title: Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience.
abstract: The main aim of phase I trials is to evaluate the tolerability and pharmacology of a new compound. However, investigating the potential for clinical benefit is also a key objective. Our phase I trial portfolio incorporates a range of new drugs, including molecular targeted agents, sometimes given together with cytotoxic agents. We performed this analysis of response rate, progression-free (PFS) and overall survival (OS) to assess the extent of clinical benefit rate (CBR: partial response (PR)+stable disease (SD)) derived from current trials. We analysed 212 consecutive patients who were treated in 29 phase I studies, from January 2005 to June 2006. All patients had progression of disease prior to study entry. The median age was 58 years (range: 18-86) with a male/female ratio of 2 : 1. A total of 148 patients (70%) were treated in 'first in human trials' involving biological agents (132 patients) or new cytotoxic compounds (16 patients) alone, and 64 patients (30%) received chemotherapy-based regimens with or without biological agents. After a median follow-up time of 34 weeks, the median PFS and OS were 11 and 43 weeks, respectively. The CBR was 53% (9% PR and 44% SD) after the first tumour evaluation after two cycles (between weeks 6 and 8) and has been maintained at 36 and 26% at 3 and 6 months, respectively. Treatment related deaths occurred in 0.47% of our patients and treatment had to be withdrawn in 11.8% of patients due to toxicity. A multivariate analysis (MVA) of 13 factors indicated that low albumin (<35 g l(-1)), lactate dehydrogenase>upper normal limit and >2 sites of metastasis were independent negative prognostic factors for OS. A risk score based on the MVA revealed that patients with a score of 2-3 had a significantly shorter OS compared to patients with a score of 0-1 (24.9 weeks, 95% CI 19.5-30.2 vs 74.1 weeks, 95% CI 53.2-96.2). This analysis shows that a significant number of patients who develop disease progression while receiving standard therapy derived benefit from participation in phase I trials. Risk scoring based on objective clinical parameters indicated that patients with a high score had a significantly shorter OS, and this may help in the process of patient selection for phase I trial entry.
authors: Royal Marsden Hospital, Institute of Cancer Research, Downs Road, Sutton SM2 5PT, UK.
authors: H-T
authors: HT
authors: Arkenau
authors: D
authors: D
authors: Olmos
authors: J E
authors: JE
authors: Ang
authors: J
authors: J
authors: de Bono
authors: I
authors: I
authors: Judson
authors: S
authors: S
authors: Kaye
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017321:Clinical Trials, Phase I as Topic; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome