A Study of Bevacizumab (Avastin®) in Combination With Temozolomide and Radiotherapy in Participants With Newly Diagnosed Glioblastoma

Glioblastoma Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Trial of Bevacizumab, Temozolomide and Radiotherapy, Followed by Bevacizumab and Temozolomide Versus Placebo, Temozolomide and Radiotherapy Followed by Placebo and Temozolomide in Patients With Newly Diagnosed Glioblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00943826
• Other study ID #: BO21990
• Secondary ID: 2008-006146-26
• Status: Completed
• Phase: Phase 3
• First received: July 17, 2009
• Last updated: August 25, 2017
• Start date: June 29, 2009
• Est. completion date: September 9, 2015

Study information

• Verified date: August 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This 2 arm study investigated the efficacy and safety of the addition of bevacizumab to the current standard of care (multimodality therapy of concurrent radiotherapy plus temozolomide followed by adjuvant temozolomide) as compared to the current standard of care alone. Participants were randomly assigned to either the bevacizumab (10 milligrams per kilogram (mg/kg) intravenously [IV] once every 2 week [q2w]) or the placebo arm, in combination with radiation therapy (total dose 60 Gray [Gy], administered as 2 Gy fractions, 5 days/week) plus temozolomide (75 milligrams per meter squared [mg/m^2] oral administration [po] daily) for 6 weeks. After a 4 week treatment break, participants continued to receive bevacizumab (10 mg/kg IV q2w) or placebo, plus temozolomide (150-200 mg/m^2 po daily on days 1-5 of each 4 week cycle) for 6 cycles of maintenance treatment or until disease progression or unacceptable toxicity, whichever occured first. Following the maintenance phase, bevacizumab (15 mg/kg iv every 3 weeks [q3w]) or placebo monotherapy continued. The time on study treatment was until disease progression.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 921
• Est. completion date: September 9, 2015
• Est. primary completion date: February 28, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• newly diagnosed glioblastoma

• World Health Organization (WHO) performance status less than or equal to (<=2)

• stable or decreasing corticosteroid dose within 5 days prior to randomization

Key Exclusion Criteria:

• evidence of recent hemorrhage on postoperative magnetic resonance imaging (MRI) of brain

• any prior chemotherapy or immunotherapy for glioblastomas and low grade astrocytomas

• any prior radiotherapy to brain

• clinically significant cardiovascular disease

• history of greater than or equal to (>=) grade 2 hemoptysis within 1 month prior to randomization

• previous centralized screening for Methylguanine-DNA methyltransferase (MGMT) status for enrollment into a clinical trial

Related Conditions & MeSH terms

• Glioblastoma

Intervention

Drug:
• Bevacizumab
10 mg/kg intravenously q2w in the Concurrent and Maintenance Phases. 15 mg/kg intravenously q3w in the Monotherapy Phase.
• Temozolomide
75 mg/m^2 once daily for 6 weeks, followed by 150-200 mg/m^2 once daily on days 1-5 of six 4 week cycles.

Radiation:
• Radiation therapy
30 fractions of 2 Gy delivered on days 1-5 per week for 6 weeks.

Drug:
• Placebo
Intravenously q2w in the Concurrent and Maintenance Phases and q3w in the Monotherapy Phase.

