Factors Influencing Time to Determination of the Recommended Phase 2 Dose in Phase 1 Clinical Trials

Abstract

Cancer clinical trials are the means to develop safe and effective novel treatment options for patients. The longer it takes for these trials to reach the recommended phase 2 dose (RP2D), the fewer therapy options are available to patients and physicians. The purpose of this study is to examine the factors that delay RP2D determination in phase 1 clinical trials. Thirty-five consecutive phase 1 clinical trials for advanced solid tumors that started between February 2006 and March 2009 in a single institution were examined for inclusion. Factors potentially contributing to trial delays were analyzed against time to determination of an RP2D (TDR). Thirty-one phase 1 clinical trials met the inclusion criteria and were included in the statistical analysis. Investigational agents under evaluation included single agent cytotoxic (N=4), monoclonal antibody (N=3), single agent cytostatic/targeted (N=16), or combination of an investigational agent and commercially available systemic chemotherapy (N=8). A protocol defined phase 2 dose decreased the TDR (P<0.001). Other factors that significantly increased TDR included a larger minimum estimated patient sample size (P=0.022), a greater number of predefined dose levels (P<0.001), and a higher number of expansion cohorts (P=0.038). Including a predefined phase 2 dose and reducing the number of dose levels and expansion cohorts may shorten phase 1 trial TDR.