Originally published as JCO Early Release 10.1200/JCO.2005.03.116 on February 7 2005

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Phase I Trial of the Cyclin-Dependent Kinase Inhibitor and Protein Kinase C Inhibitor 7-Hydroxystaurosporine in Combination With Fluorouracil in Patients With Advanced Solid Tumors

From the Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; Program of Molecular Pharmacology and Experimental Therapeutics; and Departments of Pediatrics and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Gary K. Schwartz, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: schwartg{at}mskcc.org

PURPOSE: Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01.

PATIENTS AND METHODS: FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m² over 72 hours in cycle 1 and 67.5 mg/m² over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction.

RESULTS: We escalated the weekly FU dose to 2,600 mg/m² in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 µmol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines.

CONCLUSION: The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m².

Supported by National Cancer Institute grant No. U01-CA69856.

Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001 and the American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer Molecular Targets and Cancer Therapeutics Meeting, Miami, FL, October 29-November 2, 2001.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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