Kortmansky, J., Shah, M. A., Kaubisch, A., Weyerbacher, A., Yi, S., Tong, W., Sowers, R., Gonen, M., O'Reilly, E., Kemeny, N., Ilson, D. I., Saltz, L. B., Maki, R. G., Kelsen, D. P., Schwartz, G. K. (March 2005) 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. J Clin Oncol, 23 (9). pp. 1875-84. ISSN 0732-183X (Print)0732-183X (Linking)
Abstract
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/m(2) over 72 hours in cycle 1 and 67.5 mg/m(2) 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/m(2) 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 micromol/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/m(2).
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Adult Aged Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use Area Under Curve Female Fluorouracil/administration & dosage/adverse effects/pharmacokinetics Half-Life Humans Infusions, Intravenous Male Middle Aged Neoplasms/*drug therapy Protein Kinase Inhibitors/administration & dosage/adverse effects/pharmacokinetics Staurosporine/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics Treatment Outcome |
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > prognosis |
| CSHL Authors: | |
| Communities: | CSHL labs > Maki lab |
| Depositing User: | Matt Covey |
| Date: | 20 March 2005 |
| Date Deposited: | 26 Oct 2016 20:30 |
| Last Modified: | 26 Oct 2016 20:30 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33660 |
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