Investigational New Drugs

, Volume 28, Issue 6, pp 839–843

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

  • Nicolas Penel
  • Pierre Leblond
  • Amélie Lansiaux
  • Stéphanie Clisant
  • Eric Dansin
  • Antoine Adenis
  • Jacques Bonneterre
PHASE I STUDIES

DOI: 10.1007/s10637-009-9317-6

Cite this article as:
Penel, N., Leblond, P., Lansiaux, A. et al. Invest New Drugs (2010) 28: 839. doi:10.1007/s10637-009-9317-6

Summary

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.

Keywords

Accrual timePhase 1 clinical trialsMethodology

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Nicolas Penel
    • 1
    • 2
  • Pierre Leblond
    • 3
  • Amélie Lansiaux
    • 4
    • 5
  • Stéphanie Clisant
    • 6
  • Eric Dansin
    • 1
  • Antoine Adenis
    • 7
  • Jacques Bonneterre
    • 5
    • 8
  1. 1.Département de Cancérologie GénéraleCentre Oscar LambretLilleFrance
  2. 2.Equipe d’Accueil 2694: Santé Publique, Epidémiologie et modélisation des maladiesUniversité de Lille IILilleFrance
  3. 3.Unité d’Oncologie PédiatriqueCentre Oscar LambretLilleFrance
  4. 4.Laboratoire de Pharmacologie anti-tumoraleCentre Oscar LambretLilleFrance
  5. 5.Département Universitaire de CancérologieUniversité de Lille IILilleFrance
  6. 6.Unité de Recherche CliniqueCentre Oscar LambretLilleFrance
  7. 7.Département de Cancérologie Urologique et DigestiveLilleFrance
  8. 8.Département de SénologieCentre Oscar LambretLilleFrance