapeutics. Conventional dose escalation methods identify the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). However, as cancer therapies have evolved from chemotherapy to targeted therapies, these traditional methods have become problematic. Many targeted therapies rarely produce DLT and are administered over multiple cycles, potentially resulting in the accumulation of lower-grade toxicities, which can lead to intolerance, such as dose reduction or interruption. To address this issue, we proposed dual-criterion designs that find the MTD based on both DLT and non-DLT-caused intolerance. We considered the model-based design and model-assisted design that allow real-time decision-making in the presence of pending data due to long event assessment windows. Compared to DLT-based methods, our approaches exhibit superior operating characteristics when intolerance is the primary driver for determining the MTD and comparable operating characteristics when DLT is the primary driver.