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

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 Treatment related deaths occurred in 0.47% of our patients and treatment had to be withdrawn in 11.8% of patients due to toxicity.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