Clinical trial NCT00064181: Combination Chemotherapy With or Without Celecoxib in Treating Patients With Metastatic Colorectal Cancer
Official title: Irinotecan Combined With Infusional 5-FU/Folinic Acid or Capecitabine and the Role of Celecoxib in Patients With Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the colon
adenocarcinoma of the rectum
stage IV colon cancer
stage IV rectal cancer
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2003-07-09
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: 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: This randomized phase III trial is studying two combination chemotherapy regimens and celecoxib to see how well they work compared to two combination chemotherapy regimens alone in treating patients with metastatic colorectal cancer.

Detailed description: 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.

Eligibility 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Antwerp
country: Belgium
facility: Ziekenhuis Network Antwerpen Middelheim
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Academisch Ziekenhuis der Vrije Universiteit Brussel
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Kortrijk
country: Belgium
facility: Cazk Groeninghe - Campus St-Niklaas
city: Turnhout
country: Belgium
facility: St. Elizabeth Ziekenhuis
city: Cairo
country: Egypt
facility: National Cancer Institute - Cairo
city: Berlin
country: Germany
facility: Charite - Campus Charite Mitte
city: Celle
country: Germany
facility: General Hospital
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carl Carus
city: Essen
country: Germany
facility: Kliniken Essen - Mitte
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Klinikum der Albert - Ludwigs - Universitaet Freiburg
city: Hagen
country: Germany
facility: Allgemeines Krankenhaus Hagen
city: Hamburg
country: Germany
facility: Allgemeines Krankenhaus Altona
city: Hamburg
country: Germany
facility: Universitaets-Krankenhaus Eppendorf
city: Hamm
country: Germany
facility: St. Marien Hospital
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Landau
country: Germany
facility: Vinzentiuskrankenhaus
city: Leer
country: Germany
facility: Onkologische Schwerpunktpraxis Leer
city: Magdeburg
country: Germany
facility: Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
city: Meissen
country: Germany
facility: Kreiskrankenhaus Meissen
city: Munich
country: Germany
facility: Klinikum Rechts Der Isar - Technische Universitaet Muenchen
city: Tuebingen
country: Germany
facility: Eberhard Karls Universitaet
city: Wuerzburg
country: Germany
facility: Universitaets-Hautklinik Wuerzburg
city: Budapest
country: Hungary
facility: National Institute of Oncology
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Holon
country: Israel
facility: Wolfson Medical Center
Study officials:
affiliation: Klinikum Oldenburg
name: Claus-Henning Koehne, MD
role: STUDY_CHAIR
References:
citation: Kohne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Muller L, Janssens J, Bokemeyer C, Reimer P, Link H, Spath-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. doi: 10.1093/annonc/mdm544. Epub 2007 Dec 6.
citation: De Grève J, Koehne C, Hartmann J, et al.: Capecitabine plus irinotecan versus 5-FU/FA/irinotecan ± celecoxib in first line treatment of metastatic colorectal cancer (CRC). Long-term results of the prospective multicenter EORTC phase III study 40015. [Abstract] J Clin Oncol 24 (Suppl 18): A-3577, 2006.
citation: Kohne C, De Greve J, Bokemeyer C, et al.: Capecitabine plus irinotecan versus 5-FU/FA/irinotecan +/- celecoxib in first line treatment of metastatic colorectal cancer. Safety results of the prospective multicenter EORTC phase III study 40015. [Abstract] J Clin Oncol 23 (Suppl 16): A-3525, 252s, 2005.