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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
Open-label, Combined Dose-finding (Phase I) and Efficacy-finding (Phase II) Study of RO5323441 in Combination With Bevacizumab for Patients With Recurrent Glioblastoma

Conditions
-----------------
Glioblastoma Multiforme

Intervention / Treatment
-----------------
* Drug: RO5323441 + bevacizumab [Avastin]
* Drug: bevacizumab [Avastin]


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: RO5323441 + bevacizumab [Avastin]<br>* 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<br>|
| Experimental: 2<br> | Drug: bevacizumab [Avastin]<br>* Efficacy-Finding part: 10 mg/kg intravenously once every two weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Finding Part: Dose limiting toxicity |  | Day 28 | 
| Efficacy-Finding part: Progression-free survival |  | From baseline to disease progression or death (>12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Finding part: Pharmacokinetics of RO5323441 and Avastin when combined |  | From baseline to disease progression or death (>12 months) | 
| Dose-Finding part: Safety (incidence of adverse events) |  | From baseline to disease progression or death (>12 months) | 
| Dose-Finding part: Efficacy (tumor response according to Response Assessment in Neurooncology (RANO) criteria |  | From baseline to disease progression or death (>12 months) | 
| Dose-Finding part: Glioblastoma biomarker |  | From baseline to disease progression or death (>12 months) | 
| Efficacy-Finding part: Overall Response Rate |  | From baseline to disease progression or death (>12 months) | 
| Efficacy-Finding part: Disease Control Rate |  | From baseline to disease progression or death (>12 months) | 
| Efficacy-Finding part: Duration of Response |  | From baseline to disease progression or death (>12 months) | 
| Efficacy-Finding part: Progression-free survival |  | From baseline to disease progression or death (>12 months) | 
| Efficacy-Finding part: Overall Survival |  | From baseline to disease progression or death (>12 months) | 
| Efficacy-Finding part: Safety (incidence of adverse events) |  | From baseline to disease progression or death (>12 months) | 
| Efficacy-Finding part: Glioblastoma biomarker |  | From baseline to disease progression or death (>12 months) | 
| Efficacy-Finding part: Pharmacokinetics (serum levels) of RO5323441 and Avastin when combined |  | From baseline to disease progression or death (>12 months) |