Risks and benefits of phase 1 oncology trials, 2001 through 2012.

Abstract

2552 Background: The primary objective of phase I clinical trials is to evaluate the tolerability and pharmacokinetics of a new agent. Phase I trials in oncology remain ethically controversial. Our previous analysis from year 1991 through 2002 reported a response rate of 10.6 percent and a toxicity-related death rate of 0.49 percent. An increasing number of molecular targeted agents are under investigation and these results may not reflect current phase I oncology trials. Methods: We reviewed all non-pediatric phase 1 oncology trials sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute between January 1, 2001 and December 31, 2012. We report the rates of response to treatment, of stable disease, of grade 4 toxic events, and of treatment-related deaths. Results: We analyzed 286 trials, comprising 8314 participants. All 8314 participants were evaluated for toxic events, whereas 6604 participants were evaluated for response. The overall response rate (complete and partial response) and disease control rate (complete and partial response and stable disease) were higher than in the previous analysis. (13.2 percent vs 10.6 percent, p-value < 0.0001, 52.6 percent vs 34.1 percent, p-value < 0.0001, respectively.) 1651 participants (19.86 percent) experienced at least one grade 4 toxic event that was at least possibly related to the treatment. The overall rate of death at least possibly related to the treatment was 0.99 percent. The overall rates of death due to toxic events and grade 4 toxic events were both higher than in the previous analysis. (1.02 percent vs 0.49 percent, p –value < 0.0001, 19.86 percent vs 14.3 percent, p-value < 0.0001, respectively.) All p-values reported are 2-sided. Conclusions: The rates of response and toxicity in non-pediatric phase 1 oncology trials were higher than in the previous analysis and more than 50 percent of patients achieved at least stable disease. The higher disease control rate may be due to greater use of cytostatic molecularly targeted agents. More toxic-related deaths were reported, but this may be because of the change in serious adverse events reporting requirements by the FDA. Rate of death that was probably or definitely related to the treatment remained stable at about 0.2 percent.