Joint TITE-CRM for Dual Agent Dose Finding Studies

TL;DR

This paper introduces two new model-based designs, Joint TITE-POCRM and Joint TITE-BLRM, for dual-agent dose-finding trials with late-onset safety and activity outcomes, demonstrating superior performance over existing methods.

Contribution

The paper develops and compares two innovative model-based methods for dual-agent dose-finding with late-onset outcomes, addressing a gap in current trial design approaches.

Findings

Both proposed methods outperform the comparator in simulations.

The two models show comparable performance overall.

Performance varies across different scenarios.

Abstract

Dual agent dose-finding trials study the effect of a combination of more than one agent, where the objective is to find the Maximum Tolerated Dose Combination (MTC), the combination of doses of the two agents that is associated with a pre-specified risk of being unsafe. In a Phase I/II setting, the objective is to find a dose combination that is both safe and active, the Optimal Biological Dose (OBD), that optimizes a criterion based on both safety and activity. Since Oncology treatments are typically given over multiple cycles, both the safety and activity outcome can be considered as late-onset, potentially occurring in the later cycles of treatment. This work proposes two model-based designs for dual-agent dose finding studies with late-onset activity and late-onset toxicity outcomes, the Joint TITE-POCRM and the Joint TITE-BLRM. Their performance is compared alongside a model-assisted comparator in a comprehensive simulation study motivated by a real trial example, with an extension to consider alternative sized dosing grids. It is found that both model-based methods outperform the model-assisted design. Whilst on average the two model-based designs are comparable, this comparability is not consistent across scenarios.