A Phase I Study of the Cyclin-Dependent Kinase (CDK)/Protein Kinase C (PKC) Inhibitor UCN-01 (NSC 638850) in Combination With 5-Fluorouracil in Patients With Advanced Solid Tumors

OBJECTIVES:

• Determine the maximum tolerated dose, dose limiting toxicity, and toxicity profile of fluorouracil with UCN-01 in patients with advanced or refractory solid tumors.
• Assess the clinical pharmacokinetics of this regimen and correlate with observed toxicities in these patients.
• Obtain preliminary data on the therapeutic activity of this regimen in these patients.

OUTLINE: This is a dose escalation study of fluorouracil.

Patients receive fluorouracil IV over 24 hours on days 1, 8, 15, and 22. Patients receive an initial dose of UCN-01 IV over 72 hours beginning on day 2 during course 1 and then maintenance UCN-01 IV over 36 hours beginning on day 2 during subsequent courses. Treatment repeats every 4 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of fluorouracil until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose limiting toxicity.