Comparison of Combination Chemotherapy Regimens With or Without Cetuximab in Treating Patients Who Have Undergone Surgery For Stage III Colon Cancer
Condition: Adenocarcinoma of the Colon; Stage III Colon Cancer
MeSH terms: Colonic Neoplasms
Intervention: irinotecan hydrochloride; oxaliplatin; leucovorin calcium; fluorouracil; cetuximab; Locally Directed Therapy
Intervention description: Given IV; Given IV; Given IV; Given IV; Given IV; Patients determined to have mutated KRAS (or KRAS not evaluable) will be assigned to an event monitoring arm in which adjuvant therapy will be determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification will be the responsibility of the treating oncologists.
Intervention MeSH terms: Leucovorin; Antineoplastic Agents, Immunological; Cetuximab; Fluorouracil; Oxaliplatin; Irinotecan; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Levoleucovorin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3397.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No

Summary:

      This randomized phase III trial was originally designed to compare three different
      combination chemotherapy regimens to see how well they work. As of September 1, 2004, the
      study was expanded to a total of 6 arms (the original 3 arms (A, B, C) and 3 additional arms
      which were the same as the first 3 but with cetuximab) in treating patients who have
      undergone surgery for stage III colon cancer. Drugs used in chemotherapy, such as irinotecan
      hydrochloride, fluorouracil, leucovorin calcium, and oxaliplatin, work in different ways to
      stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as
      cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to
      them without harming normal cells. Combining more than one chemotherapy drug with monoclonal
      antibody therapy and giving them after surgery may kill any remaining tumor cells. It was not
      known at the time this study was developed which combination chemotherapy regimen is more
      effective after surgery in treating colon cancer. This study had several key changes, based
      on the results of other phase III trials. As of 6/1/2005, patients no longer received
      irinotecan on this study and treatment arms B, C, E, and F were discontinued. Patients on
      arms B and C crossed to arm A. Patients on arms E and F crossed to arm D. Patients on arms C
      and F who had not gotten to irinotecan continued on arms A and D, respectively. As of
      8/18/2008, pre-screening for Kirsten rat sarcoma (KRAS) status was added with mutant KRAS (or
      KRAS not evaluable) patients put on arm G and wild-type KRAS patients randomized between arm
      A and arm D. Patients on arm G were treated per physician discretion and followed for disease
      and survival status. KRAS was determined in a central laboratory and was process for all
      patients on this study. The primary endpoint of this study was modified on 8/18/2008 to focus
      on patients having wild-type KRAS tumors. All modifications were approved by the Central
      Institution Review Board, local Institutional Review Boards, NCI, and the NCCTG Data Safety
      Monitoring Board.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed adenocarcinoma of the colon

               -  Stage III disease

               -  No resected stage IV disease

          -  No rectal cancer

               -  Gross inferior (caudad) margin of the primary tumor must be ≥ 12 cm from the anal
                  verge by rigid proctoscopy

          -  Stage III tumor must have been completely resected within the past 56 days

               -  Must have documented en bloc resection in patients with tumor adherence to
                  adjacent structures

               -  Tumor-related obstructions and colonic perforation are allowed

               -  Tumor samples must be available

          -  At least 1 pathologically confirmed positive lymph node

               -  No evidence of residual involved lymph node disease

          -  Synchronous primary colon cancer allowed

          -  No distant metastatic disease

          -  Performance status - Eastern Cooperative Oncology Group (ECOG) 0-2

          -  Absolute neutrophil count ≥ 1,500/mm^3

          -  Platelet count ≥ 100,000/mm^3

          -  Hemoglobin ≥ 9 g/dL

          -  Bilirubin ≤ 1.5 times upper limit of normal (ULN)

          -  Creatinine ≤ 1.5 times ULN

          -  No uncontrolled high blood pressure

          -  No unstable angina

          -  No symptomatic congestive heart failure

          -  No myocardial infarction with the past 6 months

          -  No New York Heart Association class III or IV heart disease

          -  No symptomatic pulmonary fibrosis

          -  No symptomatic interstitial pneumonitis

          -  No prior allergic reaction (known sensitivity) to chimerized or murine monoclonal
             antibody therapy

          -  No known allergy to platinum compounds

          -  No documented presence of human anti-mouse antibodies (HAMA)

          -  No active uncontrolled bacterial, viral, or systemic fungal infection

          -  HIV negative

          -  No clinically defined AIDS

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  No men or women of childbearing potential who are unwilling to employ adequate
             contraception

          -  No inadequately treated gastrointestinal bleeding

          -  No ≥ grade 2 pre-existing peripheral sensory or motor neuropathy

          -  No other malignancy within the past 5 years except adequately treated basal cell or
             squamous cell skin cancer, carcinoma in situ of the cervix, or lobular carcinoma in
             situ in 1 breast

          -  No other concurrent medical condition that would preclude study participation

          -  No concurrent biologic therapy

          -  No prior chemotherapy for colon cancer

          -  No other concurrent chemotherapy

          -  No prior radiotherapy for colon cancer

          -  No concurrent targeted agents

          -  No prior agents directed against epidermal growth factor-receptor

          -  No other concurrent anticancer therapy