Fluorouracil, Leucovorin, and Oxaliplatin With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II or Stage III Colon Cancer

NCT00096278 | Completed Phase 3 Results

• 3 other identifiers: NCI-2012-03017NSABP-C-08U10CA012027
• Study Type: interventional
• Target: 2,710
• Locations: 1 country
• Sites: 1

Brief Summary

This randomized phase III trial is studying giving oxaliplatin, leucovorin, and fluorouracil together with bevacizumab to see how well it works compared to oxaliplatin, leucovorin, and fluorouracil alone in treating patients who have undergone surgery for stage II or stage III colon cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as bevacizumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Bevacizumab may also stop the growth of tumor cells by stopping blood flow to the tumor. Giving chemotherapy together with bevacizumab may kill more tumor cells. It is not yet known whether treatment with oxaliplatin, leucovorin, and fluorouracil is more effective with or without bevacizumab in treating patients who have undergone surgery for colon cancer.

Conditions

Colon Adenocarcinoma; Stage IIA Colon Cancer AJCC v7; Stage IIB Colon Cancer AJCC v7; Stage IIC Colon Cancer AJCC v7; Stage IIIA Colon Cancer AJCC v7; Stage IIIB Colon Cancer AJCC v7; Stage IIIC Colon Cancer AJCC v7

Outcome Measures

Primary Outcomes (1)

• Disease-free Survival

  Where events are defined as recurrence, second primary cancer, or death from any cause

  3 years

Secondary Outcomes (1)

• Survival

  5 years

Other Outcomes (7)

• Bevacizumab Immunogenicity and Post-treatment Serum Levels of Bevacizumab in Patients Receiving Bevacizumab

  Group 2: Pre-therapy, every 2 weeks during chemotherapy/bevacizumab therapy, every 6 weeks during bevacizumab therapy and at 3 and 6 months after completion of bevacizumab therapy

• Ovarian Function in Premenopausal Women as Measured by Serum Ovarian Function Test

  Group 2: Measured pre-therapy and then every 6 months for 2 years following randomization

• Delayed Vascular Events Such as Myocardial Infarction, Central Nervous System (CNS) Ischemia, and Thrombosis in Patients Receiving Chemotherapy + Bevacizumab

  Events measured regularly during chemotherapy and bevacizumab therapy

Study Arms (2)

Arm I (mFOLFOX6)

ACTIVE COMPARATOR

Patients receive adjuvant chemotherapy comprising concurrent oxaliplatin and leucovorin calcium IV over 2 hours on day 1. Patients also receive adjuvant fluorouracil IV over 2-4 minutes on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity.

Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Oxaliplatin

Arm II (bevacizumab, mFOLFOX6)

EXPERIMENTAL

Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive adjuvant oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. Treatment repeats every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity. After completion of adjuvant chemotherapy, patients continue to receive bevacizumab alone every 14 days for 6 months in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab; Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Oxaliplatin

Interventions

Bevacizumab BIOLOGICAL

Given IV

Also known as: Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar SCT501, HD204, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501

Arm II (bevacizumab, mFOLFOX6)

Fluorouracil DRUG

Given IV

Also known as: 5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, 5FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757

Arm I (mFOLFOX6); Arm II (bevacizumab, mFOLFOX6)

Leucovorin Calcium DRUG

Given IV

Also known as: Adinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, citrovorum factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, Wellcovorin

Arm I (mFOLFOX6); Arm II (bevacizumab, mFOLFOX6)

Oxaliplatin DRUG

Given IV

Also known as: 1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669

Arm I (mFOLFOX6); Arm II (bevacizumab, mFOLFOX6)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must consent to be in the study and must have signed and dated an IRB approved consent form conforming to federal and institutional guidelines
• Randomization must occur during the three-week interval beginning on postoperative day 29 and ending on postoperative day 50
• The distal extent of the tumor must be \>= 12 cm from the anal verge on endoscopy; if the patient is not a candidate for endoscopy, then the distal extent of the tumor must be \>= 12 cm from the anal verge as determined by surgical examination
• The patient must have had an en bloc complete gross resection of tumor (curative resection) by open laparotomy or laparoscopically-assisted colectomy; patients who have had a two-stage surgical procedure, to first provide a decompressive colostomy and then in a later procedure to have the definitive surgical resection, are eligible
• Patients must have histologically confirmed adenocarcinoma of the colon that meets one of the criteria below:
• Stage II carcinoma (T3,4 N0 M0); the tumor invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissues (T3); or directly invades other organs or structures, and/or perforates visceral peritoneum (T4)
• Stage III carcinoma (any T N1,2 M0); the tumor has invaded to any depth, with involvement of regional lymph nodes
• Patients with T4 tumors that have involved an adjacent structure (e.g., bladder, small intestine, ovary, etc.) by direct extension from the primary tumor are eligible if all of the following conditions are met:
• All or a portion of the adjacent structure was removed en bloc with the primary tumor
• In the opinion of the surgeon, all grossly visible tumor was completely resected ("curative resection")
• Histologic evaluation by the pathologist confirms the margins of the resected specimen are not involved by malignant cells; and
• Local radiation therapy will not be utilized
• Patients with more than one synchronous primary colon tumor are eligible; (staging classification will be based on the more advanced primary tumor)
• Patients must have an ECOG performance status of 0 or 1
• At the time of randomization, postoperative absolute granulocyte count (AGC) must be \>= 1500/mm\^3 (or \< 1500/mm\^3, if in the opinion of the investigator, this represents an ethnic or racial variation of normal)

