A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors

Purpose: To define the maximum tolerated dose and the dose-limiting toxicity of the kinase modulator UCN-01 administered as a short (1-3 hours) infusion to patients with refractory solid tumors and to evaluate the pharmacokinetics of this novel agent. Experimental Design: Twenty-four patients (15 men, 9 women; median age, 59 years; Eastern Cooperative Oncology Group Performance Status, 0-2) were treated with UCN-01 in this phase I study. Using an accelerated titration design, six dose levels were evaluated ranging from 3 mg/m² over 3 hours to 95 mg/m² over 1 to 3 hours administered every 28 days. Plasma, urine, and saliva samples were collected for pharmacokinetic analysis. Results: Seventy courses were evaluable for toxicity. The most frequent adverse events were grade 1 to 2 nausea, vomiting, hyperglycemia, and hypotension. Hypotension was dose limiting at 95 mg/m ² when UCN-01 was administered over 1 hour. The recommended dose of UCN-01 as a short infusion is 95 mg/m² over 3 hours for the first course and 47.5 mg/m² over 3 hours for second and subsequent courses. No objective responses were observed. Mean (SD) pharmacokinetic variable values in nine patients treated at 95 mg/m² over 3 hours were volume of distribution at steady state, 14 (5.4) L; β half-life, 406 (151) hours; systemic clearance, 0.028 (0.017) L/h; C_max, 51 (16) μmol/L; and area under the curve, 19,732 (12,195) μmol/L h. Conclusions: UCN-01 is well tolerated when given at doses of 95 mg/m² over 3 hours every 28 days with second and subsequent courses given at 50% of the first course dose.