RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing
so they stop growing or die. Combining more than one drug may kill more tumor cells.
PURPOSE: Phase I trial to study the effectiveness of combination chemotherapy in treating
patients who have advanced solid tumors.
- Determine the recommended phase II dose of irinotecan, leucovorin calcium, and
fluorouracil in patients with advanced solid tumors.
- Determine the toxic effects of this regimen in these patients.
- Determine the pharmacokinetic and pharmacodynamic profiles of irinotecan and
fluorouracil in patients treated with this regimen.
- Determine the correlation of polymorphisms in the promoter region of the thymidylate
synthase gene with clinical toxicity and response in patients treated with this
- Determine the correlation of polymorphisms in the uridine diphosphate
glucuronosyltransferase 1A1 gene promoter with the extent of SN-38 glucuronidation and
severity of diarrhea in patients treated with this regimen.
- Assess any anti-tumor activity of this regimen in these patients.
OUTLINE: This is a dose-escalation study of irinotecan and fluorouracil.
Patients receive irinotecan IV continuously over 24 hours on days 1 and 15 and leucovorin
calcium IV over 30 minutes followed by fluorouracil IV continuously over 48 hours on days 2
and 16. Treatment repeats every 28 days for at least 2 courses in the absence of disease
progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of irinotecan until the maximum tolerated
dose (MTD) is determined. Once the MTD of irinotecan has been determined, additional cohorts
receive escalating doses of fluorouracil until the MTD is determined. The MTD is defined as
the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting
PROJECTED ACCRUAL: Approximately 40 patients will be accrued for this study within 20
- Histologically confirmed advanced solid tumor that has failed standard therapy or for
which no standard therapy exists
- Locally advanced, unresectable, primary or recurrent disease OR
- Metastatic disease
- Previously untreated disease allowed provided this regimen represents reasonable
- No leukemia or lymphoma
- No primary CNS malignancy or CNS metastases
- 18 and over
- ECOG 0-2
- Not specified
- Absolute granulocyte count at least 2,000/mm^3
- Platelet count at least 100,000/mm^3
- Bilirubin no greater than 1.6 mg/dL
- AST/ALT no greater than 4 times upper limit of normal
- Creatinine no greater than 1.6 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- HIV negative
- No other serious concurrent illness that would preclude study
- No active infection requiring IV antibiotics
- No known hypersensitivity to irinotecan
- No marked intolerance to fluorouracil
PRIOR CONCURRENT THERAPY:
- More than 4 weeks since prior immunotherapy and recovered
- More than 4 weeks since prior chemotherapy (at least 6 weeks for nitrosoureas or
mitomycin) and recovered
- Prior short-infusion irinotecan allowed
- Prior fluorouracil allowed
- Not specified
- At least 2 weeks since prior radiotherapy and recovered
- At least 8 weeks since prior strontium chloride Sr 89
- Recovered from prior surgery
- No concurrent cimetidine