Concurrent dose-finding of a novel cancer drug with and without a second agent
Nolan A Wages1,2, Ramy R Saleh3, Thomas M Braun4
1Department of Biostatistics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
Introduction:
More complex research questions are being posed in early-phase oncology clinical trials, necessitating design strategies tailored to contemporary study objectives. This paper describes the proposed design of a Phase I trial concurrently evaluating the safety of a hematopoietic progenitor kinase-1 inhibitor (Agent A) as a single agent and in combination with an anti-PD-1 agent in patients with advanced malignancies. The study's primary objective was to concurrently determine the maximum tolerated dose (MTD) of Agent A with and without anti-PD-1 therapy among seven possible study dose levels.
Methods:
Our solution to this challenge was to apply a continual reassessment method shift model to meet the research objectives of the study.
Results:
The application of this method is described herein, and a simulation study of the design's operating characteristics is conducted. This work was developed through collaboration and mentoring between the authors at the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual AACR/ASCO Methods in Clinical Cancer Research Workshop.
Conclusions:
The aim of this manuscript is to highlight examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying modern design conditions. Although the design is presented using an investigation of Agent A with and without anti-PD-1 therapy as an illustrative example, the approach described is not specific to these agents and could be applied to other concurrent monotherapy and combination therapy studies with well-defined binary safety endpoints.
Insights
This study introduces an adaptive clinical trial design using a continual reassessment method shift model to determine the maximum tolerated dose (MTD) for Agent A, a novel cancer therapy, alone and with anti-PD-1 agents.
Area of Science:
- Oncology
- Clinical Trial Design
- Pharmacology
Background:
- Early-phase oncology trials face complex research questions requiring innovative designs.
- Evaluating novel agents like hematopoietic progenitor kinase-1 inhibitors (Agent A) necessitates tailored study strategies.
- Combination therapies, such as Agent A with anti-PD-1 agents, are increasingly important in advanced malignancies.
Purpose of the Study:
- To propose and evaluate a novel Phase I clinical trial design.
- To concurrently determine the maximum tolerated dose (MTD) of Agent A as a single agent and in combination with an anti-PD-1 agent.
- To demonstrate the flexibility of adaptive designs in meeting contemporary oncology study objectives.
Main Methods:
- Application of a continual reassessment method shift model for dose escalation.
- Concurrent evaluation of Agent A monotherapy and combination therapy with an anti-PD-1 agent.
- Simulation study to assess the operating characteristics of the proposed adaptive design.
Main Results:
- The continual reassessment method shift model was successfully applied to the proposed Phase I trial design.
- Simulations demonstrated the feasibility and operating characteristics of the adaptive design.
- The design allows for concurrent dose determination of Agent A with and without anti-PD-1 therapy.
Conclusions:
- Adaptive designs offer flexibility for complex oncology trial objectives.
- The described approach is applicable to other concurrent monotherapy and combination studies with binary safety endpoints.
- This work highlights novel design applications to facilitate future innovative trial implementations.
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