Combination Chemotherapy With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for High Risk Stage II or Stage III Colon Cancer

NCT00112918 | Completed Phase 3 Results

• 4 other identifiers: CDR0000427299P30CA016042UCLA-0412086-01ROCHE-BO17920A
• Study Type: interventional
• Target: 3,451
• Locations: 1 country
• Sites: 1

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab (Bv) may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone in treating colon cancer in adjuvant setting. PURPOSE: This randomized phase III trial is studying two different combination chemotherapy regimens with or without bevacizumab to compare how well they work in treating patients who have undergone surgery for high risk stage II or stage III colon cancer.

Conditions

Colorectal Cancer

Keywords

stage II colon cancer; stage III colon cancer

Outcome Measures

Primary Outcomes (2)

• Disease-free Survival in Stage III Cancer Patients - Time to Event

  Disease-free survival (DFS) was defined as the time from the date of randomization to the time of a recurrence, a new occurrence of colorectal cancer or death due to any cause, whichever occurred first. Patients without an event were censored at the last date the patient was known to be disease-free. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Patients with no tumor assessments after baseline but still alive at the time of the clinical cut-off were censored at day 1.

  From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized).

• Disease-free Survival in Stage III Cancer Patients - Number of Events

  A disease-free survival (DFS) event was composed of a recurrence, a new occurrence of colorectal cancer or death due to any cause. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Triggering events for DFS are reported; a patient can have both recurrence and a new occurrence of colon cancer.

  From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized).

Secondary Outcomes (4)

• Overall Survival in Stage III Cancer Patients - Time to Event

  From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized).

• Overall Survival in Stage III Cancer Patients - Number of Events

  From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized).

• Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis

  From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized).

• Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis

  From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized).

Study Arms (3)

FOLFOX4

ACTIVE COMPARATOR

Weeks 1-24: Oxaliplatin was administered as an 85 mg/m\^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m\^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m\^2 bolus injection, and then as a 600 mg/m\^2 continuous infusion over 22 hours. Leucovorin 200 mg/m\^2 (alone), followed by 5-FU 400 mg/m\^2 bolus injection, and 5-FU 600 mg/m\^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only.

Drug: 5-Fluorouracil (5-FU); Drug: Leucovorin calcium; Drug: Oxaliplatin

FOLFOX4 + Bv

EXPERIMENTAL

Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m\^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m\^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m\^2 bolus injection, and then as a 600 mg/m\^2 continuous infusion over 22 hours. Leucovorin 200 mg/m\^2 (alone), followed by 5-FU 400 mg/m\^2 bolus injection, and 5-FU 600 mg/m\^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Biological: Bevacizumab; Drug: 5-Fluorouracil (5-FU); Drug: Leucovorin calcium; Drug: Oxaliplatin

XELOX+Bv

EXPERIMENTAL

Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m\^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m\^2 twice daily (equivalent to a total daily dose of 2000 mg/m\^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Biological: Bevacizumab; Drug: Capecitabine; Drug: Oxaliplatin

Interventions

Bevacizumab BIOLOGICAL

Administered as an intravenous infusion over 30 - 90 minutes.

FOLFOX4 + Bv; XELOX+Bv

Capecitabine DRUG

Film-coated tablets

Also known as: Xeloda®

XELOX+Bv

5-Fluorouracil (5-FU) DRUG

Administered as either a bolus injection or continuous intravenous infusion over 22 hours.

FOLFOX4; FOLFOX4 + Bv

Leucovorin calcium DRUG

Administered as a 200 mg/m\^2 infusion over 2 hours.

FOLFOX4; FOLFOX4 + Bv

Oxaliplatin DRUG

Administered as an intravenous infusion over 2 hours.

FOLFOX4; FOLFOX4 + Bv; XELOX+Bv

Eligibility Criteria

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

You may qualify if:

• Signed written informed consent obtained prior to any study specific screening procedures.
• Patient willing and able to comply with the protocol.
• Age ≥ 18 years-of-age.
• Histologically confirmed colon carcinoma, American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) Stage II or Stage III defined as a tumor location ≥ 15 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. The patient was not to be a candidate for (neo) adjuvant radiotherapy. Note: Stage II patients were to be considered as high-risk patients fulfilling one of the following criteria:
• T4 tumours,
• Patients presenting with bowel obstruction or perforation,
• Histological signs of vascular invasion (i.e. blood and lymphatic vessels) or perineural invasion,
• Patients aged less than 50 years,
• Patients with sub-optimal surgery (less than 12 nodes analyzed).
• Curative surgery not less than 4 and not more than 8 weeks prior to randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Life expectancy of ≥ 5 years.

