Clinical trial NCT00085163: Celecoxib Combined With Fluorouracil and Leucovorin in Treating Patients With Resected Stage III Adenocarcinoma (Cancer) of the Colon
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the colon
stage III colon cancer
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Dutch Colorectal Cancer Group (DCCG)
name: Arbeitsgemeinschaft fur Internistische Onkologie
name: Onkologie
name: Egyptian Foundation For Cancer Research
name: EORTC GI Group (EORTC 40023)
name: Federation Francophone de Cancerologie Digestive
name: GCCD-APIO - Grupo Cooperativo do Cancro Digestivo da Associação Portuguesa de Investigação
name: Oncológica
name: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
name: GOCCI - Gruppo Oncologico Chirurgico Cooperativo Italiano
name: GOIRC - Gruppo Oncologico Italiano di Ricerca Clinica
name: SG - Scandinavian Group
name: TTD - Grupo Español para el Tratamiento de Tumores Digestivos
First posted: 2004-06-11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
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 outcomes:
measure: Overall survival as measured by Logrank every 3 months in year 1, every 6 months in years 2-3, and annually thereafter
measure: 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
measure: 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
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Karl-Franzens-University Graz
city: Innsbruck
country: Austria
facility: Innsbruck Universitaetsklinik
city: Linz Donau
country: Austria
facility: St. Vincent's Hospital
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen
city: Salzburg
country: Austria
facility: Landeskrankenanstalten - Salzburg
city: Vienna
country: Austria
facility: Allgemeines Krankenhaus der Stadt Wien
city: Wiener Neustadt
country: Austria
facility: Allgemeines Krankenhaus
city: Antwerpen
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen Middelheim
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Haine Saint Paul
country: Belgium
facility: Hopital de Jolimont
city: Liege
country: Belgium
facility: CHU Liege - Domaine Universitaire du Sart Tilman
city: Turnhout
country: Belgium
facility: St. Elizabeth Ziekenhuis
city: 's-Gravenhage
country: Netherlands
facility: Medisch Centrum Haaglanden
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum at University of Amsterdam
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen - Lokatie Lukas
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital
city: Bergen-op-Zoom
country: Netherlands
facility: Ziekenhuis Lievensberg
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuisen
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Harderwijk
country: Netherlands
facility: Ziekenhuis St Jansdal
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Nijmegen Cancer Center at Radboud University Medical Center
city: Purmerend
country: Netherlands
facility: Waterlandziekenhuis
city: Rotterdam
country: Netherlands
facility: Daniel Den Hoed Cancer Center at Erasmus Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC - Sophia Children's Hospital
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
city: Schiedam
country: Netherlands
facility: Schieland Ziekenhuis
city: Terneuzen
country: Netherlands
facility: Ziekenhuis de Honte
city: Winterswyk
country: Netherlands
facility: Streekziekenhuis Koningin Beatrix
city: Zwolle
country: Netherlands
facility: Isala Klinieken - locatie Weezenlanden
Study officials:
affiliation: Leiden University Medical Center
name: Cornelis J.H. van de Velde, MD, PhD, FRCS, FRCPS
role: STUDY_CHAIR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Dirk J. Richel, MD, PhD
role: STUDY_CHAIR
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Michel Ducreux, MD, PhD
role: STUDY_CHAIR
References: