RATIONALE: UCN-01 may stop the growth of tumor cells by blocking the enzymes necessary for
tumor cell growth. Drugs used in chemotherapy use different ways to stop tumor cells from
dividing so they stop growing or die. Combining UCN-01 with chemotherapy may kill more tumor
PURPOSE: Phase I trial to study the effectiveness of combining UCN-01, fluorouracil, and
leucovorin in treating patients who have metastatic or unresectable solid tumors.
- 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
- 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
PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study within 16 months.
- 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
- 18 and over
- ECOG 0-2
- Not specified
- Absolute neutrophil count at least 1,500/mm3
- Platelet count at least 100,000/mm3
- Bilirubin no greater than 1.5 mg/dL
- AST and ALT no greater than 3 times upper limit of normal
- Creatinine no greater than 1.5 mg/dL OR
- Creatinine clearance at least 60 mL/min
- No known active coronary artery disease
- No pulmonary dysfunction
- 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:
- At least 4 weeks since prior immunotherapy and recovered
- No concurrent cytokines during the first course of therapy
- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and
- No concurrent systemic corticosteroids
- At least 2 weeks since prior radiotherapy and recovered
- No prior pulmonary or mediastinal radiation exceeding 40 Gy
- Recovered from prior surgery
- No other concurrent investigational agents
- No concurrent cimetidine
- No concurrent sorivudine or brivudine