Journal Article

A randomized Bayesian phase I-II dose optimization design for combination cancer therapies with progression-free survival end point

Qiu, Yingjie, Li, Mingyue

2025

Overview

Background Combination therapies involving novel agents, such as immunotherapies and targeted therapies, offer significant antitumor benefits by increasing dose intensity, targeting multiple pathways, and benefiting a broader patient population. To further explore these advantages, the National Cancer Institute (NCI) has initiated Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH) to evaluate the effectiveness of new drug combinations in treating both adults and children. However, designing dose optimization trials for these combination therapies presents substantial challenges due to the complex interactions and unique mechanisms of action. Methods To address these challenges, we propose COMPACT, a Bayesian phase I-II randomized design for combination cancer therapies that uses progression-free survival (PFS) as the primary efficacy endpoint to identify the optimal dose combination (ODC) based on restricted mean survival time (RMST). The COMPACT design jointly evaluates both toxicity and PFS, with continuous toxicity monitoring throughout the trial. Toxicity probabilities are modeled using a partial ordering assumption without relying on complex parametric models, while PFS is modeled through a Bayesian Pareto proportional hazards model with gamma-shared frailty. The trial consists of two seamlessly connected stages. In the first stage, the dose space is explored primarily based on toxicity, while PFS data are concurrently collected. In the second stage, patients are adaptively randomized to safe and potentially promising dose combinations based on PFS, and the dose combination with the highest RMST among those deemed safe is selected as the ODC. Results Simulation studies demonstrate that COMPACT has desirable operating characteristics and outperforms conventional designs in identifying the ODC, allocating more patients to ODC, while maintaining patient safety. Sensitivity analysis is performed to examine the robustness of the proposed design. A trial example is provided to facilitate the practical implementation of the proposed COMPACT design. Conclusions The proposed COMPACT design offers a novel and robust framework for combination cancer therapies with progression-free survival end point.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Antimitotic agents / Antineoplastic agents / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Bayes Theorem / Bayesian adaptive design / Cancer / Cancer therapies / Care and treatment / Chemotherapy / Clinical trials / Clinical Trials, Phase I as Topic - methods / Clinical Trials, Phase II as Topic - methods / Dosage and administration / Dose optimization / Dose-Response Relationship, Drug / Drug combination / Drug dosages / Drug therapy, Combination / FDA approval / Health Sciences / Humans / Immunotherapy / Mathematical functions / Medicine / Medicine & Public Health / Methods / Neoplasms - drug therapy / Neoplasms - mortality / Neoplasms - therapy / Optimization / Patient safety / Phase I–II trials / Progression-Free Survival / Randomized Controlled Trials as Topic - methods / Research Design / Statistical Theory and Methods / Statistics for Life Sciences / Testing / Theory of Medicine/Bioethics / Toxicity