Ali A Mokdad1,2,3, Xian-Jin Xie4, Hong Zhu2,5, David E Gerber2,5,6, Daniel F Heitjan3,5. 1. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. 2. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern, Dallas, Texas. 3. Department of Statistical Science, Southern Methodist University, Dallas, Texas. 4. College of Dentistry and College of Public Health, University of Iowa, Iowa City, Iowa. 5. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas. 6. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
Abstract
BACKGROUND: Phase I cancer trials increasingly incorporate dose-expansion cohorts (DECs), reflecting a growing demand to acquire more information about investigational drugs. Protocols commonly fail to provide a sample-size justification or analysis plan for the DEC. In this study, we develop a statistical framework for the design of DECs. METHODS: We assume the maximum tolerated dose (MTD) for the investigational drug has been identified in the dose-escalation stage of the trial. We use the 80% lower confidence bound and the 90% upper confidence bound for the response and toxicity rates, respectively, as decision thresholds for the dose-expansion stage. We calculate the operating characteristics with reference to prespecified minimum effective response rates and maximum safe DLT rates. RESULTS: We apply our framework to specify a system of DEC plans. The design comprises three components: 1) the number of subjects enrolled at the MTD, 2) the minimum number of responses necessary to indicate provisional drug efficacy, and 3) the maximum number of dose-limiting toxicities (DLTs) permitted to indicate drug safety. We demonstrate our method in an application to a cancer immunotherapy trial. CONCLUSIONS: Our simple and practical tool enables creation of DEC designs that appropriately address the safety and efficacy objectives of the trial.
BACKGROUND: Phase I cancer trials increasingly incorporate dose-expansion cohorts (DECs), reflecting a growing demand to acquire more information about investigational drugs. Protocols commonly fail to provide a sample-size justification or analysis plan for the DEC. In this study, we develop a statistical framework for the design of DECs. METHODS: We assume the maximum tolerated dose (MTD) for the investigational drug has been identified in the dose-escalation stage of the trial. We use the 80% lower confidence bound and the 90% upper confidence bound for the response and toxicity rates, respectively, as decision thresholds for the dose-expansion stage. We calculate the operating characteristics with reference to prespecified minimum effective response rates and maximum safe DLT rates. RESULTS: We apply our framework to specify a system of DEC plans. The design comprises three components: 1) the number of subjects enrolled at the MTD, 2) the minimum number of responses necessary to indicate provisional drug efficacy, and 3) the maximum number of dose-limiting toxicities (DLTs) permitted to indicate drug safety. We demonstrate our method in an application to a cancer immunotherapy trial. CONCLUSIONS: Our simple and practical tool enables creation of DEC designs that appropriately address the safety and efficacy objectives of the trial.
Authors: Julie R Brahmer; Charles G Drake; Ira Wollner; John D Powderly; Joel Picus; William H Sharfman; Elizabeth Stankevich; Alice Pons; Theresa M Salay; Tracee L McMiller; Marta M Gilson; Changyu Wang; Mark Selby; Janis M Taube; Robert Anders; Lieping Chen; Alan J Korman; Drew M Pardoll; Israel Lowy; Suzanne L Topalian Journal: J Clin Oncol Date: 2010-06-01 Impact factor: 44.544