Comparison of Combination Chemotherapy Regimens With or Without Cetuximab in Treating Patients Who Have Undergone Surgery For Stage III Colon Cancer

This study has been completed.
Sponsor:
Collaborator:
Eastern Cooperative Oncology Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00079274
First received: March 8, 2004
Last updated: January 23, 2015
Last verified: October 2014

March 8, 2004
January 23, 2015
February 2004
November 2012   (final data collection date for primary outcome measure)
Disease-free Survival (Arms A and D: Wild-type KRAS Patients) [ Time Frame: At 3 years ] [ Designated as safety issue: No ]

The primary endpoint for this study was to compare the disease-free survival (DFS) in patients with stage III colon cancer who are KRAS wild-type randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). Participants treated according to Arms B, C, E, and F treatment schedules received treatment which included irinotecan hydrochloride and therefore were not analyzed for this endpoint.

Disease-free survival is defined as the time from randomization until tumor recurrence or death, whichever is first. Estimated by the method of Kaplan and Meier.

Not Provided
Complete list of historical versions of study NCT00079274 on ClinicalTrials.gov Archive Site
  • Disease-free Survival (Arms A and D: Mutant KRAS Patients) [ Time Frame: At 3 years ] [ Designated as safety issue: No ]

    A secondary endpoint for this study was to investigate the disease-free survival (DFS) in patients with stage III colon cancer who are KRAS mutant (or KRAS-nonevaluable) and randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). Participants treated according to Arms B, C, E, and F treatment schedules received treatment which included irinotecan hydrochloride and therefore were not analyzed for this endpoint.

    Disease-free survival is defined as the time from randomization until tumor recurrence or death, whichever is first. Estimated by the method of Kaplan and Meier.

  • Disease-free Survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The time from randomization until tumor recurrence or death, whichever is first. Estimated by the method of Kaplan and Meier.
  • Overall Survival [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
    The time from randomization until death. Estimated by the method of Kaplan and Meier.
  • Toxicity [ Time Frame: Assessed up to 8 years ] [ Designated as safety issue: Yes ]
    Number of grade 3+, grade 4, and grade 5 adverse events. Based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
Not Provided
Not Provided
Not Provided
 
Comparison of Combination Chemotherapy Regimens With or Without Cetuximab in Treating Patients Who Have Undergone Surgery For Stage III Colon Cancer
A Randomized Phase III Trial of Oxaliplatin (OXAL) Plus 5-Fluorouracil (5-FU)/Leucovorin (CF) With or Without Cetuximab (C225) After Curative Resection for Patients With Stage III Colon Cancer

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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adenocarcinoma of the Colon
  • Stage III Colon Cancer
  • Drug: irinotecan hydrochloride
    Given IV
    Other Names:
    • Campto
    • Camptosar
    • CPT-11
    • irinotecan
    • U-101440E
  • Drug: oxaliplatin
    Given IV
    Other Names:
    • 1-OHP
    • Dacotin
    • Dacplat
    • Eloxatin
    • L-OHP
  • Drug: leucovorin calcium
    Given IV
    Other Names:
    • CF
    • CFR
    • LV
  • Drug: fluorouracil
    Given IV
    Other Names:
    • 5-fluorouracil
    • 5-Fluracil
    • 5-FU
  • Biological: cetuximab
    Given IV
    Other Names:
    • C225
    • C225 monoclonal antibody
    • IMC-C225
    • MOAB C225
    • monoclonal antibody C225
  • Drug: Locally Directed Therapy
    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.
  • Experimental: Arm A (combination chemotherapy)
    Patients received oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
    Interventions:
    • Drug: oxaliplatin
    • Drug: leucovorin calcium
    • Drug: fluorouracil
  • Experimental: Arm B (combination chemotherapy)
    Patients received irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
    Interventions:
    • Drug: irinotecan hydrochloride
    • Drug: leucovorin calcium
    • Drug: fluorouracil
  • Experimental: Arm C (combination chemotherapy)
    Patients received 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.
    Interventions:
    • Drug: irinotecan hydrochloride
    • Drug: oxaliplatin
    • Drug: leucovorin calcium
    • Drug: fluorouracil
  • Experimental: Arm D (combination chemotherapy, monoclonal antibody)
    Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
    Interventions:
    • Drug: oxaliplatin
    • Drug: leucovorin calcium
    • Drug: fluorouracil
    • Biological: cetuximab
  • Experimental: Arm E (combination chemotherapy, monoclonal antibody)
    Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
    Interventions:
    • Drug: irinotecan hydrochloride
    • Drug: leucovorin calcium
    • Drug: fluorouracil
    • Biological: cetuximab
  • Experimental: Arm F (combination chemotherapy, monoclonal antibody)
    Patients received cetuximab as in arm D and chemotherapy as in arm C.
    Interventions:
    • Drug: irinotecan hydrochloride
    • Drug: oxaliplatin
    • Drug: leucovorin calcium
    • Drug: fluorouracil
    • Biological: cetuximab
  • Arm G (Locally directed therapy)
    Patients determined to have mutated KRAS (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists.
    Intervention: Drug: Locally Directed Therapy

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
3397
November 2012
November 2012   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada,   Puerto Rico
Puerto Rico
 
NCT00079274
NCI-2009-00639, N0147, U10CA025224, CDR0000355132
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Principal Investigator: Steven A Alberts, MD North Central Cancer Treatment Group
National Cancer Institute (NCI)
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP