A Dose- and Efficacy-Finding Study of RO5323441 in Combination With Avastin (Bevacizumab) in Patients With Recurrent Glioblastoma

• Dose-Finding Part: Dose limiting toxicity [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Progression-free survival [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]

• Dose-Finding part: Pharmacokinetics of RO5323441 and Avastin when combined [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Dose-Finding part: Safety (incidence of adverse events) [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Dose-Finding part: Efficacy (tumor response according to Response Assessment in Neurooncology (RANO) criteria [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Dose-Finding part: Glioblastoma biomarker [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Overall Response Rate [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Disease Control Rate [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Duration of Response [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Progression-free survival [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Overall Survival [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Safety (incidence of adverse events) [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Glioblastoma biomarker [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]
• Efficacy-Finding part: Pharmacokinetics (serum levels) of RO5323441 and Avastin when combined [ Time Frame: From baseline to disease progression or death (>12 months) ] [ Designated as safety issue: No ]

This open-label, multicenter study will evaluate the safety and efficacy of RO5323441 in combination with Avastin (bevacizumab) in patients with recurrent glioblastoma. In the dose-finding part, patients will receive intravenous escalating doses of RO5323441 in combination with 10 mg/kg Avastin once every two weeks. In the efficacy-finding part, patients will be randomized to receive the established dose (from the dose-finding part) of RO5323441 plus Avastin or Avastin alone. Patients in the dose-finding part may continue treatment with RO5323441 and Avastin on the study until evidence of progressive disease or unacceptable adverse events happen. In the efficacy-finding part, patients will receive study treatment until disease progression or death.

• Drug: RO5323441 + bevacizumab [Avastin]
  Dose-Finding part: RO5323441 intravenous escalating doses once every two weeks; Efficacy-Finding part: established dose from the Dose-Finding part; Avastin: 10 mg/kg intravenously once every two weeks
• Drug: bevacizumab [Avastin]
  Efficacy-Finding part: 10 mg/kg intravenously once every two weeks

• Experimental: 1
  Intervention: Drug: RO5323441 + bevacizumab [Avastin]
• Experimental: 2
  Intervention: Drug: bevacizumab [Avastin]

Inclusion Criteria:

• Adult patients, >/=18 years of age
• Histologically confirmed glioblastoma
• Radiographic demonstration of disease progression by Response Assessment in Neurooncology (RANO) criteria following prior therapy
• Availability of at least 1 formalin-fixed paraffin-embedded tumor tissue sample
• If receiving corticosteroids, patients must have been on a stable or decreasing dose of corticosteroids
• Prior standard radiotherapy for glioblastoma
• Karnofsky Performance status >/=70
• Over 4 weeks since prior surgical resection
• Over 12 weeks from radiotherapy
• Over 4 weeks from anticancer agents

Exclusion Criteria:

• Patients had second or later glioblastoma relapse
• Patients received more than one systemic treatment regimen for glioblastoma
• Patients have secondary glioblastoma
• Prior treatment with Avastin
• Patients unable to undergo Magnetic Resonance Imaging (MRI)