Risks and benefits associated with novel phase 1 oncology trial designs

BACKGROUND. Although aggressive dose escalation strategies were designed to improve the risk‐benefit profile of phase 1 oncology trials, they have not been adequately studied. The prevalence of several novel trial designs and their association with a variety of clinical endpoints was evaluated. METHODS. A review of the literature was performed to identify phase 1 oncology studies of cytotoxic agents published from 2002 through 2004. RESULTS. Of 955 phase 1 oncology articles initially identified, 149 studies, comprising 4532 patients, were analyzed. Only 34% of studies utilized aggressive dose escalation schemes, 22% permitted intrapatient dose escalation, and only 28% enrolled fewer than 3 patients to any dose level. Studies that allowed intrapatient dose escalation or used fewer than 3 patients per dose were not associated with different rates of response or toxicity, nor did they increase the number of patients who received the recommended phase 2 dose. However, aggressive dose escalations were associated with increased rates of both hematologic (17% vs 10%) and nonhematologic (17% vs 13%) toxicity with similar response rates. Only studies that used conservative dose escalation designs and those that studied U.S. Food and Drug Administration (FDA)‐approved agents required fewer patients to complete a trial. Trials of FDA‐approved agents were also associated with higher response rates than trials of non‐FDA‐approved agents (10% vs 2%), without an increased risk of toxicity. CONCLUSIONS. Several novel aggressive design strategies intended to improve the risk‐benefit profile of phase 1 oncology trials are not associated with improved clinical outcome, and may be harmful in certain instances. Cancer 2007. Published 2007 American Cancer Society. Several novel aggressive design strategies intended to improve the risk‐benefit profile of phase 1 oncology trials, including allowing intrapatient dose escalation, escalating doses by increasing increments, and using fewer patients per dose level, are not associated with improved clinical outcome, and may be harmful in certain instances. Further research aimed at improving phase 1 oncology clinical trial design should focus on alternative strategies.