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208742 
Journal Article 
Letter 
Indifferently pursued or unowned drugs: who should lead where companies do not tread?[comment] 
Sausville, EA 
2005 
Yes 
Journal of Clinical Oncology
ISSN: 0732-183X
EISSN: 1527-7755 
23 
9 
1796-1798 
English 
15699481 
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). 
*Antineoplastic Agents/tu [Therapeutic Use]; *Drug Industry; Humans; *Neoplasms/dt [Drug Therapy]; *Orphan Drug Production; *Protein Kinase Inhibitors/tu [Therapeutic Use]; *Staurosporine/aa [Analogs & Derivatives]; *Staurosporine/tu [Therapeutic Use]; 0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 112953-11-4 (7-hydroxystaurosporine); 62996-74-1 (Staurosporine)