Simultaneously optimizing dose and schedule of a new cytotoxic agent.
BACKGROUND
Traditionally, phase I clinical trial designs are based upon one predefined course of treatment while varying among patients the dose given at each administration. In actual medical practice, patients receive a schedule comprised of several courses of treatment, and some patients may receive one or more dose reductions or delays during treatment. Consequently, the overall risk of toxicity for each patient is a function of both actual schedule of treatment and the differing doses used at each adminstration.


OBJECTIVE
Our goal is to provide a practical phase I clinical trial design that more accurately reflects actual medical practice by accounting for both dose per administration and schedule.


METHODS
We propose an outcome-adaptive Bayesian design that simultaneously optimizes both dose and schedule in terms of the overall risk of toxicity, based on time-to-toxicity outcomes. We use computer simulation as a tool to calibrate design parameters.


RESULTS
We describe a phase I trial in allogeneic bone marrow transplantation that was designed and is currently being conducted using our new method. Our computer simulations demonstrate that our method outperforms any method that searches for an optimal dose but does not allow schedule to vary, both in terms of the probability of identifying optimal (dose, schedule) combinations, and the numbers of patients assigned to those combinations in the trial.


CONCLUSIONS
Our design requires greater sample sizes than those seen in traditional phase I studies due to the larger number of treatment combinations examined. Our design also assumes that the effects of multiple administrations are independent of each other and that the hazard of toxicity is the same for all administrations.


CONCLUSIONS
Our design is the first for phase I clinical trials that is sufficiently flexible and practical to truly reflect clinical practice by varying both dose and the timing and number of administrations given to each patient.
Braun
Thomas M
TM
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA. tombraun@umich.edu
Thall
Peter F
PF
Nguyen
Hoang
H
de Lima
Marcos
M
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001374:Azacitidine / Q000008:administration & dosage*; D016026:Bone Marrow Transplantation; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D020714:Maximum Tolerated Dose; D012107:Research Design; D018401:Sample Size; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine