Accelerated Titration Designs for Phase I Clinical Trials in Oncology

作者：Richard Simon, Larry Rubinstein, Susan G. Arbuck, Michaele C. Christian, Boris Freidlin, Jerry M. Collins · 发表于：JNCI Journal of the National Cancer Institute · 年份：1997 · DOI：10.1093/jnci/89.15.1138 · 被引用次数：642 · 研究领域：Statistical Methods in Clinical Trials、Cancer Treatment and Pharmacology、Cancer Genomics and Diagnostics

BACKGROUND: Many cancer patients in phase I clinical trials are treated at doses of chemotherapeutic agents that are below the biologically active level, thus reducing their chances for therapeutic benefit. Current phase I trials often take a long time to complete and provide little information about interpatient variability or cumulative toxicity. PURPOSE: Our objective was to develop alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information (i.e., cumulative toxicity and maximum tolerated dose) needed to plan phase II trials is obtained. METHODS: We fit a stochastic model to data from 20 phase I trials involving the study of nine different drugs. We then simulated new data from the model with the parameters estimated from the actual trials and evaluated the performance of alternative phase I designs on this simulated data. Four designs were evaluated. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial...