Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience

• Published in: British journal of cancer Vol. 98; no. 6; pp. 1029 - 1033
• Main Authors: Arkenau, H-T, Olmos, D, Ang, J E, de Bono, J, Judson, I, Kaye, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.03.2008; Nature Publishing Group
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Clinical outcomes; Clinical Study; Clinical Trials, Phase I as Topic; Disease Progression; Drug Resistance; Epidemiology; Female; Humans; Male; Medical sciences; Middle Aged; Molecular Medicine; Oncology; Patient Selection; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome; Tumors; phase I trial; prognostic factors; outcome; survival; Human; Cancerology; Prognosis; Treatment; Phase I trial; Hospital; Survival
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6604218

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 Treatment related deaths occurred in 0.47% of our patients and treatment had to be withdrawn in 11.8% of patients due to toxicity.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.