RATIONALE: Drugs used in chemotherapy such as irinotecan, capecitabine, leucovorin, and fluorouracil use different ways to stop tumor cells from dividing so they stop growing or die. Celecoxib may stop the growth of colorectal cancer by stopping blood flow to the tumor. It is not yet known which combination chemotherapy regimen with or without celecoxib is more effective in treating metastatic colorectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of two combination chemotherapy regimens with or without celecoxib in treating patients who have metastatic colorectal cancer.

Condition	Treatment or Intervention	Phase
adenocarcinoma of the colon adenocarcinoma of the rectum stage IV colon cancer Stage IV rectal cancer	Drug: capecitabine  Drug: celecoxib  Drug: fluorouracil  Drug: irinotecan  Drug: leucovorin calcium  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: growth factor antagonist therapy	Phase III

Further Study Details: 

OBJECTIVES:

• Compare the progression-free survival of patients with metastatic colorectal cancer treated with capecitabine and irinotecan vs fluorouracil, leucovorin calcium, and irinotecan with vs without celecoxib.
• Compare the safety of these regimens in these patients.
• Compare the response rate in patients treated with these regimens.
• Compare the time to treatment failure and overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, double-blind*, multicenter study. Patients are stratified according to participating center, prior adjuvant therapy (yes vs no), and risk group (poor vs intermediate vs good). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive irinotecan IV over 30-90 minutes on days 1 and 22; oral capecitabine twice daily on days 1-15 and 22-36; and oral celecoxib twice daily on days 1-42.
• Arm II: Patients receive irinotecan and capecitabine as in arm I and oral placebo twice daily on days 1-42.
• Arm III: Patients receive irinotecan IV over 30-90 minutes on days 1, 15, and 29; leucovorin calcium (CF) IV over 2 hours and fluorouracil (5-FU) IV over 22 hours on days 1, 2, 15, 16, 29, and 30; and oral celecoxib twice daily on days 1-42.
• Arm IV: Patients receive irinotecan, CF, and 5-FU as in arm III and oral placebo twice daily on days 1-42. In all arms, treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. If all chemotherapy is discontinued due to toxicity, patients may continue celecoxib or placebo until disease progression, unacceptable toxicity, or starting a new cytotoxic regimen.

NOTE: *The double-blind treatment only applies to the celecoxib and placebo randomization

Patients are followed every 2 months.

PROJECTED ACCRUAL: A total of 692 patients (173 per treatment arm) will be accrued for this study within 3.5 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum
• Metastatic disease
• Measurable disease
• Patients who received prior radiotherapy must have measurable or evaluable disease outside the radiotherapy field
• No CNS metastases

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• WBC at least 3,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 2 times upper limit of normal (ULN)
• AST and ALT no greater than 2.5 times ULN (5 times ULN in the presence of liver metastases)

Renal

• Creatinine clearance at least 51 mL/min
• No severe renal impairment

Cardiovascular

• No severe cardiac disease
• No uncontrolled angina pectoris
• No myocardial infarction within the past 6 months

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 6 months after study participation
• No active Crohn's disease
• No other malignancy except adequately treated carcinoma in situ of the cervix or nonmelanoma skin cancer
• No other uncontrolled severe medical condition
• No psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up

PRIOR CONCURRENT THERAPY: Biologic therapy

• No concurrent active or passive immunotherapy for colon cancer

Chemotherapy

• No prior chemotherapy for metastatic disease

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy
• No concurrent radiotherapy

Surgery

• Not specified

Other

• At least 6 months since prior adjuvant therapy
• More than 4 weeks since prior investigational drugs
• No concurrent sorivudine or chemically related analogues (e.g., brivudine)
• No other concurrent investigational drugs
• No other concurrent cytotoxic agents
• No concurrent prophylactic fluconazole
• No concurrent or planned cyclo-oxygenase-2 (COX-2) inhibitors or nonsteroidal anti-inflammatory drugs
• No concurrent chronic use of full-dose aspirin (325 mg/day or greater)
• Concurrent low-dose (cardioprotective) aspirin prophylaxis (no more than 325 mg every other day OR no more than 162.5 mg per day) allowed

Belgium
      Academisch Ziekenhuis der Vrije Universiteit Brussel, Brussels,  1090,  Belgium
      Cazk Groeninghe - Campus St-Niklaas, Kortrijk,  B-8500,  Belgium
      Institut Jules Bordet, Brussels,  1000,  Belgium
      St. Elizabeth Ziekenhuis, TURNHOUT,  2300,  Belgium
      Universitair Ziekenhuis Antwerpen, Edegem,  B-2650,  Belgium
      Ziekenhuis Network Antwerpen Middelheim, Antwerp,  2020,  Belgium
Egypt
      National Cancer Institute - Cairo, Cairo,  Egypt
Germany
      Allgemeines Krankenhaus Altona, Hamburg,  22763,  Germany
      Allgemeines Krankenhaus Hagen, Hagen,  D-58095,  Germany
      Charite - Campus Charite Mitte, Berlin,  D-10117,  Germany
      Eberhard Karls Universitaet, Tuebingen,  D-72076,  Germany
      General Hospital, CELLE,  29223,  Germany
      Kliniken Essen - Mitte, ESSEN,  D-45136,  Germany
      Klinikum der Albert - Ludwigs - Universitaet Freiburg, Freiburg,  D-79106,  Germany
      Klinikum der J.W. Goethe Universitaet, Frankfurt,  D-60590,  Germany
      Klinikum Rechts Der Isar - Technische Universitaet Muenchen, Munich,  D-81675,  Germany
      Kreiskrankenhaus Meissen, Meissen,  D-01662,  Germany
      Onkologische Schwerpunktpraxis Leer, Leer,  D-26789,  Germany
      St. Marien Hospital, Hamm,  59065,  Germany
      Universitaets-Hautklinik Wuerzburg, Wuerzburg,  D-97080,  Germany
      Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg, Magdeburg,  D-39120,  Germany
      Universitaets-Krankenhaus Eppendorf, Hamburg,  D-20246,  Germany
      Universitatsklinikum Carl Gustav Carl Carus, Dresden,  D-01307,  Germany
      Vinzentiuskrankenhaus, Landau,  D-76829,  Germany
      Westpfalz-Klinikum GmbH, Kaiserslautern,  D-67653,  Germany
Hungary
      National Institute of Oncology, Budapest,  1122,  Hungary
Israel
      Rambam Medical Center, Haifa,  31096,  Israel
      Wolfson Medical Center, Holon,  58100,  Israel

Study chairs or principal investigators

Claus-Henning Koehne, MD,  Klinikum Oldenburg   

Study ID Numbers:  CDR0000309572; EORTC-40015; NCT00064181
Record last reviewed:  March 2005
Last Updated:  March 15, 2005
Record first received:  July 8, 2003
ClinicalTrials.gov Identifier:  NCT00064181
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08