Locations

Country	Name	City	State
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Calvary North Adelaide; North Adeliade Oncology Centre	North Adelaide	South Australia
Australia	Royal Melbourne Hospital; Hematology and Medical Oncology	Parkville	Victoria
Australia	Prince of Wales Hospital; Department of Medical Oncology	Randwick	New South Wales
Australia	North Shore Private Hospital; Northern Specialist Centre	St Leonards	New South Wales
Australia	Royal North Shore Hospital; Department of Medical Oncology	St Leonards	New South Wales
Australia	Princess AleXandra Hospital; Department of Medical Oncology	Woolloongabba	Queensland
Belgium	Clin Univ de Bxl Hôpital Erasme	Bruxelles
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	UZ Antwerpen	Edegem
Belgium	AZ Sint Lucas (Sint Lucas)	Gent
Belgium	CHU Sart-Tilman	Liège
Belgium	AZ Delta (Campus Wilgenstraat)	Roeselare
Canada	Tom Baker Cancer Centre-Calgary	Calgary	Alberta
Canada	Cross Cancer Institute ; Dept of Medical Oncology	Edmonton	Alberta
Canada	Hamilton Health Sciences - Juravinski Cancer Centre	Hamilton	Ontario
Canada	Cancer Centre of Southeastern Ontario; Kingston General Hospital	Kingston	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Hopital Notre-Dame	Montreal	Quebec
Canada	McGill University; Montreal Neurological Institute; Oncology	Montreal	Quebec
Canada	Ottawa Hospital Regional Cancer Centre; Neuro-Oncology	Ottawa	Ontario
Canada	Chuq - Hopital Hotel Dieu de Quebec	Quebec City	Quebec
Canada	Saskatoon Cancer Centre; Uni of Saskatoon Campus	Saskatoon	Saskatchewan
Canada	Princess Margaret Hospital; Pencer Brain Tumour Centre, 18-727	Toronto	Ontario
Canada	Sunnybrook Odette Cancer Centre	Toronto	Ontario
Canada	BC Cancer Agency, Vancouver Clinic; Dept. of Medical Oncology	Vancouver	British Columbia
Canada	CancerCare Manitoba; Neuro-Oncology	Winnipeg	Manitoba
Denmark	Aalborg Universitetshospital, Klinik Kirurgi-Kræft, Onkologisk afd.	Aalborg
Denmark	Righospitalet, Hæmatologisk Klinik	København Ø
Denmark	Odense Universitetshospital, Onkologisk Afdeling R	Odense
France	Hopital Avicenne; Rhumatologie	Bobigny
France	Hopital Saint Andre; Département de Radiothérapie Et D'Oncologie Médicale	Bordeaux
France	Institut Bergonie; Gastro Enterologie Oncologie	Bordeaux
France	Hopital neurologique Pierre Wertheimer - CHU Lyon; Neurologie	Bron
France	Centre Jean Perrin; Hopital De Jour	Clermont Ferrand
France	Hopital Beaujon; Oncologie	Clichy
France	Centre Georges François Leclerc	Dijon
France	Hopital de La Timone - CHU de Marseille; Service de neuro-oncologie - Hôpital Adultes - 12ème étage	Marseille
France	Centre Val Aurelle Paul Lamarque; Medecine B3	Montpellier
France	Hôpital Central; Departement de Neuro-Oncologie	Nancy
France	Hopital Pitié Salpétrière - CHU; Service de neurologie 2 - Mazarin	Paris
Germany	Universitätsklinikum "Carl Gustav Carus"; Klinik und Poliklinik für Neurochirurgie	Dresden
Germany	Justus-Liebig-Universität Giessen; Neurochirurgische Klinik	Gießen
Germany	Universitatsklinikum Hamburg-Eppendorf; Klinik und Poliklinik fur Neurochirurgie	Hamburg
Germany	Universitatsklinikum Heidelberg; Abteilung Neuroonkologie	Heidelberg
Germany	Ärztehaus Velen	Ibbenbühren
Germany	Klinikum der Johannes Gutenberg Uni Mainz; Studienz. Neurologie, Klinik und Poliklinik Neurologie	Mainz
Germany	Uni Klinikum München - Großhardern; Med. Klinik U. Poliklinik III - Abt. Onkologie u. Hämatologie	München
Greece	Univ General Hosp Heraklion; Medical Oncology	Heraklion
Greece	University Hospital of Larissa; Oncology	Larissa
Greece	Papageorgiou General Hospital; Medical Oncology	Thessaloniki
Hong Kong	Dr Stephen Yau; Clinical oncology	Hong Kong
Hong Kong	Hong Kong Sanatorium & Hospital; Comprehensive Oncology Centre	Hong Kong
Hong Kong	Queen Mary Hospital; Microbiology Dept.	Hong Kong
Hungary	Magyar Honvedseg Egeszsegugyi Kozpont	Budapest
