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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

Phase 3
18 Years
Not Enrolling
Colorectal Cancer

Thank you

Trial Information

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

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

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.

Inclusion Criteria

Inclusion Criteria

1. Signed written informed consent obtained prior to any study specific screening

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

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

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:


- 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


- 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).

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

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.

Outcome Time Frame:

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

Safety Issue:


Principal Investigator

Joel Randolph Hecht, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Jonsson Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

December 2004

Completion Date:

June 2012

Related Keywords:

  • Colorectal Cancer
  • stage II colon cancer
  • stage III colon cancer
  • Colonic Neoplasms
  • Colorectal Neoplasms



Jonsson Comprehensive Cancer Center at UCLA Los Angeles, California  90095-1781