UCN-01, Fluorouracil, and Leucovorin in Treating Patients With Metastatic or Unresectable Solid Tumors

OBJECTIVES:

• Determine the maximum tolerated dose of fluorouracil when given in combination with UCN-01 and leucovorin calcium in patients with metastatic or unresectable solid tumors.
• Determine the clinical toxic effects of this regimen in these patients.
• Determine the pharmacokinetics of these drugs in these patients.
• Correlate, if possible, the pharmacokinetics of these drugs with clinical toxicity in these patients.
• Assess the pharmacodynamic effects of these drugs in these patients.
• Assess any clinical activity of this regimen in patients with measurable disease.

OUTLINE: This is a dose-escalation study of fluorouracil (5-FU).

Patients receive leucovorin calcium (CF) IV over 2 hours and 5-FU IV (at the midpoint of CF administration) on day 1, followed by UCN-01 IV over 36-72 hours, on weeks 1-3. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of 5-FU until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. The recommended phase II dose (RPIID) is defined as the dose preceding the MTD. At least 6 additional patients are treated at the RPIID.

PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study within 16 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor that is metastatic or unresectable and for which no standard curative or palliative measures exist or are effective
• No brain metastases or primary CNS malignancy

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,500/mm3
• Platelet count at least 100,000/mm3

Hepatic

• Bilirubin no greater than 1.5 mg/dL
• AST and ALT no greater than 3 times upper limit of normal

Renal

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

Cardiovascular

• No known active coronary artery disease

Pulmonary

• No pulmonary dysfunction

Other

• HIV negative
• No history of unusually severe and/or prolonged toxicity during prior therapy with fluorouracil (5-FU) or 5-FU prodrugs
• No diabetes mellitus requiring insulin or oral hypoglycemic therapy
• No ongoing or active infection requiring IV antibiotics
• No other serious concurrent medical illness that would preclude study
• No psychiatric illness or social situations that would preclude study
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 4 weeks since prior immunotherapy and recovered
• No concurrent cytokines during the first course of therapy

Chemotherapy

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

Endocrine therapy

• No concurrent systemic corticosteroids

Radiotherapy

• At least 2 weeks since prior radiotherapy and recovered
• No prior pulmonary or mediastinal radiation exceeding 40 Gy

Surgery

• Recovered from prior surgery

Other

• No other concurrent investigational agents
• No concurrent cimetidine
• No concurrent sorivudine or brivudine