A Study of Onartuzumab (MetMAb) in Combination With Bevacizumab Compared to Bevacizumab Alone or Onartuzumab Monotherapy in Patients With Recurrent Glioblastoma

• Progression-free survival (investigator-assessed): onartuzumab + bevacizumab versus placebo + bevacizumab [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Progression-free survival (investigator-assessed) in subgroup with Met-positive glioblastoma: onartuzumab + bevacizumab versus placebo + bevacizumab [ Time Frame: 21 months ] [ Designated as safety issue: No ]

• Overall survival in all patients [ Time Frame: 21 months ] [ Designated as safety issue: Yes ]
• Overall survival rate at 9 months (OS-9) in all patients [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Progression-free survival at 6 months (PFS-6) in all patients [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Objective response rate in all patients according to Response Assessment in Neuro-Oncology (RANO) criteria [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Duration of response in all patients [ Time Frame: 21 months ] [ Designated as safety issue: Yes ]
• Safety: Incidence of adverse events in all patients [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Immunogenicity: anti-therapeutic antibodies (ATAs) levels [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Overall survival in Met-positive glioblastoma patients [ Time Frame: 21 months ] [ Designated as safety issue: Yes ]
• Overall survival rate at 9 months (OS-9) in Met-positive glioblastoma patients [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Progression-free survival at 6 months (PFS-6) in patients with Met positive tumors [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Objective response rate in patients with Met-positive tumors according to Response Assessment in Neuro-Oncology (RANO) criteria [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Duration of response in patients with Met-positive tumors [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Safety: Incidence of adverse events in patients with Met-positive tumors [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Immunogenicity: anti-therapeutic antibodies (ATAs) levels [ Time Frame: Pre-dose and 30 min post-dose Day 1, Cycles 1-4 ] [ Designated as safety issue: No ]
• Pharmacokinetics: Cmin/Cmax [ Time Frame: Pre-dose and 30 min post-dose Day 1, Cycles 1-4 ] [ Designated as safety issue: No ]

This randomized, double-blind, placebo-controlled, multicenter phase II study will evaluate the safety and efficacy of onartuzumab (MetMAb) in combination with bevacizumab as compared to bevacizumab alone and of onartuzumab as monotherapy in patients with recurrent glioblastoma. Patients will be randomized 1:1:1 to receive either placebo plus bevacizumab every 3 weeks, or onartuzumab plus bevacizumab, or onartuzumab plus placebo. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

• Drug: onartuzumab
  Intravenous repeating dose
• Drug: bevacizumab
  Intravenous repeating dose
• Drug: onartuzumab placebo
  Intravenous repeating dose
• Drug: bevacizumab placebo
  Intravenous repeating dose

• Active Comparator: A: placebo + bevacizumab
  Interventions:

  • Drug: bevacizumab
  • Drug: onartuzumab placebo
• Experimental: B: onartuzumab + bevacizumab
  Interventions:

  • Drug: onartuzumab
  • Drug: bevacizumab
• Experimental: C: onartuzumab + placebo
  Interventions:

  • Drug: onartuzumab
  • Drug: bevacizumab placebo

Inclusion Criteria:

• Adult patients, >/= 18 years of age
• Histologically confirmed glioblastoma at first recurrence after concurrent or adjuvant chemoradiotherapy
• Imaging confirmation of first tumor progression or regrowth as defined by RANO criteria
• Prior treatment with temozolomide
• No more than one prior chemotherapy
• No prior treatment with bevacizumab or other VEGF- or VEGF-receptor-targeted agent
• No prior exposure to experimental treatment targeting either HGF or Met pathway
• No prior treatment with prolifeprospan 20 with carmustine wafer
• No prior intracerebral agent
• Recovery from the toxic effects of prior therapy
• No evidence of recent haemorrhage on baseline MRI of the brain
• No need for urgent palliative intervention for primary disease (e.g. impending herniation)
• Karnofsky performance status >/= 70%
• Stable or decreasing dose of corticosteroids within 5 days prior to randomization
• Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field
• Patients who have undergone recent surgery for recurrent or progressive tumor are eligible provided that: surgery must have confirmed the recurrence, a minimum of 28 days must have elapsed from the day of surgery to randomization and for core or needle biopsy, a minimum of 7 days must have elapsed prior to randomization, and craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization
• Availability of formalin fixed paraffin embedded tumor tissue representative of glioblastoma

Exclusion Criteria:

• Pregnant or lactating women
• Inadequate hematologic, renal or liver function
• History or presence of serious cardio-vascular disease
• New York Heart Association Grade II or greater congestive heart failure
• History of another malignancy in the previous 3 years, except for in situ cancer or basal or squamous cell skin cancer
• Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg while on antihypertensive medication)
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomization
• Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
• Known hypersensitivity to any excipients of onartuzumab or bevacizumab