MC-Keyboard: A Practical Phase I Trial Design for Targeted Therapies and Immunotherapies Integrating Multiple-Grade Toxicities

Authors

Liyun Jiang
Zhulin Yin
Fangrong Yan
Ying Yuan

Publication Date

8-1-2024

Journal

Journal of Immunotherapy and Precision Oncology

Abstract

In targeted therapies and immunotherapies, the occurrence of low-grade (e.g., grade 1-2) toxicities (LGT) is common, while dose-limiting toxicities (DLT) are relatively rare. As a result, conventional phase I trial designs, solely based on DLTs and disregarding milder toxicities, are problematic when evaluating these novel therapies.

Methods: To address this issue, we propose a novel phase I design called a multiple-constraint keyboard (MC-Keyboard) that integrates multiple toxicity constraints, accounting for both DLT and LGT, for precise dose escalation and de-escalation, and identification of the maximum tolerated dose (MTD). As a model-assisted design, an important feature of MC-Keyboard is that its dose-escalation or de-escalation rule can be pretabulated and incorporated into the trial protocol before the initiation of the trial, greatly simplifying its implementation.

Results: The simulation study showed that the MC-Keyboard had high accuracy in identifying the MTD and is safer than some existing designs.

Conclusion: The MC-Keyboard provides a novel, simple, and safe approach to assessing safety and identifying the MTD for targeted therapies and immunotherapies.

Keywords

mmunotherapy, targeted therapies, dose finding, model-assisted designs, toxicity grade, multiple-toxicity constraints

DOI

10.36401/JIPO-23-35

PMID

39219992

PMCID

PMC11361345

PubMedCentral® Posted Date

8-19-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes