Irinotecan and Celecoxib in Treating Patients With Unresectable or Metastatic Colorectal Cancer

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of irinotecan when administered with celecoxib in patients with unresectable or metastatic colorectal cancer.

Secondary

• 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 treatment groups.

• 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.

DISEASE CHARACTERISTICS:

• 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

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• More than 12 weeks

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• WBC ≥ 3,000/mm^3

Hepatic

• AST and ALT ≤ 2.5 times upper limit of normal
• Bilirubin normal
• No Gilbert's disease

Renal

• Creatinine normal OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Gastrointestinal

• Able to receive oral medications
• No prior inflammatory bowel disease
• No active ulcer disease or gastritis
• No contraindications for sigmoidoscopy
• No active colostomy

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• 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:

Biologic therapy

• No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF)

Chemotherapy

• 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) and recovered
• No prior irinotecan

Endocrine therapy

• Not specified

Radiotherapy

• 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

Surgery

• No prior abdominoperineal resection

Other

• 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