Justification of the starting dose as the main determinant of accrual time in dose-seeking oncology phase 1 trials.

INTRODUCTION

New drug development is a time- and resource-consuming process. Phase 1 trials constitute a major key-step of this development. Shortening the accrual time is of major importance.

METHODS

292 published phase-1-trials were retrospectively reviewed to establish the determinants of accrual time using Log-rank test and then Cox Model.

RESULTS

Out of 292 trials (1997-2008), only 107 reports (36%) described the accrual time (median: 20 months, 5-72). Phase-2-recommended dose was established in 87 studies (81%). Most studies investigated regimens including cytotoxic drugs (77%) or molecular targeted therapies (29%). Under univariate analysis, two parameters shortened the accrual time: studies conducted in USA vs. other places (19 vs. 21 months p = 0.03) and regimen with more than 2 dose-escalated drugs (13 vs. 21 months, p = 0.003). One parameter was significantly associated with longer accrual time: starting dose justified by animal toxicology data vs. previous clinical trials (22 vs. 19 months, p = 0.03). Most of parameters did not significantly affect the accrual time: nature of investigated drugs, duration of treatment cycle, phase 1 dedicated to specific tumoral subtypes, number of centers, method of drug escalation (classical 3+3 vs. accelerated titration design), type of increment (modified Fibonacci method vs. others) and presence of expansion of cohort at the phase-II-recommended dose. Cox model analysis retained one determinant: starting dose justified by animal toxicology data: HR = 2.00 [1.45-5.20], p = 0.047.

CONCLUSION

Few parameters influence the accrual time of dose-escalation phase-1 trials. Real first-in-man phase 1 studies based on starting dose estimated from animal toxicological data require longer accrual time.