A Study Comparing the Efficacy and Safety of Vanucizumab and FOLFOX With Bevacizumab and FOLFOX in Participants With Untreated Metastatic Colorectal Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: 5-FU; Bevacizumab; Folinic acid; Oxaliplatin; Vanucizumab
Intervention description: 5-FU will be administered according to dose and schedule described in respective arm.; Bevacizumab will be administered according to dose and schedule described in respective arm.; Folinic acid will be administered according to dose and schedule described in respective arm.; Oxaliplatin will be administered according to dose and schedule described in respective arm.; Vanucizumab will be administered according to dose and schedule described in respective arm.
Intervention MeSH terms: Leucovorin; Folic Acid; Bevacizumab; Oxaliplatin; Levoleucovorin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 197.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a Phase 2 multicenter, randomized, parallel arms, double-blind study of vanucizumab
      to evaluate the efficacy and safety of vanucizumab in combination with oxaliplatin, folinic
      acid, and 5-fluorouracil (5-FU) (mFOLFOX-6) versus bevacizumab (Avastin) + mFOLFOX-6 in
      participants with previously untreated metastatic colorectal cancer (mCRC). The study
      consists of 2 parts: a safety run-in open-label, single-arm part (Part 1) and a randomized,
      parallel-arms, double-blind part (Part 2). During Part 1 at least 6 eligible participants
      will receive 2000 milligrams (mg) vanucizumab every 2 weeks + mFOLFOX-6 in order to confirm
      the dose and schedule that will be used in Part 2. In Part 2, all eligible participants will
      be randomized in a ratio of 1:1 to receive either mFOLFOX-6 + vanucizumab or mFOLFOX-6 +
      bevacizumab. Study treatment (induction and maintenance) will be given on Day 1 of each
      14-day cycle. Induction therapy will consist of up to 8 cycles of mFOLFOX-6 plus either
      bevacizumab or vanucizumab. Maintenance therapy will consist of 5-fluorouracil and folinic
      acid plus either vanucizumab or bevacizumab for up to 24 months or until disease progression,
      unacceptable toxicity, Investigator decision or consent withdrawal, whichever occurs first.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed mCRC not amenable to potentially curative
             resection with at least one measurable metastatic lesion, as defined by RECIST v1.1

          -  Eastern Cooperative Oncology Group (World Health Organization) performance status of 0
             or 1

          -  Adequate hematologic, liver, coagulation, renal, and cardiovascular function

          -  Recovery from all reversible AEs of previous medical therapies to baseline or National
             Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 1,
             except for alopecia (any grade)

          -  Negative serum pregnancy test within 7 days prior to starting study treatment in
             premenopausal women and women less than (< 2) years after the onset of menopause

        Exclusion Criteria:

          -  Any prior systemic therapy (including chemotherapy, antibody therapy, tyrosine kinase
             inhibitors, immunotherapy, hormonal therapy) before Day 1 of Cycle 1 for treatment of
             mCRC

          -  Malignancies other than CRC within 5 years prior to randomization, except for those
             with a minimal risk of metastasis or death, such as adequately treated carcinoma in
             situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer,
             ductal carcinoma in situ treated surgically with curative intent

          -  Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to
             Day 1 of Cycle 1, except palliative radiotherapy to bone lesions within 7 days prior
             to Day 1 of Cycle 1

          -  Treatment with any other investigational agent or participation in another clinical
             trial with therapeutic intent within 28 days prior to Day 1 of Cycle

          -  Pregnant or lactating women

          -  Symptomatic central nervous system (CNS) metastases or carcinomatous meningitis.
             Asymptomatic patients must be clinically stable with regard to their CNS/ meningeal
             metastatic involvement, have completed previous therapy (including radiation and/ or
             surgery) at least 4 weeks prior to study drug administration, are not receiving
             steroid therapy or taper, and are not receiving anti-convulsive medication for any CNS
             involvement

          -  Active infection requiring IV antibiotics

          -  Active autoimmune disease that is not controlled by nonsteroidal anti-inflammatory
             drugs (NSAIDs), inhaled corticosteroids, or the equivalent of less than or equal to
             (</=) 10 mg/day prednisone

          -  Sensory peripheral neuropathy greater than or equal to (>/=) Grade 2

          -  Significant cardiovascular or cerebrovascular disease within 6 months prior to Day 1
             of Cycle 1

          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation

          -  Current use of anticoagulants at therapeutic doses within 7 days prior to study drug
             administration. Prophylactic use of unfractioned heparin or low molecular weight
             heparin is permitted

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1 of Cycle 1 or abdominal surgery, abdominal interventions or significant
             abdominal traumatic injury within 60 days prior to Day 1 of Cycle 1

          -  History of intra-abdominal inflammatory process within 6 months prior to Day 1 of
             Cycle 1 including but not limited to peptic ulcer disease, diverticulitis, or colitis

          -  Colonic prosthesis (stent) implant in place

          -  History of abdominal or tracheo-oesophageal fistula or gastrointestinal (GI)
             perforation or intra abdominal abscess within 6 months prior to Day 1 of Cycle 1

          -  History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction
             including sub-occlusive disease related to the underlying disease or a requirement for
             routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months
             prior to Day 1 of Cycle 1

          -  Chronic daily treatment with NSAID (occasional use for the symptomatic relief of
             medical conditions, for example headache or fever is allowed)

          -  Chronic daily treatment with corticosteroids (dose > 10 mg/day methylprednisolone
             equivalent) excluding inhaled steroids

          -  Evidence of abdominal free air not explained by paracentesis or recent surgical
             procedure

          -  Metastatic disease that involve major airways or blood vessels, or centrally located
             mediastinal tumor masses (< 30 millimeter from the carina) of large volume

          -  History of bronchopulmonary hemorrhage NCI CTCAE >/= Grade 2 within 2 months prior to
             randomization

          -  Severe, nonhealing or open wound, active ulcer, or untreated bone fracture

          -  Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene
             polymorphism predisposing the patient for 5-FU toxicity

          -  Any other condition, diseases, metabolic dysfunction, active or uncontrolled
             infections/inflammation, physical examination finding, mental status or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates participation in the clinical study due to safety concerns, compliance
             with clinical study procedures or that may affect the interpretation of the results