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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Bevacizumab; Drug: Onartuzumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 135
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Hamilton Health Sciences - Juravinski Cancer Centre
    • London, Ontario, Canada, N6A 4L6
      • London Health Sciences Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Science Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital; Pencer Brain Tumour Centre, 18-727
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • McGill University; Montreal Neurological Institute; Oncology
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CHUS Hopital Fleurimont; CRC
• France
  • Bobigny, France, 93009
    • Hopital Avicenne; Neurologie
  • Bron, France, 69677
    • Hopital neurologique Pierre Wertheimer - CHU Lyon; Neurologie
  • Lille, France, 59037
    • Hôpital Roger Salengro
  • Marseille, France, 13385
    • Hopital de La Timone - CHU de Marseille; Service de neuro-oncologie - Hôpital Adultes - 12ème étage
  • Montpellier, France, 34298
    • Centre Val Aurelle Paul Lamarque; Medecine B3
  • Nancy, France, 54000
    • Hôpital Central; Departement de Neuro-Oncologie
  • Paris, France, 75651
    • Hopital Pitié Salpétrière - CHU; Service de neurologie 2 - Mazarin
  • Saint Herblain, France, 44805
    • Ico Rene Gauducheau; Oncologie
  • Toulouse Cedex 9, France, 31059
    • Hopital Purpan
• Germany
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn; Medizinische Klinik und Poliklinik I; Allgemeine Innere Medizin
  • Frankfurt am Main, Germany, 60528
    • Klinikum Joh.Wolfg.Goethe-UNI Senckenbergisches Institut für Neuroonkologie
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg-Eppendorf; Klinik und Poliklinik fur Neurochirurgie
  • Ibbenbühren, Germany, 49479
    • Ärztehaus Velen
  • Köln, Germany, 50937
    • Universitatsklinikum Koln
  • Mainz, Germany, 55131
    • Klinikum der Johannes Gutenberg Uni Mainz; Studienz. Neurologie, Klinik und Poliklinik Neurologie
  • München, Germany, 81377
    • Uni Klinikum München - Großhardern; Med. Klinik U. Poliklinik III - Abt. Onkologie u. Hämatologie
  • Oldenburg, Germany, 26121
    • Pius-Hospital
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40133
      • Ospedale Bellaria; U.O. Oncologia Medica
    • Cesena, Emilia-Romagna, Italy, 47023
      • Presidio Ospedaliero Marconi Bufalini; U.O. di Oncologia
    • Parma, Emilia-Romagna, Italy, 43100
      • A.O. Universitaria Di Parma; Oncologia Medica
  • Lombardia
    • Brescia, Lombardia, Italy, 25123
      • Spedali Civili di Brescia
    • Milano, Lombardia, Italy, 20122
      • Fondazione IRCCS Ospedale Maggiore Policlinico; Gastroenterologia
    • Milano, Lombardia, Italy, 20133
      • Fondazione IRCCS Istituto Neurologico C. Besta; Neuro-oncologia Sperimentale e Terapia Genica
  • Piemonte
    • Torino, Piemonte, Italy, 10126
      • Azienda Ospedaliera Città della Salute e della Scienza di Torino
  • Toscana
    • Pisa, Toscana, Italy, 56100
      • Az. Osp. Pisana Ospedale S. Chiara; U.O. Di Reumatologia
• Spain
  • Barcelona, Spain, 08908
    • Institut Catala d Oncologia Hospital Duran i Reynals
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial; Servicio de Farmacia
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal; Servicio de Oncologia
  • Madrid, Spain, 28050
    • HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Oncologia
  • Malaga, Spain, 29010
    • Hospital Regional Universitario Carlos Haya; Servicio de Oncologia
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universitaria de Navarra; Servicio de Oncologia
• Switzerland
  • Geneve, Switzerland, 1211
    • HUG; Oncologie
  • Zürich, Switzerland, 8091
    • UniversitätsSpital Zürich; Klinik für Neurologie
• United Kingdom
  • Bristol, United Kingdom, BS2 8ED
    • Bristol Haematology and Oncology Centre
  • London, United Kingdom, W1G 6AD
    • Sarah Cannon Research Institute
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham City Hospital; David Evans Centre
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama At Birmingham; Neuro-Oncology
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center; Neurosurgery
    • San Francisco, California, United States, 94143
      • USCF - Neurosurgery
    • Stanford, California, United States, 94305
      • Stanford Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Florida
    • Englewood, Florida, United States, 34223
      • Florida Cancer Specialists - Englewood
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists (St. Petersburg - St. Anthony's Professional Building)
    • Tampa, Florida, United States, 33647
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • North Western Univ; Neurology
    • Evanston, Illinois, United States, 60201
      • Northshore University Health System; Cardiology
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • Hatton Research Institutes
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Cancer Center - Tennessee Oncology, Pllc
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Research Inst.
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virgina
    • Richmond, Virginia, United States, 23226
      • Virginia Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98101
      • Seattle Cancer Care Alliance; Investigational Drug Service

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival (PFS) as Assessed by Investigator According to Response Assessment in Neuro-Oncology (RANO) Criteria	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)	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

Outcome Measure	Time Frame
Overall Survival (All Participants)	Baseline until death (up to approximately 18 months)
Percentage of Participants who Survived at Month 9 (All Participants)	Month 9
Percentage of Participants who are Progression Free at Month 6, as Assessed by RANO Criteria (All Participants)	Month 6
Percentage of Participants With Objective Response (OR), as Assessed by RANO Criteria (All Participants)	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	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)	Baseline up to approximately 3 years 8 months
Percentage of Participants With Serum Anti-Therapeutic Antibody (ATAs) to Onartuzumab	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)	Baseline until death (up to approximately 18 months)
Percentage of Participants who Survived at Month 9 (in Participants With Met-Positive Glioblastoma)	Month 9
Percentage of Participants who are Progression Free at Month 6, as Assessed by RANO Criteria (in Participants With Met-Positive Glioblastoma)	Month 6
Percentage of Participants With Objective Response (OR), as Assessed by RANO Criteria (in Participants With Met-Positive Glioblastoma)	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)	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	Baseline up to approximately 3 years 8 months
Minimum Observed Serum Concentration (Cmin) of Onartuzumab	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	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	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	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)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 29, 2012
• Primary Completion (ACTUAL): January 21, 2016
• Study Completion (ACTUAL): January 21, 2016

Study Registration Dates

• First Submitted: June 28, 2012
• First Submitted That Met QC Criteria: June 28, 2012
• First Posted (ESTIMATE): July 2, 2012

Study Record Updates

• Last Update Posted (ACTUAL): February 5, 2018
• Last Update Submitted That Met QC Criteria: February 2, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: GO27819; 2011-005912-27 (EUDRACT_NUMBER)