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
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
- 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.
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
3. For patients with colostomy, unwilling to delay revision until at least 28 days after
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.