Celecoxib Combined With Fluorouracil and Leucovorin in Treating Patients With Resected Stage III Adenocarcinoma (Cancer) of the Colon

Multicenter, Double-Blind, Placebo-Controlled Randomized Phase III Study of Adjuvant Therapy With Celecoxib in Combination With Chemotherapy in Patients With Curatively Resected Stage III Colon Cancer

RATIONALE: Drugs used in chemotherapy, such as fluorouracil and leucovorin, 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. It is not yet known whether fluorouracil and leucovorin are more effective with or without celecoxib in treating resected stage III adenocarcinoma (cancer) of the colon.

PURPOSE: This randomized phase III trial is studying celecoxib, fluorouracil, and leucovorin to see how well they work compared to fluorouracil and leucovorin in treating patients who have undergone surgery for stage III colon cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Procedure: adjuvant therapy; Drug: celecoxib

Detailed Description

OBJECTIVES:

Primary

• Compare disease-free survival of patients with curatively resected stage III adenocarcinoma of the colon treated with adjuvant fluorouracil and leucovorin calcium with or without celecoxib.

Secondary

• Compare the overall survival, the occurrence of new primary colon cancer, and the development of new polyps in patients treated with these regimens.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to ≥ 4 tumor-positive lymph nodes (yes vs no), form of adjuvant chemotherapy (infusional vs bolus), low-dose aspirin for cardiovascular prophylaxis (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive fluorouracil and leucovorin calcium IV for up to 6 courses in the absence of disease recurrence or unacceptable toxicity. Patients also receive oral celecoxib twice daily.
• Arm II: Patients receive oral placebo twice daily and fluorouracil and leucovorin calcium as in arm I.

In both arms, treatment with celecoxib or placebo continues for 3 years in the absence of disease recurrence or unacceptable toxicity.

Patients are followed annually for 2 years.

PROJECTED ACCRUAL: A total of 1,450 patients (725 per treatment arm) will be accrued for this study within 2 years.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, A-8010
    • Karl-Franzens-University Graz
  • Innsbruck, Austria, A-6020
    • Innsbruck Universitaetsklinik
  • Linz, Austria, 4020
    • Krankenhaus der Elisabethinen
  • Linz Donau, Austria, 4010
    • St. Vincent's Hospital
  • Salzburg, Austria, A-5020
    • Landeskrankenanstalten - Salzburg
  • Vienna, Austria, A-1090
    • Allgemeines Krankenhaus der Stadt Wien
  • Wiener Neustadt, Austria, 2700
    • Allgemeines Krankenhaus
• Belgium
  • Antwerpen, Belgium, B-2020
    • Ziekenhuis Netwerk Antwerpen Middelheim
  • Brussels, Belgium, 1070
    • Hopital Universitaire Erasme
  • Edegem, Belgium, B-2650
    • Universitair Ziekenhuis Antwerpen
  • Haine Saint Paul, Belgium, 7100
    • Hôpital de Jolimont
  • Liege, Belgium, B-4000
    • CHU Liege - Domaine Universitaire du Sart Tilman
  • Turnhout, Belgium, 2300
    • St. Elizabeth Ziekenhuis
• Netherlands
  • 's-Gravenhage, Netherlands, 2501 CK
    • Medisch Centrum Haaglanden
  • 's-Hertogenbosch, Netherlands, 5211 NL
    • Jeroen Bosch Ziekenhuis
  • Amsterdam, Netherlands, 1091 HA
    • Onze Lieve Vrouwe Gasthuis
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum at University of Amsterdam
  • Apeldoorn, Netherlands, 7334 DZ
    • Gelre Ziekenhuizen - Lokatie Lukas
  • Arnhem, Netherlands, 6800 TA
    • Rijnstate Hospital
  • Bergen-op-Zoom, Netherlands, 4624 VT
    • Ziekenhuis Lievensberg
  • Deventer, Netherlands, 7415 CM
    • Deventer Ziekenhuisen
  • Eindhoven, Netherlands, 5602 ZA
    • Catharina Ziekenhuis
  • Enschede, Netherlands, 7500 KA
    • Medisch Spectrum Twente
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen
  • Harderwijk, Netherlands, 3840 AC
    • Ziekenhuis St Jansdal
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center
  • Nieuwegein, Netherlands, 3435 CM
    • Sint Antonius Ziekenhuis
  • Nijmegen, Netherlands, 6500 HB
    • Nijmegen Cancer Center at Radboud University Medical Center
  • Purmerend, Netherlands, 1440 AG
    • Waterlandziekenhuis
  • Rotterdam, Netherlands, NL-3083
    • Ikazia Ziekenhuis
  • Rotterdam, Netherlands, 3008 AE
    • Daniel Den Hoed Cancer Center at Erasmus Medical Center
  • Rotterdam, Netherlands, 3015 GJ
    • Erasmus MC - Sophia Children's Hospital
  • Schiedam, Netherlands, NL-3116
    • Schieland Ziekenhuis
  • Terneuzen, Netherlands, NL-4535
    • Ziekenhuis de Honte
  • Winterswyk, Netherlands, 7101 BN
    • Streekziekenhuis Koningin Beatrix
  • Zwolle, Netherlands, NL-8000 GM
    • Isala Klinieken - Locatie Weezenlanden

