Phase 1 Oncology Clinical Trials for Related Subpopulations: The Power Walk Design
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0092-86 I5/2002 Copyright
0 2002 Drug Information Association Inc.
PHASE 1 ONCOLOGY CLINICAL TRIALS FOR RELATED SUBPOPULATIONS: THE POWER WALK DESIGN* GEORGENE SCHROEDER, MS, JEFFA. SLOAN,PHD, STEPHENCHA,MS, PAMELAATHERTON, MS, CRISTINEALLMER,BS, AND CHARLES ERLICHMAN, MD Mayo Clinic and Mayo Foundation, Rochester, Minnesota
Motivcrtion/Background: This paper addresses designing a Phase 1 trial where the doseresponse curve differs across patient subpopulations. We examine a design which “power walks” through clinically ineffective dose levels, accruing from either subpopulation, until dose limiting toxicity appears. The design then splits into two Phase 1 trials for each subpopulation. Methods/Results: We performed simulation studies of I0000 Phase 1 trials comparing the “power walk” design to the alternatives. The power walk design correctly estimates the maximum tolerated dose (MTD) up to 20% more ojien. The power walk design performs best with a steep dose-response curve, and overestimates the MTD roughly 10% of the time. Conclusions: The power walk design is appropriate to obtain MTDs for separate patient subpopulations where the initial dose is clinically ineffective or substantially below the MTD. A power walk design study involves fewer patients and achieves the correct MTD more ofen. The power walk design is not recommended when the initial dose level is near the MTD. Key Words: Oncology; Phase 1 trial; Heterogeneous subpopulations; Simulation studies; Dose-response curve
INTRODUCTION ONE OF THE WELL known limitations to the generalizability of Phase 1 clinical trial results is the heterogeneity of the patient population under study (1,2). Although it is possible to unduly restrict the eligibility criteria to a homogeneous subpopulation, it will limit the accrual rate. However, situations do arise where there is reason to suspect that specific
Reprint address: Jeff A. sloan, PhD. 6-129 Charlton Building, 200 First Street SW, Rochester, MN 55905 (e-mail: [email protected]). *This work was suppofled by grants CA15083-24, CA69912-04. and CA25224.
patient subpopulations will react differently to a pharmaceutical agent in terms of the MTD. Running concurrent Phase 1 trials to obtain separate MTD estimates would seem inefficient and potentially expose a greater number of patients to risk. Ignoring the differences in subpopulations and running a single Phase 1 trial would likely result in an inaccurate estimate of the MTD. We present and examine a method for obtaining separate MTD estimates for related subpopulations in a single Phase 1 trial. The power walk design allows for unrestricted accrual into a single Phase 1 trial from two subpopulations until an incidence of dose limiting toxicity is observed. At that point,
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separate accrual streams for each subpopulation are initiated so that MTD estimates are obtained for each subpopulation.
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