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

Phase 3

Completed

Conditions: Adenocarcinoma of the Colon
Stage III Colon Cancer

Interventions: Drug: irinotecan hydrochloride
Drug: Locally Directed Therapy
Drug: leucovorin calcium
Drug: oxaliplatin
Drug: fluorouracil
Biological: cetuximab

Registration Number: NCT00079274

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3397

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm D (combination chemotherapy, monoclonal antibody)	leucovorin calcium	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.
Arm D (combination chemotherapy, monoclonal antibody)	cetuximab	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.
Arm E (combination chemotherapy, monoclonal antibody)	leucovorin calcium	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.
Arm E (combination chemotherapy, monoclonal antibody)	fluorouracil	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.
Arm F (combination chemotherapy, monoclonal antibody)	oxaliplatin	Patients received cetuximab as in arm D and chemotherapy as in arm C.
Arm A (combination chemotherapy)	leucovorin calcium	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.
Arm B (combination chemotherapy)	irinotecan hydrochloride	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.
Arm F (combination chemotherapy, monoclonal antibody)	fluorouracil	Patients received cetuximab as in arm D and chemotherapy as in arm C.
Arm B (combination chemotherapy)	leucovorin calcium	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.
Arm C (combination chemotherapy)	leucovorin calcium	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.
Arm F (combination chemotherapy, monoclonal antibody)	leucovorin calcium	Patients received cetuximab as in arm D and chemotherapy as in arm C.
Arm F (combination chemotherapy, monoclonal antibody)	cetuximab	Patients received cetuximab as in arm D and chemotherapy as in arm C.
Arm G (Locally directed therapy)	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.
Arm E (combination chemotherapy, monoclonal antibody)	irinotecan hydrochloride	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.
Arm E (combination chemotherapy, monoclonal antibody)	cetuximab	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.
Arm A (combination chemotherapy)	oxaliplatin	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.
Arm A (combination chemotherapy)	fluorouracil	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.
Arm B (combination chemotherapy)	fluorouracil	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.
Arm C (combination chemotherapy)	irinotecan hydrochloride	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.
Arm C (combination chemotherapy)	oxaliplatin	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.
Arm C (combination chemotherapy)	fluorouracil	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.
Arm D (combination chemotherapy, monoclonal antibody)	oxaliplatin	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.
Arm D (combination chemotherapy, monoclonal antibody)	fluorouracil	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.
Arm F (combination chemotherapy, monoclonal antibody)	irinotecan hydrochloride	Patients received cetuximab as in arm D and chemotherapy as in arm C.

Primary Outcome Measures

Name	Time	Method
Disease-free Survival (Arms A and D: Wild-type KRAS Patients)	At 3 years	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.

Secondary Outcome Measures

Name	Time	Method
Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) (Arms A and D: Mutant KRAS Patients)	Assessed up to 8 years	The maximum grade for each type of toxicity will be recorded for each patient 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). The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) (Arms A and D: Wild-type KRAS Patients)	Assessed up to 8 years	The maximum grade for each type of toxicity will be recorded for each patient 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). The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Disease-free Survival (Arms A and D: Mutant KRAS Patients)	At 3 years	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.
Overall Survival as Measured by the 3-year Event-free Rate (Arms A and D: Mutant KRAS Patients)	Up to 3 years	Evidence of death from any cause within 3 years counted as events in the time to event- Kaplan Meier analysis of overall survival for 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. The 3-year event-free rates (percentage) are report below for mutant KRAS patients.
Overall Survival as Measured by the 3-year Event-free Rate (Arms A and D: Wild-type KRAS Patients)	Up to 3 years	Evidence of death from any cause within 3 years counted as events in the time to event- Kaplan Meier analysis of overall survival for 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. The 3-year event free rates (percentage) are reported below for Wild-type KRAS Patients.

Trial Locations

Locations (875): Northeast Alabama Regional Medical Center
🇺🇸
Anniston, Alabama, United States
Clearview Cancer Institute
🇺🇸
Huntsville, Alabama, United States
Mobile Infirmary Medical Center
🇺🇸
Mobile, Alabama, United States
Providence Hospital
🇺🇸
Southfield, Michigan, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Banner Thunderbird Medical Center
🇺🇸
Glendale, Arizona, United States
Banner Desert Medical Center
🇺🇸
Mesa, Arizona, United States
Banner Baywood Medical Center
🇺🇸
Mesa, Arizona, United States
Banner Good Samaritan Medical Center
🇺🇸
Phoenix, Arizona, United States
Western Regional CCOP
🇺🇸
Phoenix, Arizona, United States
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Northeast Alabama Regional Medical Center
🇺🇸Anniston, Alabama, United States