Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control.
We present a Bayesian adaptive design for dose finding of a combination of two drugs in cancer phase I clinical trials. The goal is to estimate the maximum tolerated dose (MTD) as a curve in the two-dimensional Cartesian plane. We use a logistic model to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity. The model is re-parameterized in terms of parameters clinicians can easily interpret. Trial design proceeds using univariate escalation with overdose control, where at each stage of the trial, we seek a dose of one agent using the current posterior distribution of the MTD of this agent given the current dose of the other agent. At the end of the trial, an estimate of the MTD curve is proposed as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial design and percent of dose recommendation at dose combination neighborhoods around the true MTD curve. We also examine the performance of the approach under model misspecifications for the true dose-toxicity relationship.
Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd., Los Angeles, CA, 90048, U.S.A.
Mourad
M
Tighiouart
Steven
S
Piantadosi
André
A
Rogatko
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001499:Bayes Theorem; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D062787:Drug Overdose / Q000517:prevention & control*; D006801:Humans; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*
D004338:Drug Combinations
cancer phase I trials; continuous dose; dose limiting toxicity; drug combination; escalation with overdose control; maximum tolerated dose