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

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Abstract

Objective:

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.

Methods:

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).

Results:

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).

Conclusions:

Including a predefined phase 2 dose and reducing the number of dose levels and expansion cohorts may shorten phase 1 trial TDR.

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