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Abstract
Combination therapy of two antitumor agents may provide treatment additivity or synergy. Phase I trials for combination therapy search for the maximum tolerated dose (MTD) for combined agents. The conventional approach is to preselect an escalation path, usually increasing the dose of one agent and then another, and to use the standard 3 + 3 design. However, this procedure may miss the optimum dose combination, prolong the time it takes, and increase the number of patients necessary to reach the MTD. In this study, we present strategies for a comprehensive search for MTD for a two-agent combination therapy. We evaluate algorithms based on two-stage and three-stage design as well as variations in cohort size. A two-dimensional isotonic estimation method for toxicity rate is provided. We use simulation methods to compare 2 + 1 + 3 vs. 3 + 3 cohort sizes. We conclude that the comprehensive search proposed in our study can be more practical and efficient in identifying the MTD in combination-therapy of two agents.
Notes
The row and column heads represent the dose levels from 1 (lowest), 2 (middle), to 3 (highest) for 2 agents. The number in the cells represents a combination of two dose levels from two agents, with the first number for agent 1 and second for agent 2.
The number in each dose combination represents the DLT used in simulation experiment. The bolded values are dose combinations for which we will consider appropriate if a trial selects them as MTD. Scenarios 1 and 3 represents different level of asymmetry in DLT and Scenario 2 is for a symmetric DLT structure.
Combinations as the acceptable recommendations of MTD defined in Table 2 are in bold. Combinations with DLT over 40% are in italic. Results are derived from 10,000 simulations.
Combinations as the acceptable recommendations of MTD defined in Table 2 are in bold. Combinations with DLT over 40% are in italic. Results are derived from 10,000 simulations.