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Targeted-Agent Continual Reassessment Method: A Novel Bayesian Enrichment Design for Phase I Trials of Molecularly
Clement Ma1,2, David S Shulman1,2, Hasan Al-Sayegh1
1Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
The novel TARGET-CRM design improves enrollment of cancer patients with rare genomic alterations in early-phase trials. This adaptive method optimizes dose finding while maintaining trial safety and accuracy compared to traditional designs.
Area of Science:
- Oncology
- Clinical Trial Design
- Genomics
Background:
- Targeted therapies offer promise for relapsed/refractory cancers, with patient response often linked to specific genomic alterations.
- Optimizing clinical trial designs to enroll patients with these specific alterations is crucial for treatment development.
- Current trial designs often fail to enrich for patients most likely to benefit from targeted agents.
Purpose of the Study:
- To develop and evaluate the adaptive Targeted Agent-Continual Reassessment Method (TARGET-CRM) for optimizing dose finding in early-phase oncology trials.
- To enhance the enrollment of patients with specific genomic alterations in phase I trials.
- To compare the performance of TARGET-CRM against standard CRM and 3+3 designs.
Main Methods:
- Patients were stratified into cohorts based on tumor type and presence of rare genomic alterations.
- The TARGET-CRM design allowed patients with rare genomic alterations to enroll at a lower dose level.
- Simulations were used to compare the accuracy, safety (DLT rate), and enrollment proportion of cohort B patients across different trial designs.
Main Results:
- TARGET-CRM achieved higher enrollment of patients with rare genomic alterations (90%-100%) compared to CRM (~85%) and 3+3 (~79%).
- The dose-limiting toxicity (DLT) rate and accuracy in identifying the maximum tolerated dose (MTD) were comparable between TARGET-CRM and CRM.
- These findings remained consistent across various trial sample sizes and patient population compositions.
Conclusions:
- The Bayesian adaptive TARGET-CRM design effectively maximizes enrollment of patients likely to respond to targeted agents in phase I dose-finding trials.
- TARGET-CRM demonstrates similar or superior accuracy and safety compared to traditional CRM and 3+3 designs.
- This adaptive design represents a significant advancement for trials involving targeted therapies in oncology.
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