Hungary	Borsod-Abaúj-Zemplén Megyei Kórház és Egyetemi Oktató Kórház; Neurosurgery	Miskolc
Hungary	Pécsi Tudományegyetem Áok; Onkoterapias Intezet	Pecs
Israel	Rambam Medical Center; Oncology	Haifa
Israel	Hadassah Hebrew University Hospital; Leslie and Michael Gaffin Center for Neuro-Oncology	Jerusalem
Israel	Rabin MC; Davidof Center - Oncology Institute	Petach Tikva
Israel	Chaim Sheba MC; Pediatric Hematology Oncology	Tel Hashomer
Italy	Ausl Di Bologna-Ospedale Bellaria;U.O. Oncologia Medica	Bologna	Emilia-Romagna
Italy	Ospedale Bufalini	Forli	Emilia-Romagna
Italy	Fondazione IRCCS Istituto Neurologico C. Besta; Neuro-oncologia Sperimentale e Terapia Genica	Milano	Lombardia
Italy	Az. Osp. S. Maria; Dept. Di Oncologia Medica	Terni	Umbria
Italy	Azienda Ospedaliera Le Molintte di Torino; Dipartimento Di Neurologia - Oncologia	Torino	Piemonte
Italy	Ospedale di Treviso, Universita di Padova; Neurosurgery Dept	Treviso	Veneto
Japan	Hiroshima University Hospital; Neurosurgery	Hiroshima
Japan	Tsukuba University Hospital; Neurology	Ibaraki
Japan	Kumamoto University Hospital; Neurosurgery	Kumamoto
Japan	Kitano Hospital; Neurosurgery	Osaka
Japan	Saitama Medical University International Medical Center; Clinical and Medical Oncology	Saitama
Japan	Komagome Hospital; Neurosurgery	Tokyo
Japan	Kyorin University Hospital; Neurosurgery	Tokyo
Japan	National Cancer Center Hospital; Neurosurgery	Tokyo
Korea, Republic of	Pusan National University Hospital; Neuro Sugery	Busan
Korea, Republic of	Kyungpook National University Hosital; Neuro Sugery	Daegu
Korea, Republic of	National Cancer Centre; Neurosurgery Dept	Goyang-si
Korea, Republic of	Chonnam National University Hwasun Hospital	Jeollanam-do
Korea, Republic of	Asan Medical Center; Medical Oncology	Seoul
Korea, Republic of	Samsung Medical Center; Neurosurgery Department	Seoul
Korea, Republic of	Seoul National Uni Hospital; Dept. of Internal Medicine/Hematology/Oncology	Seoul
Korea, Republic of	Yonsei University Severance Hospital; Medical Oncology	Seoul
Netherlands	VU MEDISCH CENTRUM; Dept. of Medical Oncology	Amsterdam
Netherlands	Catharina Ziekenhuis; Dept of Internal Medicin	Eindhoven
Netherlands	Utrecht University Medical Centre; Dept of Medical Oncology and UPC	Utrecht
New Zealand	Auckland city hospital; Auckland Regional Cancer Centre and Blood Service	Auckland
New Zealand	Christchurch Hospital; Dept of Oncology	Christchurch
New Zealand	Waikato Hospital; Regional Cancer Center	Hamilton
Poland	Bialostockie Centrum Onkologii; Oddzial Onkologii Klinicznej	Bialystok
Poland	Centrum Onkologii;Im. Franciszka Lukaszczyka;Onkologii	Bydgoszcz
Poland	Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie; Klinika Neurochirurgii i Neurochirurgii Dzi	Lublin
Portugal	IPO de Coimbra; Servico de Oncologia Medica	Coimbra
Portugal	Hospital de Santa Maria; Servico de Oncologia Medica	Lisboa
Portugal	IPO de Lisboa; Servico de Neurologia	Lisboa
Portugal	Hospital de Sao Joao; Servico de Oncologia	Porto
Romania	Institut Oncologic Prof. Dr. Alexandru Trestioreanu; Departament Radioterapie	Bucharest
Romania	Institut Oncologic Ion Chiricuta; Departament Radioterapie	Cluj-napoca
Romania	Spital Clinic Judetean Mures; Oncologie	Targu Mures
Russian Federation	N.N.Burdenko Main Military Clinical Hospital; Oncology Dept	Moscow
Russian Federation	Russian Research Oncology Center n.a. N.N. Blokhin of the RAMS; Department of Neurosurgery	Moscow
Russian Federation	Scientific Research Neurosurgery Institute; Dept. of Neurooncology	Moscow
Russian Federation	Institution of Higher Professional Learning Military; Neurooncology	St. Petersburg
Spain	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona
Spain	Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia	Barcelona
Spain	Institut Catala d Oncologia Hospital Duran i Reynals	Barcelona
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	Hospital Universitario La Paz; Servicio de Oncologia	Madrid
