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
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. Disease-free Survival (Arms A and D: Wild-type KRAS Patients)

      SECONDARY OBJECTIVES:

      I. Disease-free Survival (Arms A and D: Mutant KRAS Patients) II. Disease-free Survival III.
      Overall Survival IV. Toxicity

      OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
      positive lymph node involvement (1-3 vs 4 or more), histology (high [poorly differentiated or
      undifferentiated] vs low [well to moderately differentiated]), and clinical T stage (T1 or T2
      vs T3 vs T4). Patients are randomized to 1 of 6 treatment arms (as of 6/1/2005, patients are
      randomized to treatment arms I and IV only; arms II, III, V, and VI are closed to accrual).
      As of 8/18/2008, pre-screening for 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.

      ARM A: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV
      over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeats
      every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent
      disease.

      ARM B (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm I
      for remainder of therapy): Patients receive irinotecan hydrochloride IV over 2 hours on day 1
      and leucovorin calcium and fluorouracil as in arm A. Treatment repeats every 14 days for up
      to 12 courses in the absence of unacceptable toxicity or recurrent disease.

      ARM C (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm I
      for remainder of therapy): Patients receive the same treatment as in arm A for 6 courses
      followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment
      continues in the absence of unacceptable toxicity or recurrent disease.

      ARM D: Patients receive cetuximab* IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin
      calcium, and fluorouracil as in arm A. Treatment repeats every 14 days for up to 12 courses
      in the absence of unacceptable toxicity or recurrent disease.

      ARM E (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm D
      for remainder of therapy): Patients receive cetuximab* as in arm D and irinotecan
      hydrochloride, leucovorin calcium, and fluorouracil as in arm B. Treatment repeats every 14
      days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

      ARM F (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm D
      for remainder of therapy): Patients receive cetuximab* as in arm D and chemotherapy as in arm
      C.

      ARM G (added as of 8/18/2008, mutant KRAS (or KRAS not evaluable) patients): Locally directed
      therapy.

      NOTE: *Cetuximab is administered over 2 hours at a higher dose on day 1 of course 1 only.

      Quality of life (QOL) is assessed at baseline, 3 months, and at the end of therapy. As of
      8/18/2008, QOL was discontinued.

      Patients are followed for a maximum of 8 years from randomization.
    

Intervention name(s): irinotecan hydrochloride; oxaliplatin; leucovorin calcium; fluorouracil; cetuximab; Locally Directed Therapy
Intervention type(s): Drug; Drug; Drug; Drug; Biological; Drug
Intervention description(s): 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.
Other intervention name(s): Campto; Camptosar; CPT-11; irinotecan; U-101440E; 1-OHP; Dacotin; Dacplat; Eloxatin; L-OHP; CF; CFR; LV; 5-fluorouracil; 5-Fluracil; 5-FU; C225; C225 monoclonal antibody; IMC-C225; MOAB C225; monoclonal antibody C225
Intervention MeSH terms: Leucovorin; Antineoplastic Agents, Immunological; Cetuximab; Fluorouracil; Oxaliplatin; Irinotecan; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Levoleucovorin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment