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Colon AdenocarcinomaPhase 3NCT00096278

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

A Phase 3 study testing Bevacizumab, Fluorouracil and Leucovorin Calcium in people with Colon Adenocarcinoma and Stage IIA Colon Cancer AJCC v7, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Bevacizumab, Fluorouracil and Leucovorin Calcium
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2,710 participants
Where
1 siteUnited States
Study dates
15 Sep 2004to 31 Dec 2012
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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)
  • At the time of randomization, the postoperative platelet count must be >= 100,000/mm^3
  • Bilirubin must be =< ULN for the lab unless the patient has a chronic grade 1 bilirubin elevation due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin
  • Alkaline phosphatase must be < 2.5 x ULN for the lab
  • AST must be < 1.5 x ULN for the lab
  • If AST is > ULN, serologic testing for hepatitis B and C must be performed and results must be negative
  • Serum creatinine =< 1.5 x ULN for the lab
  • Urine protein/creatinine (UPC) ratio of < 1.0; patients with a UPC ratio >= 1.0 must undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate < 1 gm of protein in the 24-hour urine collection in order to participate in the study
  • Patients with prior malignancies, including colorectal cancers, are eligible if they have been disease-free for >= 5 years and are deemed by their physician to be at low risk for recurrence; patients with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum that have been effectively treated are eligible, even if these conditions were diagnosed within 5 years prior to randomization

Who cannot join

  • 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
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  • 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
  • Symptomatic peripheral vascular disease
  • PT/INR > 1.5, unless the patient is on therapeutic doses of warfarin. If so, the following criteria must be met for enrollment:
  • The subject must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin
  • The subject must not have active bleeding or a pathological condition that is associated with a high-risk of bleeding
  • Concomitant halogenated antiviral agents
  • Clinically significant peripheral neuropathy at the time of randomization (defined in the NCI Common Terminology Criteria for Adverse Events Version 3.0 [CTCAE v3.0] as grade 2 or greater neurosensory or neuromotor toxicity)
  • Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude any of the study therapy drugs; specifically excluded are the following cardiac conditions:
  • New York Heart Association Class III or IV cardiac disease
  • History of myocardial infarction within 12 months before study entry
  • Unstable angina within 12 months before study entry; and
  • Symptomatic arrhythmia
  • History of chronic or persistent viral hepatitis or other chronic liver disease
  • Pregnancy or lactation at the time of proposed randomization; eligible patients of reproductive potential (both sexes) must agree to use adequate contraceptive methods during study therapy and for at least 3 months after the completion of bevacizumab
  • Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Surgical Adjuvant Breast and Bowel Project

    Pittsburgh, Pennsylvania, 15212-5234

Other trials in United States

About this study

Official title: A Phase III Clinical Trial Comparing Infusional 5-Fluorouracil (5-FU), Leucovorin, and Oxaliplatin (mFOLFOX6) Every Two Weeks With Bevacizumab to the Same Regimen Without Bevacizumab for the Treatment of Patients With Resected Stages II and III Carcinoma of the Colon

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging disease-free survival (DFS).

SECONDARY OBJECTIVES:

  1. To compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging survival (S).

TERTIARY OBJECTIVES:

  1. To assess the persistence of proteinuria following the discontinuation of bevacizumab.

II. To correlate the development of proteinuria with clinical sequelae. III. To evaluate the risk factors for development of proteinuria. IV. To determine the effect of discontinuation of bevacizumab on hypertension. V. To estimate the incidence of delayed vascular events such as myocardia infarction, CNS ischemia, and thrombosis in patients receiving chemotherapy + bevacizumab.

VI. To assess the effect of bevacizumab on ovarian function in premenopausal women.

VII. To assess the incidence rate of immunogenicity and examine post-treatment serum levels of bevacizumab in patients receiving bevacizumab.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms.

ARM I: 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.

ARM II: 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.

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

Medical subject headings
Colonic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BevacizumabBiological

    Also called Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin

    Given IV

  • FluorouracilDrug

    Also called 5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione

    Given IV

  • Leucovorin CalciumDrug

    Also called Adinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate

    Given IV

  • OxaliplatinDrug

    Also called 1-OHP, Ai Heng, Aiheng, Dacotin

    Given IV

Study groups in NCT00096278
Study groupRoleWhat they receive
Arm I (mFOLFOX6)Active comparatorPatients 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.
Receives: Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Oxaliplatin
Arm II (bevacizumab, mFOLFOX6)ExperimentalPatients 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.
Receives: Biological: Bevacizumab; Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Oxaliplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Disease-free Survival

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

    Measured: 3 years

Secondary outcomes (1)

  1. Survival

    Percentage of patients who did not experience an event where events are defined as death from any cause.

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Nov 2004 (estimated)
  2. Study start15 Sep 2004
  3. Primary completion12 Mar 2009
  4. Study completion31 Dec 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
2,710 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00096278
Sponsor's protocol ID
NCI-2012-03017
Other IDs
NCI-2012-03017, NSABP-C-08, NSABP-C-08, U10CA012027
Status last verified
Jul 2019
First submitted
9 Nov 2004
Last updated
30 Jul 2019

Publications

  • 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.

    PubMed 38315963

  • 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.

    PubMed 33356421

  • 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.

    PubMed 31811950

  • 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.

    PubMed 31268130

  • 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.

    PubMed 28006055

  • 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.

    PubMed 23233715

  • 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.

    PubMed 21997132

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Bevacizumab, Fluorouracil and Leucovorin Calcium in people with Colon Adenocarcinoma and Stage IIA Colon Cancer AJCC v7, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Dec 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Disease-free Survival (time frame: 3 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00096278, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jul 2019.

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