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

• ClinicalTrials.gov Identifier: NCT00079274
• Recruitment Status: Completed
• First Posted: March 10, 2004
• Results First Posted: February 9, 2015
• Last Update Posted: May 13, 2020
• Sponsor: National Cancer Institute (NCI)
• Collaborator: Eastern Cooperative Oncology Group
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: March 8, 2004
• First Posted Date: March 10, 2004
• Results First Submitted Date: December 5, 2013
• Results First Posted Date: February 9, 2015
• Last Update Posted Date: May 13, 2020
• Study Start Date: February 2004
• Actual Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 23, 2015)

Disease-free Survival (Arms A and D: Wild-type KRAS Patients) [ Time Frame: 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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: November 30, 2018)

• Disease-free Survival (Arms A and D: Mutant KRAS Patients) [ Time Frame: 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: Wild-type KRAS Patients) [ Time Frame: 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.
• Overall Survival as Measured by the 3-year Event-free Rate (Arms A and D: Mutant KRAS Patients) [ Time Frame: 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.
• 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) [ Time Frame: 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.
• 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) [ Time Frame: 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Adenocarcinoma of the Colon
• Stage III Colon Cancer

Intervention

• 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.

Study Arms

• 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

Publications *

• Lee H, Sha D, Foster NR, Shi Q, Alberts SR, Smyrk TC, Sinicrope FA. Analysis of tumor microenvironmental features to refine prognosis by T, N risk group in patients with stage III colon cancer (NCCTG N0147) (Alliance). Ann Oncol. 2020 Apr;31(4):487-494. doi: 10.1016/j.annonc.2020.01.011. Epub 2020 Jan 25.
• Penney KL, Banbury BL, Bien S, Harrison TA, Hua X, Phipps AI, Sun W, Song M, Joshi AD, Alberts SR, Allegra CJ, Atkins J, Colangelo LH, George TJ, Goldberg RM, Lucas PC, Nair SG, Shi Q, Sinicrope FA, Wolmark N, Yothers G, Peters U, Newcomb PA, Chan AT. Genetic Variant Associated With Survival of Patients With Stage II-III Colon Cancer. Clin Gastroenterol Hepatol. 2020 Nov;18(12):2717-2723.e3. doi: 10.1016/j.cgh.2019.11.046. Epub 2019 Dec 4.
• Taieb J, Shi Q, Pederson L, Alberts S, Wolmark N, Van Cutsem E, de Gramont A, Kerr R, Grothey A, Lonardi S, Yoshino T, Yothers G, Sinicrope FA, Zaanan A, André T. Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies. Ann Oncol. 2019 Sep 1;30(9):1466-1471. doi: 10.1093/annonc/mdz208.
• Zaanan A, Shi Q, Taieb J, Alberts SR, Meyers JP, Smyrk TC, Julie C, Zawadi A, Tabernero J, Mini E, Goldberg RM, Folprecht G, Van Laethem JL, Le Malicot K, Sargent DJ, Laurent-Puig P, Sinicrope FA. Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy: A Pooled Analysis From 2 Randomized Clinical Trials. JAMA Oncol. 2018 Mar 1;4(3):379-383. doi: 10.1001/jamaoncol.2017.2899.
• Sinicrope FA, Shi Q, Allegra CJ, Smyrk TC, Thibodeau SN, Goldberg RM, Meyers JP, Pogue-Geile KL, Yothers G, Sargent DJ, Alberts SR. Association of DNA Mismatch Repair and Mutations in BRAF and KRAS With Survival After Recurrence in Stage III Colon Cancers : A Secondary Analysis of 2 Randomized Clinical Trials. JAMA Oncol. 2017 Apr 1;3(4):472-480. doi: 10.1001/jamaoncol.2016.5469.
• Sticca RP, Alberts SR, Mahoney MR, Sargent DJ, Finstuen LM, Nelson GD, Husted TM, Franko J, Goldman CD, Pockaj BA. Current use and surgical efficacy of laparoscopic colectomy in colon cancer. J Am Coll Surg. 2013 Jul;217(1):56-62; discussion 62-3. doi: 10.1016/j.jamcollsurg.2013.02.023. Epub 2013 Apr 24.
• Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH Jr, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012 Apr 4;307(13):1383-93. doi: 10.1001/jama.2012.385.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2015): 3397
• Original Enrollment: Not Provided
• Actual Study Completion Date: November 2012
• Actual Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States, Canada, Puerto Rico

Administrative Information

• NCT Number: NCT00079274
• Other Study ID Numbers: NCI-2009-00639; N0147; U10CA025224 ( U.S. NIH Grant/Contract ); CDR0000355132 ( Registry Identifier: PDQ (Physician Data Query) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Eastern Cooperative Oncology Group

Investigators

• Principal Investigator: Steven A Alberts, MD; North Central Cancer Treatment Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: April 2020