You may not qualify if:

• Patients \< 18 years old
• Colon tumor other than adenocarcinoma, i.e., sarcoma, lymphoma, carcinoid, etc
• Rectal tumors, i.e. a tumor located \< 12 cm from the anal verge on endoscopy, or by surgical exam if the patient is not a candidate for endoscopy
• Isolated, distant, or non-contiguous intra-abdominal metastases, even if resected
• Any systemic or radiation therapy initiated for this malignancy
• Any significant bleeding that is not related to the primary colon tumor within 6 months before study entry
• Serious or non-healing wound, skin ulcers, or bone fracture
• Gastroduodenal ulcer(s) determined by endoscopy to be active
• Invasive procedures defined as follows:
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
• Anticipation of need for major surgical procedures during the course of the study
• Core biopsy or other minor procedure, excluding placement of a vascular access device, within 7 days prior to randomization
• Uncontrolled blood pressure defined as \> 150/90 mmHg
• History of TIA or CVA
• History of arterial thrombotic event within 12 months before study entry

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• NSABP Foundation Inc: collaborator

Study Sites (1)

National Surgical Adjuvant Breast and Bowel Project

Pittsburgh, Pennsylvania, 15212-5234, United States

Location

Related Publications (7)

• Chen L, Wang Y, Cai C, Ding Y, Kim RS, Lipchik C, Gavin PG, Yothers G, Allegra CJ, Petrelli NJ, Suga JM, Hopkins JO, Saito NG, Evans T, Jujjavarapu S, Wolmark N, Lucas PC, Paik S, Sun M, Pogue-Geile KL, Lu X. Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer. J Clin Oncol. 2024 May 1;42(13):1520-1530. doi: 10.1200/JCO.23.01080. Epub 2024 Feb 5.

  PMID: 38315963 DERIVED

• Cohen R, Taieb J, Fiskum J, Yothers G, Goldberg R, Yoshino T, Alberts S, Allegra C, de Gramont A, Seitz JF, O'Connell M, Haller D, Wolmark N, Erlichman C, Zaniboni A, Lonardi S, Kerr R, Grothey A, Sinicrope FA, Andre T, Shi Q. Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials. J Clin Oncol. 2021 Feb 20;39(6):642-651. doi: 10.1200/JCO.20.01600. Epub 2020 Dec 23.

  PMID: 33356421 DERIVED

• 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.

  PMID: 31811950 DERIVED

• 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, Andre 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.

  PMID: 31268130 DERIVED

• 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.

  PMID: 28006055 DERIVED

• Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013 Jan 20;31(3):359-64. doi: 10.1200/JCO.2012.44.4711. Epub 2012 Dec 10.

  PMID: 23233715 DERIVED

• Yothers G, Sargent DJ, Wolmark N, Goldberg RM, O'Connell MJ, Benedetti JK, Saltz LB, Dignam JJ, Blackstock AW; ACCENT Collaborative Group. Outcomes among black patients with stage II and III colon cancer receiving chemotherapy: an analysis of ACCENT adjuvant trials. J Natl Cancer Inst. 2011 Oct 19;103(20):1498-506. doi: 10.1093/jnci/djr310. Epub 2011 Oct 12.

  PMID: 21997132 DERIVED

MeSH Terms

Conditions

Colonic Neoplasms

Interventions

Bevacizumab; Immunoglobulin G; Disulfides; Fluorouracil; dehydroftorafur; Leucovorin; Oxaliplatin

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin Isotypes; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes

Results Point of Contact

• Title: Director, Division of Regulatory Affairs
• Organization: NSABP Foundation, Inc.

412-330-4600

Study Officials

• Carmen J Allegra

  NSABP Foundation Inc

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2004
• First Posted: November 9, 2004
• Study Start: September 15, 2004
• Primary Completion: March 12, 2009
• Study Completion: December 31, 2012
• Last Updated: July 30, 2019
• Results First Posted: December 3, 2012

Record last verified: 2019-07

Locations

US (1)