Clinical trial NCT00265811: Combination Chemotherapy With or Without Cetuximab in Treating Patients With Stage III Colon Cancer That Was Completely Removed By Surgery
Official title: Adjuvant Treatment of Fully Resected Stage III Colon Cancer With FOLFOX-4 Versus FOLFOX-4 Plus Cetuximab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: stage III colon cancer
adenocarcinoma of the colon
Lead sponsor: Federation Francophone de Cancerologie Digestive
Sponsor class: OTHER
First posted: 2005-12-15
Enrollment: 2559
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin, or fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy with or without cetuximab after surgery may kill any remaining tumor cells and keep colon cancer from coming back. It is not yet known whether giving combination chemotherapy together with cetuximab is more effective than giving combination chemotherapy alone in treating colon cancer.

PURPOSE: This randomized phase III trial is studying combination chemotherapy and cetuximab to see how well they work compared to combination chemotherapy alone in treating patients with stage III colon cancer that was completely removed by surgery.

Detailed description: OBJECTIVES:

Primary

* Compare the disease-free survival rates in patients with completely resected stage III colon cancer treated with adjuvant oxaliplatin, leucovorin calcium, and fluorouracil with vs without cetuximab.

Secondary

* Compare the 3-year disease-free survival rate and 5-year overall survival rate in patients treated with these regimens.
* Compare the overall survival of patients treated with these regimens.
* Compare the treatment compliance of patients treated with these regimens.
* Determine the prognostic factors and markers predictive for relapse and/or treatment efficacy in patients treated with these regimens.
* Compare the safety of these regimens in these patients.

OUTLINE: This is an open-label, randomized, controlled, multicenter study. Patients are stratified according to obstruction/perforation status (no obstruction and no perforation vs obstruction and/or perforation), N stage (N1 vs N2), and T stage (T1-3 vs T4). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oxaliplatin IV over 2 hours on day 1 and leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 22 hours on days 1 and 2.
* Arm II: Patients receive chemotherapy as in arm I plus cetuximab IV over 1-2 hours on days 1 and 8.

In both arms, treatment repeats every 14 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for approximately 5 years.

PROJECTED ACCRUAL: A total of 2,000 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed stage III adenocarcinoma of the colon
* Must have undergone curative resection (R0) within the past 28-56 days

  * No radiotherapy prior to surgery
* carcinoembryonic antigen (CEA) ≤ 1.5 times upper limit of normal (ULN) after surgery
* No rectal cancer located within 15 cm from the anal verge by endoscopy or under the peritoneal reflection at surgery
* No metastatic spread at baseline assessment
* No prior or concurrent CNS disease by physical exam

PATIENT CHARACTERISTICS:

Performance status

* WHO 0-1

Life expectancy

* At least 5 years

Hematopoietic

* WBC ≥ 3,000/mm\^3
* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 9 g/dL

Hepatic

* Bilirubin ≤ 1.5 times ULN
* AST and ALT ≤ 2.5 times ULN
* Alkaline phosphatase ≤ 1.5 times ULN

Renal

* Creatinine ≤ 1.5 times ULN

Cardiovascular

* No coronary artery disease
* No myocardial infarction within the past 12 months
* No high risk of uncontrolled arrhythmia

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No inflammatory bowel disease
* No other malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix
* No significant traumatic injury within the past 28 days
* No known hypersensitivity to any of the components of the study drugs
* No medical, geographical, sociological, psychological, or legal condition that would preclude study participation
* No peripheral neuropathy ≥ grade 1
* No other significant disease that would preclude study participation

PRIOR CONCURRENT THERAPY:

Chemotherapy

* No prior chemotherapy

Radiotherapy

* See Disease Characteristics
* No prior abdominal or pelvic irradiation

Surgery

* See Disease Characteristics
* Recovered from prior surgery
* More than 28 days since prior major surgical procedure or open biopsy
* No concurrent major surgical procedure

Primary outcomes:
measure: Disease-free survival
timeFrame: 3-years DFS
Secondary outcomes:
measure: Overall survival
timeFrame: 5 years
Other outcomes:
Locations:
city: Avignon
country: France
facility: Hopital Duffaut
city: Caen
country: France
facility: CHU de Caen
city: Libourne
country: France
facility: Hopital Robert Boulin
city: Paris
country: France
facility: Hopital Bichat - Claude Bernard
city: Paris
country: France
facility: CHU Pitie-Salpetriere
city: Paris
country: France
facility: Hopital Tenon
city: Saint Brieuc Cedex 1
country: France
facility: Centre Hospitalier Yves Le Foll
city: Valence
country: France
facility: Nouvelle Clinique Generale
Study officials:
affiliation: CHU Pitie-Salpetriere
name: Julien Taieb, MD
role: STUDY_CHAIR
References:
citation: Taieb J, Puig PL, Bedenne L. Cetuximab plus FOLFOX-4 for fully resected stage III colon carcinoma: scientific background and the ongoing PETACC-8 trial. Expert Rev Anticancer Ther. 2008 Feb;8(2):183-9. doi: 10.1586/14737140.8.2.183.
citation: Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Jul;15(8):862-73. doi: 10.1016/S1470-2045(14)70227-X. Epub 2014 Jun 11.
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citation: Cohen R, Taieb J, Fiskum J, Yothers G, Goldberg R, Yoshino T, Alberts S, Allegra C, de Gramont A, Seitz JF, O'Connell M, Haller D, Wolmark N, Erlichman C, Zaniboni A, Lonardi S, Kerr R, Grothey A, Sinicrope FA, Andre T, Shi Q. Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials. J Clin Oncol. 2021 Feb 20;39(6):642-651. doi: 10.1200/JCO.20.01600. Epub 2020 Dec 23.
citation: Salem ME, Yin J, Goldberg RM, Pederson LD, Wolmark N, Alberts SR, Taieb J, Marshall JL, Lonardi S, Yoshino T, Kerr RS, Yothers G, Grothey A, Andre T, De Gramont A, Shi Q. Evaluation of the change of outcomes over a 10-year period in patients with stage III colon cancer: pooled analysis of 6501 patients treated with fluorouracil, leucovorin, and oxaliplatin in the ACCENT database. Ann Oncol. 2020 Apr;31(4):480-486. doi: 10.1016/j.annonc.2019.12.007. Epub 2020 Jan 16.
citation: Taieb J, Shi Q, Pederson L, Alberts S, Wolmark N, Van Cutsem E, de Gramont A, Kerr R, Grothey A, Lonardi S, Yoshino T, Yothers G, Sinicrope FA, Zaanan A, Andre T. Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies. Ann Oncol. 2019 Sep 1;30(9):1466-1471. doi: 10.1093/annonc/mdz208.