Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms

Purpose: To define the maximum tolerated dose (MTD) and dose-limiting toxic ity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurospo rine), administered as a 72-hour continuous intravenous infusion(CIV). Patients and Methods: Forty-seven patients with refractory neoplasms receiv ed UCN-01 during this phase I trial. Total, free plasma, and salivary conce ntrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylat ion state of the protein kinase C (PKC) substrate alpha-adducin and the abr ogation of DNA damage checkpoint also were assessed. Results: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 m g/m(2)/d for 3 days. Avid plasma protein binding of UCN-01,as measured duri ng the trial, dictated a change in dose escalation and administration sched ules. Therefore, nine patients received drug on the initial 2-week schedule , and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m( 2)/d for 3 days included hyperglycemia with resultant metabolic acidosis, p ulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic de terminations at the recommended dose of 42.5 mg/m(2)/d for 3 days included mean total plasma concentration of 36.4 muM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 1 4.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concen tration was 111 nmol/L of UCN-01. One partial response was observed in a pa tient with melanoma, and one protracted period ( > 2.5 years) of disease st ability was observed in a patient with alk-positive anaplastic large-cell l ymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substr ate phosphorylation and the DNA damage-related Gp checkpoint. Conclusion: UCN-01 can be administered safely as an initial 72-hour CIV wit h subsequent monthly doses administered as 36-hour infusions. (C) 2001 by A merican Society of Clinical Oncology.