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

Investigational New Drugs - Tập 28 - Trang 839-843 - 2009
Nicolas Penel1,2, Pierre Leblond3, Amélie Lansiaux4,5, Stéphanie Clisant6, Eric Dansin1, Antoine Adenis7, Jacques Bonneterre5,8
1Département de Cancérologie Générale, Centre Oscar Lambret, Lille, France
2Equipe d’Accueil 2694: Santé Publique, Epidémiologie et modélisation des maladies, Université de Lille II, Lille, France
3Unité d’Oncologie Pédiatrique, Centre Oscar Lambret, Lille, France
4Laboratoire de Pharmacologie anti-tumorale, Centre Oscar Lambret, Lille, France
5Département Universitaire de Cancérologie, Université de Lille II, Lille, France
6Unité de Recherche Clinique, Centre Oscar Lambret, Lille, France
7Département de Cancérologie Urologique et Digestive, Lille, France
8Département de Sénologie, Centre Oscar Lambret, Lille, France

Tóm tắt

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.

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Investigational New Drugs

Tập 28

839-843

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