Flexible Use of Copula-Type Model for Dose-Finding in Drug Combination Clinical Trials

• Activity Number: 385 - Biomarkers, Endpoint Validation and Other Topics
• Type: Contributed
• Date/Time: Thursday, August 12, 2021 : 12:00 PM to 1:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Koichi Hashizume* and Jun Tsuchida and Takashi Sozu
• Companies: Graduate School of Engineering, Tokyo University of Science and Doshisha University and Faculty of Engineering, Tokyo University of Science
• Keywords: Combining drugs; Copula regression; Maximum tolerated dose; Oncology; Phase I trial; Synergistic toxicity

Abstract

Identifying the maximum tolerated dose combination (MTDC) is a critical objective for oncology phase I drug combination trials. Copula-type models (CTM) used for dose-finding exhibit distinct advantages over other models used in existing competitive designs. For example, their application enables the consideration of dose-limiting toxicities attributable to each of the two agents. However, if combination therapies exhibit extreme synergistic toxicity, CTMs are liable to induce biases due to the Frechet–Hoeffding (F-H) bounds. Consequently, the dose-finding performance may be worse than those of other competitive designs. This study was designed to improve the performance of the design based on CTMs while maintaining the useful properties of CTM. We propose an extension of the parameter space of the interaction term in CTMs. This method releases the F-H bounds, making the estimation of toxicity probabilities more flexible. Simulation studies revealed that the performance (e.g., the proportion of MTDC selection) of this method is better than that of the existing CTMs and comparable with those of other competitive designs, irrespective of the existence of extreme synergistic toxicity.