Fluorouracil Plus UCN-01 in Treating Patients With Advanced or Refractory Solid Tumors

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

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. UCN-01 may increase the effectiveness of a chemotherapy drug by making tumor cells more sensitive to the drug.

PURPOSE: Phase I trial to study the effectiveness of fluorouracil plus UCN-01 in treating patients who have advanced or refractory 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.

PROJECTED ACCRUAL: Approximately 6-48 patients will be accrued for this study within approximately 14 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor that is refractory to standard therapy or for which no standard therapy exists
• Measurable or evaluable disease
• No CNS metastasis or primary CNS malignancy

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• Not specified

Hematopoietic:

• WBC greater than 3,500/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• SGOT and SGPT no greater than 2.5 times upper limit of normal

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance greater than 60 mL/min

Cardiovascular:

• No history of coronary artery disease documented by prior myocardial infarction, angiography, or coronary-artery bypass grafting
• No cardiac arrhythmias or congestive heart failure within the past 6 months
• Stable atrial fibrillation on standard treatment allowed at discretion of investigator

Pulmonary:

• DLCO at least 60% of predicted

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 months after study
• No active serious or uncontrolled infection
• HIV negative
• No diabetes
• No other medical condition that would preclude study

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

Biologic therapy:

• At least 4 weeks since prior immunotherapy and recovered

Chemotherapy:

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin) and recovered
• Prior fluorouracil allowed

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior mediastinal radiotherapy
• At least 4 weeks since prior radiotherapy and recovered

Surgery:

• Not specified

Other:

• No concurrent anticonvulsant medications