Department of Experimental Statistics, Louisiana State University, Baton Rouge, Louisiana, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Biometrics. 2023 Dec;79(4):2907-2919. doi: 10.1111/biom.13840. Epub 2023 Mar 6.
In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to optimize the dose of oncology drugs. DROID consists of two seamlessly connected stages. In the first stage, patients are sequentially enrolled and adaptively assigned to investigational doses to establish the therapeutic dose range (TDR), defined as the range of doses with acceptable toxicity and efficacy profiles, and the recommended phase 2 dose set (RP2S). In the second stage, patients are randomized to the doses in RP2S to assess the dose-response relationship and identify the optimal dose. The simulation study shows that DROID substantially outperforms the conventional approach, providing a new paradigm to efficiently optimize the dose of targeted oncology drugs. DROID aligns with the approach of a randomized, parallel dose-response trial design recommended by the FDA in the Guidance on Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases.
在靶向治疗时代，人们越来越关注基于几十年前为化疗开发的“越多越好”范式的肿瘤药物的发展。最近，美国食品和药物管理局（FDA）启动了 Optimus 项目，以改革肿瘤药物开发中的剂量优化和选择范式。为了适应这一范式转变，我们提出了一种用于肿瘤药物临床试验的剂量优化方法（DROID）。DROID 利用了经过充分验证的剂量范围研究框架，该框架几十年来一直被用于开发非肿瘤药物，并将其与已建立的肿瘤剂量发现设计相结合，以优化肿瘤药物的剂量。DROID 由两个无缝连接的阶段组成。在第一阶段，患者按顺序入组，并适应性地分配到研究剂量，以确定治疗剂量范围（TDR），即具有可接受的毒性和疗效特征的剂量范围，以及推荐的 2 期剂量集（RP2S）。在第二阶段，患者随机分配到 RP2S 中的剂量，以评估剂量反应关系并确定最佳剂量。模拟研究表明，DROID 显著优于传统方法，为高效优化靶向肿瘤药物的剂量提供了一种新的范式。DROID 与 FDA 在《优化治疗肿瘤疾病的人用处方药和生物制品剂量的指南》中推荐的随机平行剂量反应试验设计方法一致。
