A Study of Onartuzumab (MetMAb) in Combination With Bevacizumab Compared to Bevacizumab Alone or Onartuzumab Monotherapy in Participants With Recurrent Glioblastoma - Full Text View

Purpose

This randomized, double-blind, placebo-controlled, multicenter phase II study will evaluate the safety and efficacy of onartuzumab in combination with bevacizumab as compared to bevacizumab alone in participants with recurrent glioblastoma. Participants will be randomized 1:1 to receive either placebo plus bevacizumab every 3 weeks, or onartuzumab plus bevacizumab. Study treatment will continue until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death.

Condition	Intervention	Phase
Glioblastoma	Drug: Bevacizumab Drug: Onartuzumab Drug: Placebo	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Participant, Investigator Primary Purpose: Treatment
Official Title:	A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study Evaluating the Efficacy and Safety of Onartuzumab in Combination With Bevacizumab or Onartuzumab Monotherapy in Patients With Recurrent Glioblastoma

Resource links provided by NLM:

Drug Information available for: Bevacizumab

Genetic and Rare Diseases Information Center resources: Glioblastoma Glioma Neuroepithelioma

U.S. FDA Resources

Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:

Progression-free survival (PFS) as Assessed by Investigator According to Response Assessment in Neuro-Oncology (RANO) Criteria [ Time Frame: Baseline until disease progression, intolerable toxicity, participant or physician decision, or death, whichever occurs first (assessed every 6 weeks up to 18 months) ]
Progression-free survival (PFS) as Assessed by Investigator According to RANO Criteria (in Participants With Met-Positive Glioblastoma) [ Time Frame: Baseline until disease progression, intolerable toxicity, participant or physician decision, or death, whichever occurs first (assessed every 6 weeks up to 18 months) ]

Secondary Outcome Measures:

Overall Survival (All Participants) [ Time Frame: Baseline until death (up to approximately 18 months) ]
Percentage of Participants who Survived at Month 9 (All Participants) [ Time Frame: Month 9 ]
Percentage of Participants who are Progression Free at Month 6, as Assessed by RANO Criteria (All Participants) [ Time Frame: Month 6 ]
Percentage of Participants With Objective Response (OR), as Assessed by RANO Criteria (All Participants) [ Time Frame: Baseline until disease progression, intolerable toxicity, participant or physician decision, or death, whichever occurs first (assessed every 6 weeks up to 18 months) ]
Duration of Response, as Assessed by RANO Criteria [ Time Frame: Baseline until disease progression, intolerable toxicity, participant or physician decision, or death, whichever occurs first (assessed every 6 weeks up to 18 months) ]
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to approximately 3 years 8 months ]
Percentage of Participants With Serum Anti-Therapeutic Antibody (ATAs) to Onartuzumab [ Time Frame: Predose (0 hour) on Day 1 of Cycles 1, 2, 3, 4, at study completion or study drug discontinuation visit (up to approximately 3.5 years; Cycle length: 21 days) ]
Overall Survival (in Participants With Met-Positive Glioblastoma) [ Time Frame: Baseline until death (up to approximately 18 months) ]
Percentage of Participants who Survived at Month 9 (in Participants With Met-Positive Glioblastoma) [ Time Frame: Month 9 ]
Percentage of Participants who are Progression Free at Month 6, as Assessed by RANO Criteria (in Participants With Met-Positive Glioblastoma) [ Time Frame: Month 6 ]
Percentage of Participants With Objective Response (OR), as Assessed by RANO Criteria (in Participants With Met-Positive Glioblastoma) [ Time Frame: Baseline until disease progression, intolerable toxicity, participant or physician decision, or death, whichever occurs first (assessed every 6 weeks up to 18 months) ]
Duration of Response, as Assessed by RANO Criteria (in Participants With Met-Positive Glioblastoma) [ Time Frame: Baseline until disease progression, intolerable toxicity, participant or physician decision, or death, whichever occurs first (assessed every 6 weeks up to 18 months) ]
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Participants With Met-Positive Glioblastoma [ Time Frame: Baseline up to approximately 3 years 8 months ]
Minimum Observed Serum Concentration (Cmin) of Onartuzumab [ Time Frame: predose (0 hour) on Day 1 of Cycles 1, 2, 3, 4, at study completion or study drug discontinuation visit (up to approximately 3.5 years) (Cycle length: 21 days; infusion duration: Onartuzumab 60 minutes) ]
Maximum Observed Serum Concentration (Cmax) of Onartuzumab [ Time Frame: predose (0 hour) and 30 minutes post dose on Day 1 of Cycles 1, 2, 3, 4, at study completion or study drug discontinuation visit (up to approximately 3.5 years) (Cycle length: 21 days; infusion duration: Onartuzumab 60 minutes) ]
Minimum Observed Serum Concentration (Cmin) of Bevacizumab [ Time Frame: predose (0 hour) on Day 1 of Cycles 1, 2, 3, 4, at study completion or study drug discontinuation visit (up to approximately 3.5 years) (Cycle length: 21 days; infusion duration: Bevacizumab 90 minutes) ]
Maximum Observed Serum Concentration (Cmax) of Bevacizumab [ Time Frame: predose (0 hour) and 30 minutes post dose on Day 1 of Cycles 1, 2, 3, 4, at study completion or study drug discontinuation visit (up to approximately 3.5 years) (Cycle length: 21 days; infusion duration: Bevacizumab 90 minutes) ]


