PURPOSE A novel phase I trial design was used to determine the maximum-tolerated dose (MTD) and pharmacokinetics for penclomedine when administered as an intravenous (i.v.) infusion over 1 hour daily for 5 days, repeated every 28 days. This study also tests the feasibility of a novel two-stage design for phase I trials. PATIENTS AND METHODS Twenty-eight patients with advanced malignancy who met standard eligibility criteria were treated with i.v. penclomedine. The initial daily dose was 50 mg/m2. Dose escalations were planned using a modified Fibonacci sequence. One patient was enrolled on each dose level during the first stage of this trial. In the second stage, patients were enrolled in cohorts of three, proceeding in an up-and-down manner based on toxicities observed. MTD was determined by logistic regression analysis. Pharmacokinetic assessment was performed during the first cycle of treatment. RESULTS Dose-limiting toxicities (DLT) observed during this trial were principally neurologic and were self-limited. Although hematologic toxicity was rare, the few patients with significant hematologic changes experienced late nadirs with prolonged time to recovery. The MTD was estimated as 381 mg/m2 (80% CI, 343 to 415 mg/m2). Although there was a long elimination half-life, accumulation of penclomedine over the 5 days of administration was negligible. CONCLUSION The novel trial design used in this study was safe and appeared effective in limiting the numbers of patients treated at lower-dose levels. Reversible neurotoxicity was dose-limiting. Although the estimated MTD was 381 mg/m2, any dose within the CI would be reasonable for phase II study.
A two‐stage phase II clinical trial design with nested criteria for early stopping and efficacy