You may not qualify if:

• Macroscopic or microscopic evidence of remaining tumour. Patients should never have had any evidence of metastatic disease (including presence of tumour cells in the ascites). The isolated finding of cytokeratin positive cells in bone marrow is not considered evidence of metastatic disease for purposes of this study.
• Carcinoembryonic antigen \> 1.5 x upper limit of normal (ULN) after surgery (during screening period).
• For patients with colostomy, unwilling to delay revision until at least 28 days after treatment completion.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, not fully healed wounds, or anticipation of the need for major surgical procedure during the course of the study. Any central venous access device (CVAD) for chemotherapy administration must be inserted at least 2 days prior to treatment start.
• Previous anti-angiogenic treatment for any malignancy; cytotoxic chemotherapy, radiotherapy or immunotherapy for colon cancer.
• Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
• Females with a positive or no pregnancy test (within 7 days before treatment start) unless childbearing potential can be otherwise excluded (postmenopausal i.e. amenorrheic for at least 2 years, hysterectomy or oophorectomy).
• Lactating women.
• Fertile women (\< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.
• History or evidence upon physical examination of central nervous disease (CNS) disease (eg, primary brain tumour, seizure not controlled with standard medical therapy, any brain metastases).
• History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake.
• Clinically significant (ie, active) cardiovascular disease. This includes, but is not limited to, the following examples: cerebrovascular accidents (≤ 6 months prior to randomization), myocardial infarction (≤ 1 year prior to randomization), uncontrolled hypertension (\>150/100 mmHg) while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, clinically significant electrocardiogram (ECG) findings (e.g. QTc ≥ 440 msecs \[male\] 460 msecs \[female\] or ≥ 2º atrioventricular block, etc.).
• Patients who suffer from serious cardiac arrhythmia requiring medication can enter the study only if they are considered to be in a stable condition regarding both the arrhythmia and their medication. Patients with pacemakers are allowed to enter the study only if they are considered as being in a stable condition. In case of doubt, the investigator should obtain a consultation with a local cardiologist.
• Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication.
• Interstitial pneumonia or extensive symptomatic fibrosis of the lungs.

Sponsors & Collaborators

• Hoffmann-La Roche: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Jonsson Comprehensive Cancer Center at UCLA

Los Angeles, California, 90095-1781, United States

Location

Related Publications (7)

• Gallois C, Shi Q, Meyers JP, Iveson T, Alberts SR, de Gramont A, Sobrero AF, Haller DG, Oki E, Shields AF, Goldberg RM, Kerr R, Lonardi S, Yothers G, Kelly C, Boukovinas I, Labianca R, Sinicrope FA, Souglakos I, Yoshino T, Meyerhardt JA, Andre T, Papamichael D, Taieb J. Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials. J Clin Oncol. 2023 Feb 1;41(4):803-815. doi: 10.1200/JCO.21.02726. Epub 2022 Oct 28.

  PMID: 36306483 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

• Chibaudel B, Henriques J, Rakez M, Brenner B, Kim TW, Martinez-Villacampa M, Gallego-Plazas J, Cervantes A, Shim K, Jonker D, Guerin-Meyer V, Mineur L, Banzi C, Dewdney A, Dejthevaporn T, Bloemendal HJ, Roth A, Moehler M, Aranda E, Van Cutsem E, Tabernero J, Schmoll HJ, Hoff PM, Andre T, de Gramont A. Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer: A Secondary Analysis of the AVANT Trial. JAMA Netw Open. 2020 Oct 1;3(10):e2020425. doi: 10.1001/jamanetworkopen.2020.20425.

  PMID: 33074326 DERIVED

• Salem ME, Yin J, Goldberg RM, Pederson LD, Wolmark N, Alberts SR, Taieb J, Marshall JL, Lonardi S, Yoshino T, Kerr RS, Yothers G, Grothey A, Andre T, De Gramont A, Shi Q. Evaluation of the change of outcomes over a 10-year period in patients with stage III colon cancer: pooled analysis of 6501 patients treated with fluorouracil, leucovorin, and oxaliplatin in the ACCENT database. Ann Oncol. 2020 Apr;31(4):480-486. doi: 10.1016/j.annonc.2019.12.007. Epub 2020 Jan 16.

  PMID: 32085892 DERIVED

• Andre T, Vernerey D, Im SA, Bodoky G, Buzzoni R, Reingold S, Rivera F, McKendrick J, Scheithauer W, Ravit G, Fountzilas G, Yong WP, Isaacs R, Osterlund P, Liang JT, Creemers GJ, Rakez M, Van Cutsem E, Cunningham D, Tabernero J, de Gramont A. Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol. 2020 Feb;31(2):246-256. doi: 10.1016/j.annonc.2019.12.006. Epub 2019 Dec 18.

  PMID: 31959341 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

• de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, Andre T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. doi: 10.1016/S1470-2045(12)70509-0. Epub 2012 Nov 16.

  PMID: 23168362 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms

Interventions

Bevacizumab; Capecitabine; Fluorouracil; Leucovorin; Oxaliplatin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffman-LaRoche

800-821-8590

Study Officials

• Joel Randolph Hecht, MD

  Jonsson Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 2, 2005
• First Posted: June 3, 2005
• Study Start: December 1, 2004
• Primary Completion: June 1, 2010
• Study Completion: June 1, 2012
• Last Updated: August 27, 2013
• Results First Posted: September 6, 2012

Record last verified: 2013-06

Locations

US (1)