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon

  • 15 cm above anal verge
  • Stage III disease (any pT, N1-2, M0)
• No rectal cancer
• Must have undergone curative radical resection (R0 resection) within the past 6 weeks

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• WHO 0-1

Life expectancy

• Not specified

Hematopoietic

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

Hepatic

• AST ≤ 5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• None of the following conditions within the past 6 months:

  • Myocardial infarction
  • Unstable angina
  • Symptomatic congestive heart failure
  • Serious uncontrolled cardiac arrhythmia
  • Cerebrovascular accident or transient ischemic attack
  • Deep vein thrombosis
  • Other significant thromboembolic event

Pulmonary

• No pulmonary embolism within the past 6 months

Gastrointestinal

• No active gastric or duodenal ulceration within the past year
• No gastrointestinal bleeding within the past year
• No partial or complete bowel obstruction
• No known chronic malabsorption
• No active inflammatory bowel disease or chronic diarrhea (more than 4 stools/day)

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• HIV negative
• No AIDS-related illness
• No prior hypersensitivity to fluorouracil, leucovorin calcium, celecoxib, other COX-2 inhibitors, NSAIDs, salicylates, or sulfonamides
• No other severe acute or chronic medical condition or laboratory abnormality that would preclude study participation, study drug administration, or study results interpretation
• No psychological, familial, sociological, or geographical condition that would preclude study compliance
• No concurrent active infection
• No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix or basal cell or squamous cell skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent sargramostim (GM-CSF) or molgramostim

Chemotherapy

• Not specified

Endocrine therapy

• No more than 4 weeks of concurrent orally/nasally inhaled steroids over a 6-month period

  • Concurrent mometasone (or fluticasone) allowed if patients require ≥ 4 weeks of inhaled steroid therapy
• At least 30 days since other prior steroids
• No concurrent hormonal therapy

Radiotherapy

• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• No prior total colectomy or other major surgery that would result in substantial alteration in transit to absorption of oral medication

Other

• More than 30 days since prior investigational medication
• No prior systemic anticancer treatment for colon cancer
• No concurrent prophylactic fluconazole
• No concurrent lithium

• No concurrent chronic* use of full dose aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase-2 (COX-2) inhibitors

  • Aspirin at cardioprotective doses (i.e., 80 mg daily or equivalent) allowed
• No concurrent participation in any other clinical study
• No other concurrent experimental agents (e.g., other COX-2 inhibitors, matrix metalloproteinase inhibitors, inhibitors of the vascular endothelial growth factor/Flk-1 pathway, or inhibitors of the epidermal growth factor receptor pathway) NOTE: *Chronic use is defined as a frequency of 7 consecutive days (1 week) for more than 3 weeks/year or more than 21 days throughout the year

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Disease-free survival as measured by Logrank every 3 months in year 1, every 6 months in years 2-3, and annually thereafter

Secondary Outcome Measures

Outcome Measure
Overall survival as measured by Logrank every 3 months in year 1, every 6 months in years 2-3, and annually thereafter
Time occurrence of new primary colon cancer and new polyps as measured by Logrank every 3 months in year 1, every 6 months in years 2-3, and annually thereafter
Toxicity as measured by CTC AE version 2.0 every 3 months in year 1, every 6 months in years 2-3, and annually thereafter

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Federation Francophone de Cancerologie Digestive; Arbeitsgemeinschaft fur Internistische Onkologie; Dutch Colorectal Cancer Group (DCCG); Onkologie; Egyptian Foundation For Cancer Research; EORTC GI Group (EORTC 40023); GCCD-APIO - Grupo Cooperativo do Cancro Digestivo da Associação Portuguesa de Investigação; Oncológica; Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente; GOCCI - Gruppo Oncologico Chirurgico Cooperativo Italiano; GOIRC - Gruppo Oncologico Italiano di Ricerca Clinica; SG - Scandinavian Group; TTD - Grupo Español para el Tratamiento de Tumores Digestivos
• Investigators: Study Chair: Dirk J. Richel, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Actual): November 1, 2005

Study Registration Dates

• First Submitted: June 10, 2004
• First Submitted That Met QC Criteria: June 10, 2004
• First Posted (Estimate): June 11, 2004

Study Record Updates

• Last Update Posted (Estimate): October 20, 2015
• Last Update Submitted That Met QC Criteria: October 19, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: adenocarcinoma of the colon; stage III colon cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Cyclooxygenase 2 Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Celecoxib; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: EORTC-40023; PETACC-5