Enrollment:	135
Study Start Date:	June 2012
Study Completion Date:	January 2016
Primary Completion Date:	January 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Onartuzumab + Bevacizumab All participants will receive onartuzumab intravenous (IV) infusion followed by bevacizumab IV infusion every 3 weeks.	Drug: Bevacizumab Participants will receive bevacizumab 15 milligrams per kilogram (mg/kg) IV infusion every 3 weeks until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death. Drug: Onartuzumab Participants will receive onartuzumab 15 mg/kg IV infusion every 3 weeks until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death. Other Name: MetMAb, RO5490258
Active Comparator: Placebo + Bevacizumab All participants will receive placebo matched with onartuzumab followed by bevacizumab IV infusion every 3 weeks.	Drug: Bevacizumab Participants will receive bevacizumab 15 milligrams per kilogram (mg/kg) IV infusion every 3 weeks until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death. Drug: Placebo Participants will receive placebo matched with onartuzumab until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death.

Arms

Assigned Interventions

Experimental: Onartuzumab + Bevacizumab

All participants will receive onartuzumab intravenous (IV) infusion followed by bevacizumab IV infusion every 3 weeks.

Drug: Bevacizumab

Participants will receive bevacizumab 15 milligrams per kilogram (mg/kg) IV infusion every 3 weeks until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death.

Drug: Onartuzumab

Participants will receive onartuzumab 15 mg/kg IV infusion every 3 weeks until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death.

Other Name: MetMAb, RO5490258

Active Comparator: Placebo + Bevacizumab

All participants will receive placebo matched with onartuzumab followed by bevacizumab IV infusion every 3 weeks.

Drug: Bevacizumab

Participants will receive bevacizumab 15 milligrams per kilogram (mg/kg) IV infusion every 3 weeks until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death.

Drug: Placebo

Participants will receive placebo matched with onartuzumab until disease progression, unacceptable toxicity, participants or physician decision to discontinue, or death.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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 line of chemotherapy
No prior treatment with bevacizumab or other vascular endothelial growth factor (VEGF)- or VEGF-receptor-targeted agent
No prior exposure to experimental treatment targeting either hepatocyte growth factor (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 hemorrhage on baseline magnetic resonance imaging (MRI) of the brain
No need for urgent palliative intervention for primary disease (e.g. impending herniation)
Karnofsky performance status greater than or equal to (>=) 70 percent (%)
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 participant must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field
Participants 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 greater than [>]150 millimeter of mercury (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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01632228

Show 63 Study Locations

Sponsors and Collaborators

Hoffmann-La Roche

Investigators


Study Director:	Clinical Trials	Hoffmann-La Roche

More Information


Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT01632228 History of Changes
Other Study ID Numbers:	GO27819 2011-005912-27 ( EudraCT Number )
Study First Received:	June 28, 2012
Last Updated:	January 26, 2017

Additional relevant MeSH terms:


Glioblastoma Astrocytoma Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue	Bevacizumab Antibodies, Monoclonal Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Antineoplastic Agents Immunologic Factors

ClinicalTrials.gov processed this record on June 27, 2017