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

Sponsor:	North Central Cancer Treatment Group
Collaborators:	National Cancer Institute (NCI) Eastern Cooperative Oncology Group
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00079274

Purpose

RATIONALE: Drugs used in chemotherapy, such as irinotecan, fluorouracil, leucovorin, 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 is not yet known which combination chemotherapy regimen is more effective after surgery in treating colon cancer. (As of 6/1/2005, patients will no longer receive irinotecan on this study.)

PURPOSE: This randomized phase III trial is comparing three different combination chemotherapy regimens to see how well they work when given with or without cetuximab in treating patients who have undergone surgery for stage III colon cancer. (As of 6/1/2005, patients will no longer receive irinotecan on this study.)

Condition	Intervention	Phase
Colorectal Cancer	Biological: cetuximab Drug: fluorouracil Drug: irinotecan hydrochloride Drug: leucovorin calcium Drug: oxaliplatin	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Calcium Cancer Colorectal Cancer

Drug Information available for: Fluorouracil Leucovorin Citrovorum factor Oxaliplatin Irinotecan U 101440E Irinotecan hydrochloride Cetuximab Calcium gluconate Leucovorin Calcium Folinic acid calcium salt pentahydrate

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Disease-free survival at 3 years [ Designated as safety issue: No ]

Secondary Outcome Measures:

Overall survival [ Designated as safety issue: No ]

Estimated Enrollment:	3768
Study Start Date:	February 2004
Primary Completion Date:	November 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm I Patients receive oxaliplatin 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.	Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV
Experimental: Arm II Patients receive irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm I. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.	Drug: fluorouracil Given IV Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV
Experimental: Arm III Patients receive the same treatment as in arm I for 6 courses followed by the same treatment as in arm II for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.	Drug: fluorouracil Given IV Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV
Experimental: Arm IV Patients receive cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.	Biological: cetuximab Given IV Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV
Experimental: Arm V Patients receive cetuximab as in arm IV and irinotecan, leucovorin calcium, and fluorouracil as in arm II. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.	Biological: cetuximab Given IV Drug: fluorouracil Given IV Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV
Experimental: Arm VI Patients receive cetuximab as in arm IV and chemotherapy as in arm III.	Biological: cetuximab Given IV Drug: fluorouracil Given IV Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV

Detailed Description:

OBJECTIVES:

Compare the disease-free survival of patients with curatively resected stage III colon cancer treated with adjuvant irinotecan vs oxaliplatin with fluorouracil and leucovorin calcium vs both regimens given consecutively (all irinotecan-containing treatment arms are closed to accrual as of 6/1/2005).
Compare the disease-free survival of patients treated with these regimens with vs without cetuximab.

Secondary

Compare the overall survival of patients treated with these regimens.
Compare the disease-free and overall survival of patients whose tumors express epidermal growth factor receptor treated with these regimens.
Compare the toxic effects of these regimens in these patients.
Compare the quality of life, measures of patient satisfaction, nutrition, and cancer risk in patients treated with these regimens.

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).

Arm I: Patients receive oxaliplatin 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 II (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm I for remainder of therapy): Patients receive irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm I. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
Arm III (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 I for 6 courses followed by the same treatment as in arm II for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.
Arm IV: Patients receive cetuximab* IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
Arm V (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm IV for remainder of therapy): Patients receive cetuximab* as in arm IV and irinotecan, leucovorin calcium, and fluorouracil as in arm II. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
Arm VI (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm IV for remainder of therapy): Patients receive cetuximab* as in arm IV and chemotherapy as in arm III.

NOTE: *Cetuximab is administered over 2 hours at a higher dose on day 1 of course 1 only.

Quality of life is assessed at baseline, before course 6, and at the end of therapy.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 3 years.

PROJECTED ACCRUAL: A total of 3,768 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	18 Years to 69 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

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

PATIENT CHARACTERISTICS:

Age

18 to 69

Performance status

ECOG 0-2

Life expectancy

Not specified

Hematopoietic

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

Hepatic

Bilirubin ≤ 1.5 times upper limit of normal (ULN)

Renal

Creatinine ≤ 1.5 times ULN

Cardiovascular

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

Pulmonary

No symptomatic pulmonary fibrosis
No symptomatic interstitial pneumonitis

Immunologic

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

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 2 months after study participation
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

PRIOR CONCURRENT THERAPY:

Biologic therapy

No concurrent biologic therapy
No concurrent oprelvekin
No concurrent pegfilgrastim

Chemotherapy

No prior chemotherapy for colon cancer
No other concurrent chemotherapy

Endocrine therapy

Not specified

Radiotherapy

No prior radiotherapy for colon cancer

Surgery

See Disease Characteristics

Other

No prior agents directed against epidermal growth factor-receptor
No concurrent ketoconazole or other potent inhibitors of CYP3A4 (e.g., itraconazole or voriconazole)
No other concurrent anticancer therapy
No concurrent targeted agents

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00079274

Show 745 Study Locations

Sponsors and Collaborators

North Central Cancer Treatment Group

National Cancer Institute (NCI)

Eastern Cooperative Oncology Group

Investigators

Study Chair:	Steven R. Alberts, MD	Mayo Clinic
Investigator:	Albert M. Bernath, MD	CCOP - Geisinger Clinic and Medical Center
Principal Investigator:	Frank Sinicrope, MD	Mayo Clinic
Investigator:	Emily Chan, MD, PhD	Vanderbilt-Ingram Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Featured trial article This link exits the ClinicalTrials.gov site

Publications:

Alberts, SR, Sargent DJ, Smyrk TC, et al.: Adjuvant mFOLFOX6 with or without cetuxiumab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): results from NCCTG Intergroup Phase III Trial N0147. [Abstract] J Clin Oncol 28 (Suppl 18): A-CRA3507, 2010.

Goldberg RM, Sargent DJ, Thibodeau SN, et al.: Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147. [Abstract] J Clin Oncol 28 (Suppl 15): A-3508, 2010.

Jatoi A, Green EM, Rowland KM Jr, Sargent DJ, Alberts SR. Clinical Predictors of Severe Cetuximab-Induced Rash: Observations from 933 Patients Enrolled in North Central Cancer Treatment Group Study N0147. Oncology. 2009 Jul 22;77(2):120-123 [Epub ahead of print]

Responsible Party:	Jan C. Buckner, North Central Cancer Treatment Group
ClinicalTrials.gov Identifier:	NCT00079274 History of Changes
Obsolete Identifiers:	NCT00170092
Other Study ID Numbers:	CDR0000355132, NCCTG-N0147, ECOG-N0147
Study First Received:	March 8, 2004
Last Updated:	November 15, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

stage III colon cancer
adenocarcinoma of the colon

Additional relevant MeSH terms:

Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Oxaliplatin
Irinotecan

Cetuximab
Camptothecin
Leucovorin
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins

ClinicalTrials.gov processed this record on February 09, 2012