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

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)

URL: https://www.ncbi.nlm.nih.gov/pubmed/15699481
DOI: 10.1200/JCO.2005.03.116

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: http://repository.cshl.edu/id/eprint/33660

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving