Ma Clement, Shulman David S, Al-Sayegh Hasan, DuBois Steven G, London Wendy B
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Harvard Medical School, Boston, MA.
JCO Precis Oncol. 2024 Dec;8:e2400360. doi: 10.1200/PO.24.00360. Epub 2024 Dec 23.
Novel therapies targeting specific genomic alterations are a promising treatment approach for relapsed/refractory cancer. Patients with specific alterations may be more likely to respond. Trial designs should maximize opportunities for such patients to enroll on these trials. Existing designs do not enrich for patients with specific alterations. We developed the adaptive Targeted Agent-Continual Reassessment Method (TARGET-CRM) to optimize dose finding and enrich for patients with specific alterations, and applied it in a pediatric phase I trial.
Patients were stratified to cohort A (unspecified tumors) or cohort B (rare genomic alterations). The TARGET-CRM design permits cohort B patients to immediately enroll at one dose level below the currently evaluated dose level instead of waiting for an open slot at the current dose level. Using simulations, we compared the operating characteristics (accuracy-the proportion of trials in which the true maximum tolerated dose [MTD] was identified/recommended; safety-the dose-limiting toxicity [DLT] rate; the proportion of cohort B patients enrolled) of the TARGET-CRM, standard CRM, and 3 + 3 designs across various scenarios.
The proportion of enrolled patients who were cohort B was higher for TARGET-CRM (90%-100%) compared with CRM (approximately 85%) and 3 + 3 (approximately 79%). The DLT rate and rate the true MTD was recommended were similar for TARGET-CRM and CRM, differing by only 0%-4% and 0%-4%, respectively. Results were similar regardless of trial sample size and proportion of cohort B patients in the population.
In phase I dose-finding trials of targeted agents, the Bayesian adaptive TARGET-CRM design maximizes enrollment of patients hypothesized as most likely to benefit from the targeted agent, while maintaining similar or superior accuracy and safety as the CRM and 3 + 3 designs.
针对特定基因组改变的新型疗法是复发/难治性癌症一种很有前景的治疗方法。具有特定改变的患者可能更易产生反应。试验设计应最大程度地为这类患者提供参与这些试验的机会。现有设计并未富集具有特定改变的患者。我们开发了适应性靶向药物连续重新评估方法（TARGET-CRM）以优化剂量探索并富集具有特定改变的患者，并将其应用于一项儿科I期试验。
患者被分层至队列A（未明确肿瘤类型）或队列B（罕见基因组改变）。TARGET-CRM设计允许队列B的患者立即在低于当前评估剂量水平的一个剂量水平入组，而不是等待当前剂量水平有空缺。通过模拟，我们比较了TARGET-CRM、标准CRM和3+3设计在各种情况下的操作特性（准确性——确定/推荐真实最大耐受剂量[MTD]的试验比例；安全性——剂量限制毒性[DLT]率；队列B入组患者的比例）。
与CRM（约85%）和3+3（约79%）相比，TARGET-CRM队列B入组患者的比例更高（90%-100%）。TARGET-CRM和CRM的DLT率以及推荐真实MTD的比例相似，分别仅相差0%-4%和0%-4%。无论试验样本量和队列B患者在总体中的比例如何，结果均相似。
在靶向药物的I期剂量探索试验中，贝叶斯适应性TARGET-CRM设计在保持与CRM和3+3设计相似或更优准确性和安全性的同时，最大程度地使假设最可能从靶向药物中获益的患者入组。
