title: Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter?
abstract: Phase-I trials traditionally involve dose-escalation to determine the maximal tolerated dose (MTD). With conventional chemotherapy, efficacy is generally deemed to be dose-dependent, but the same may not be applicable to molecularly targeted agents (MTAs). We analysed consecutive patients included in Phase-I trials at the Royal Marsden Hospital from 5 January 2005 to 6 June 2006. We considered only trials of monotherapy MTAs in which the MTD was defined. Three patient cohorts (A, B, and C) were identified according to the dose received as a percentage of the final trial MTD (0-33%, 34-65%, >66%). Potential efficacy was assessed using the non-progression rate (NPR), that is, complete/partial response or stable disease for at least 3 months by RECIST. A total of 135 patients having progressive disease before enrolment were analysed from 15 eligible trials. Median age was 57 years (20-86); male : female ratio was 1.8 : 1. Cohort A, B, and C included 28 (21%), 22 (16%), and 85 (63%) patients; NPR at 3 and 6 months was 21% and 11% (A), 50% and 27% (B), 31% and 14% (C), respectively, P=0.9. Median duration of non-progression (17 weeks; 95% CI=13-22) was not correlated with the MTD level, P=0.9. Our analysis suggests that the potential for clinical benefit is not confined to patients treated at doses close to the MTD in Phase-I trials of MTAs.
authors.affiliation: Royal Marsden Hospital and The Institute of Cancer Research, Drug Development Unit, Downs Road, SM2 5PT, Sutton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Postel-Vinay
authors.forename: H-T
authors.initials: HT
authors.lastname: Arkenau
authors.forename: D
authors.initials: D
authors.lastname: Olmos
authors.forename: J
authors.initials: J
authors.lastname: Ang
authors.forename: J
authors.initials: J
authors.lastname: Barriuso
authors.forename: S
authors.initials: S
authors.lastname: Ashley
authors.forename: U
authors.initials: U
authors.lastname: Banerji
authors.forename: J
authors.initials: J
authors.lastname: De-Bono
authors.forename: I
authors.initials: I
authors.lastname: Judson
authors.forename: S
authors.initials: S
authors.lastname: Kaye
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic / Q000592:standards* / Q000706:statistics & numerical data; D018450:Disease Progression; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D018579:Patient Selection; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents