Extension of Interval Design to Finding Maximum Tolerated Combinations of Two Anti-Cancer Agents

• Activity Number: 321
• Type: Contributed
• Date/Time: Tuesday, August 6, 2013 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Lixin Han*+ and Stephanie Green
• Companies: Pfizer and Pfizer
• Keywords: dose limiting toxicity ; maximum tolerated dose ; maximum tolerated combination ; toxicity probability interval ; cumulative cohort design ; optimal interval design

Abstract

As the number of anti-cancer agents of different mechanisms increases, it has become increasingly important to investigate combinations of agents. Often the first step is to find the maximum tolerated combinations (MTC) of two agents. Methodologies for MTC finding are often extension of methodologies employed to find the maximum tolerated dose (MTD) for a single agent. One category of successful MTD finding methods is "interval design." In this work, the interval design is explored for MTC finding in the setting of two-agent combinations. The rule of combination assignment is similar to the rule of dose assignment in the single agent setting: if the observed toxicity rate is lower than the lower bound of the interval, escalate, possibly to two neighboring combinations, and subject to certain restrictions; if the observed toxicity rate is higher than the upper bound of the interval, de-escalate, possibly to two neighboring combinations; otherwise, stay at the current combination. At the completion of the MTC finding trial, isotonic estimates of toxicity rates are used to find MTC(s). Simulations have shown that the proposed method is feasible and advantageous in some settings.