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

• ClinicalTrials.gov Identifier: NCT00112918
• Recruitment Status: Completed
• First Posted: June 3, 2005
• Results First Posted: September 6, 2012
• Last Update Posted: August 27, 2013
• Sponsor: Hoffmann-La Roche
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: June 2, 2005
• First Posted Date: June 3, 2005
• Results First Submitted Date: June 1, 2012
• Results First Posted Date: September 6, 2012
• Last Update Posted Date: August 27, 2013
• Study Start Date: December 2004
• Actual Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 6, 2012)

• Disease-free Survival in Stage III Cancer Patients - Time to Event [ Time Frame: From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]
  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.
• Disease-free Survival in Stage III Cancer Patients - Number of Events [ Time Frame: From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]
  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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: June 19, 2013)

• Overall Survival in Stage III Cancer Patients - Time to Event [ Time Frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]
  Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the analysis were censored at the date they were last known to be alive.
• Overall Survival in Stage III Cancer Patients - Number of Events [ Time Frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]
  An overall survival event was death due to any cause.
• Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis [ Time Frame: From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). ]
  Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the clinical cut-off date (30 June 2012) were censored at the date they were last known to be alive.
• Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis [ Time Frame: From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). ]
  An overall survival event was death due to any cause.

• 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: Combination Chemotherapy With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for High Risk Stage II or Stage III Colon Cancer
• Official Title: A Randomized, Three Arm Multinational Phase III Study to Investigate Bevacizumab (q3w or q2w) in Combination With Either Intermittent Capecitabine Plus Oxaliplatin (XELOX) (q3w) or Fluorouracil/Leucovorin With Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 Regimen Alone as Adjuvant Chemotherapy in Colon Carcinoma: The AVANT Study

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.

Detailed Description

This was an open-label Phase III, multicenter, multinational, randomized, 3-arm study designed to evaluate the efficacy and safety of bevacizumab in combination with either intermittent fluorouracil/leucovorin with oxaliplatin (FOLFOX4) or capecitabine plus oxaliplatin (XELOX) versus FOLFOX4 regimen alone, as adjuvant chemotherapy in colon carcinoma.

The treatment phase consisted of two parts of 24 weeks for a total of 48 weeks. The first part (weeks 1 to 24) consisted of treatment with either FOLFOX4, FOLFOX4 in combination with bevacizumab, or XELOX in combination with bevacizumab. The second part (weeks 25 to 48) consisted of single-agent bevacizumab for patients randomized to either bevacizumab-containing arm, but was only an observation period for patients assigned to the FOLFOX4-alone arm.

Patients were to be followed for recurrence/new occurrence of colorectal cancer and survival. Patients who experienced a confirmed recurrence, occurrence of a new colorectal cancer during therapy, or experienced unacceptable toxicity were to be taken off study treatment but remain in study follow-up. Patients that came off therapy due to a confirmed recurrence/appearance of new colorectal cancer, were to be followed for survival until the end of the study follow-up period. The primary analysis was performed 36 months after the last patient has been randomized. After the primary analysis, patients continue to be followed for survival for at least a further 2 years ie, until all patients have been followed-up for at least 5 years following randomization.

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

Intervention

• Biological: Bevacizumab
  Administered as an intravenous infusion over 30 - 90 minutes.
• Drug: Capecitabine
  Film-coated tablets
  Other Name: Xeloda®
• Drug: 5-Fluorouracil (5-FU)
  Administered as either a bolus injection or continuous intravenous infusion over 22 hours.
• Drug: Leucovorin calcium
  Administered as a 200 mg/m^2 infusion over 2 hours.
• Drug: Oxaliplatin
  Administered as an intravenous infusion over 2 hours.

Study Arms

• Active Comparator: FOLFOX4

  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.

  Interventions:

  • Drug: 5-Fluorouracil (5-FU)
  • Drug: Leucovorin calcium
  • Drug: Oxaliplatin
• Experimental: FOLFOX4 + Bv

  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).

  Interventions:

  • Biological: Bevacizumab
  • Drug: 5-Fluorouracil (5-FU)
  • Drug: Leucovorin calcium
  • Drug: Oxaliplatin
• Experimental: XELOX+Bv

  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).

  Interventions:

  • Biological: Bevacizumab
  • Drug: Capecitabine
  • Drug: Oxaliplatin

Publications *

• 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.
• 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.
• 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. Erratum In: JAMA Netw Open. 2021 Feb 1;4(2):e210700.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 6, 2012): 3451
• Original Enrollment: Not Provided
• Actual Study Completion Date: June 2012
• Actual Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Signed written informed consent obtained prior to any study specific screening procedures.
2. Patient willing and able to comply with the protocol.
3. Age ≥ 18 years-of-age.

4. 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).
5. Curative surgery not less than 4 and not more than 8 weeks prior to randomization.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Life expectancy of ≥ 5 years.

Exclusion Criteria

1. 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.
2. Carcinoembryonic antigen > 1.5 x upper limit of normal (ULN) after surgery (during screening period).
3. For patients with colostomy, unwilling to delay revision until at least 28 days after treatment completion.
4. 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.
5. Previous anti-angiogenic treatment for any malignancy; cytotoxic chemotherapy, radiotherapy or immunotherapy for colon cancer.
6. 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).
7. 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).
8. Lactating women.
9. Fertile women (< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.
10. 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).
11. History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake.

12. 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.

13. Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication.
14. Interstitial pneumonia or extensive symptomatic fibrosis of the lungs.
15. Known peripheral neuropathy ≥ Common terminology criteria for adverse events (CTCAE) version 3.0 Grade 1. Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible.
16. Organ allografts requiring immunosuppressive therapy.
17. Serious, non-healing wound, ulcer, or bone fracture.
18. Evidence of bleeding diathesis or coagulopathy.
19. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes.
20. Chronic, daily treatment with high-dose aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day).
21. Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
22. Serious intercurrent infections (uncontrolled or requiring treatment).
23. Known dihydropyrimidine dehydrogenase deficiency.
24. Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
25. Patients with known allergy to Chinese hamster ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other components of the study drugs.
26. History or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications.

27. Presence of proteinuria at baseline as defined by:

    - Patients with > 1 g of protein/24 hour by a 24-hour urine collection.

28. Any laboratory values at baseline are as follows:

Haematology:

• Absolute neutrophil count (ANC) < 1.5 x 109/L
• Platelet count < 100 x 10^9/L
• Haemoglobin < 9 g/dL (may be transfused to maintain or exceed this level)
• International normalized ratio (INR) > 1.5
• Activated partial prothrombin time (APTT) ≥ 1.5 x ULN

Biochemistry:

• Total bilirubin > 1.5 x ULN
• aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) > 2.5 x ULN
• Alkaline phosphatase (ALP) > 2.5 x ULN
• Serum creatinine > 1.5 x ULN or creatinine clearance ≤ 50 mL/min (e.g. Cockcroft-Gault formula).

Sex/Gender

• Sexes Eligible for Study: All

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

Administrative Information

• NCT Number: NCT00112918
• Other Study ID Numbers: CDR0000427299; P30CA016042 ( U.S. NIH Grant/Contract ); UCLA-0412086-01; ROCHE-BO17920A
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Not Provided
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Jonsson Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Joel Randolph Hecht, MD; Jonsson Comprehensive Cancer Center

• PRS Account: Hoffmann-La Roche
• Verification Date: June 2013