RATIONALE: Drugs used in chemotherapy, such as irinotecan, work in different ways to stop
tumor cells from dividing so they stop growing or die. Celecoxib may stop the growth of
tumor cells by blocking the enzymes necessary for their growth. Giving irinotecan with
celecoxib may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of irinotecan when
given with celecoxib in treating patients with unresectable or metastatic colorectal cancer.
- Determine the maximum tolerated dose of irinotecan when administered with celecoxib in
patients with unresectable or metastatic colorectal cancer.
- Determine the dose-limiting toxic effects and non-dose-limiting toxic effects of this
regimen in these patients.
- Determine the incidence and intensity of diarrhea and myelotoxicity in patients treated
with this regimen.
- Determine any responses in patients treated with this regimen.
- Determine potential mechanisms for irinotecan-induced diarrhea and protective effects
of celecoxib on diarrhea prevention in patients treated with this regimen.
OUTLINE: This is a dose-escalation study of irinotecan. Patients are assigned to 1 of 2
- Group I: Patients receive a fixed dose of irinotecan IV over 90 minutes on days 1, 8,
15, and 22 and oral celecoxib twice daily on days 10-42. Courses repeat every 42 days
in the absence of disease progression or unacceptable toxicity.
- Group II: Patients receive irinotecan as in group I at escalating doses and oral
celecoxib twice daily on days 0-42. Treatment continues as in group I.
Cohorts of 3-6 patients receive escalating doses of irinotecan until the maximum tolerated
dose (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 toxicity.
PROJECTED ACCRUAL: A total of 18-30 patients (9 for group I, 9-21 for group II) will be
accrued for this study within 1-2 years.
- Histologically confirmed colorectal cancer
- Metastatic or unresectable disease
- Failed first-line or second-line therapy OR recurred after receiving
fluorouracil-based adjuvant chemotherapy
- No known brain metastases
- 18 and over
- ECOG 0-2 OR
- Karnofsky 60-100%
- More than 12 weeks
- Absolute neutrophil count ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- WBC ≥ 3,000/mm^3
- AST and ALT ≤ 2.5 times upper limit of normal
- Bilirubin normal
- No Gilbert's disease
- Creatinine normal OR
- Creatinine clearance ≥ 60 mL/min
- No symptomatic congestive heart failure
- No unstable angina pectoris
- No cardiac arrhythmia
- Able to receive oral medications
- No prior inflammatory bowel disease
- No active ulcer disease or gastritis
- No contraindications for sigmoidoscopy
- No active colostomy
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 3 months after study
- No prior allergic reaction to compounds of similar chemical or biological composition
to irinotecan, celecoxib, sulfonamides, or other study agents
- No active or ongoing infection
- No other concurrent uncontrolled illness
- No psychiatric illness or social situation that would preclude study compliance
PRIOR CONCURRENT THERAPY:
- No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF)
- See Disease Characteristics
- No more than 2 prior different chemotherapy regimens, including adjuvant therapy
- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
- No prior irinotecan
- Not specified
- More than 4 weeks since prior radiotherapy and recovered
- No prior radiotherapy of more than 3,000 cGy
- No prior radiotherapy to extended marrow-generating fields
- No prior abdomino-pelvic irradiation
- No prior abdominoperineal resection
- More than 2 weeks since prior cyclo-oxygenase-2 (COX-2) inhibitors
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No other concurrent investigational agents
- No other anticancer therapy
- No other concurrent COX-2 inhibitors
- Low-dose aspirin allowed