Journal of Clinical Oncology, Vol 19, Issue 8
(April), 2001: 2319-2333
© 2001 American Society for Clinical Oncology
Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients With Refractory Neoplasms
By Edward A. Sausville,
Susan G. Arbuck,
Richard Messmann,
Donna Headlee,
Kenneth S. Bauer,
Richard M. Lush,
Anthony Murgo,
William D. Figg,
Tyler Lahusen,
Susan Jaken,
Xiu-xian Jing,
Michel Roberge,
Eiichi Fuse,
Takashi Kuwabara,
Adrian M. Senderowicz
From the Developmental Therapeutics Program Clinical Trials Unit, Medicine Branch, and Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; Department of Pathology, College of Medicine, University of Vermont, Burlington, VT; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada; and Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co, Ltd, Shizuoka, Japan.
Address reprint requests to Edward A. Sausville, MD, PhD, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Executive Plaza North Building, Ste 8000, 6130 Executive Blvd, Rockville, MD 20852; email: Sausville{at}nih.gov
PURPOSE: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV).
PATIENTS AND METHODS: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed.
RESULTS: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m2/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. 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/m2/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m2/d for 3 days included mean total plasma concentration of 36.4 µM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G2 checkpoint.
CONCLUSION: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.
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