Combination Chemotherapy With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for High Risk Stage II or Stage III Colon Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms; Colonic Neoplasms
Intervention: Bevacizumab; Capecitabine; 5-Fluorouracil (5-FU); Leucovorin calcium; Oxaliplatin
Intervention description: Administered as an intravenous infusion over 30 - 90 minutes.; Film-coated tablets; Administered as either a bolus injection or continuous intravenous infusion over 22 hours.; Administered as a 200 mg/m^2 infusion over 2 hours.; Administered as an intravenous infusion over 2 hours.
Intervention MeSH terms: Leucovorin; Bevacizumab; Capecitabine; Fluorouracil; Oxaliplatin; Calcium; Levoleucovorin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3451.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stage II colon cancer; stage III colon cancer

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.
    

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).