Introduction

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.

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Competing Interests

Conflicts of Interest: None.

Author notes

Sources of Support: The research of Drs Jiang and Yan was supported in part by National Natural Science Foundation of China (funding nos. 82304252 and 82273735).

This work is published under a CC-BY-NC-ND 4.0 International License.

Supplementary data