Spain	Hospital Regional Universitario Carlos Haya; Servicio de Oncologia	Malaga
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
Sweden	Sahlgrenska Universitetssjukhuset; Jubileumskliniken	Göteborg
Sweden	Skånes University Hospital, Skånes Department of Onclology	Lund
Sweden	Norrlands Universitetssjukhus; Cancer Centrum	Umea
Sweden	Akademiska sjukhuset, Onkologkliniken	Uppsala
Switzerland	HUG; Oncologie	Geneve
United Kingdom	Queen Elizabeth Medical Centre; Neurosurgery	Birmingham
United Kingdom	Bristol Haematology and Oncology Centre	Bristol
United Kingdom	The Royal Marsden NHS Foundation Trust; Oncology	London
United Kingdom	Northern Centre for Cancer Care;Oncology	Newcastle Upon Tyne
United Kingdom	Nottingham City Hospital; Dept of Haematology	Nottingham
United Kingdom	Queen's Hospital; Oncology	Romford
United Kingdom	Weston Park Hospital; Cancer Clinical Trials Centre	Sheffield
United Kingdom	Royal Marsden Hospital; Dept of Medical Oncology	Sutton
United Kingdom	The Clatterbridge Cancer Ctr For Oncolgy	Wirral
United States	University of Colorado	Aurora	Colorado
United States	University of Alabama At Birmingham; Neuro-Oncology	Birmingham	Alabama
United States	University of Virgina	Charlottesville	Virginia
United States	Hatton Research Institutes	Cincinnati	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	Oncology-Evanston Nthwest Healthcare Kellogg Cancer Care Ctr	Evanston	Illinois
United States	UCLA	Los Angeles	California
United States	Sarah Cannon Cancer Center and Research Institute	Nashville	Tennessee
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Denmark,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  New Zealand,  Poland,  Portugal,  Romania,  Russian Federation,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator	PFS is defined as time from randomization to disease progression (PD) or death. PD was assessed using adapted Macdonald response criteria (modified World Health Organization [WHO] criteria) based on 3 components: radiological tumor assessments using Magnetic Resonance Imaging [MRI] scans,neurological assessment and changes in corticosteroid use. PD is assessed as greater than or equal to(>=) 25% increase in sum of products of the longest diameters of all index lesions (enhancing,measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing,non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment.	Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months)
Primary	Co-Primary: Overall Survival (OS)	Overall Survival was defined as the time from randomization to death due to any cause.	Randomization until OS Event (Until data cutoff= 28 February 2013 [up to 42.2 months])
Secondary	PFS as Assessed by an Independent Review Facility	An Independent Review Facility reviewed the MRI scans used by investigator to evaluate radiological tumor response. PFS is defined as time from randomization to PD or death. PD was assessed using adapted Macdonald response (modified WHO) criteria based on 3 components: radiological tumor assessments using MRI scans, neurological assessment and changes in corticosteroid use. PD is assessed as >=25% increase in sum of products of the longest diameters of all index lesions (enhancing, measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing, non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment.	Randomization until PFS Event (Until data cutoff= 31 March 2012 [up to 29.5 months])
Secondary	Kaplan-Meier (KM) Estimate of One Year Overall Survival	KM estimate of one year overall survival (probability to survive for at least 1 year) was reported. Corresponding 95% confidence interval (CI) was calculated using Greenwood's formula.	Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months])
Secondary	Kaplan-Meier (KM) Estimate of Two Year Overall Survival	KM estimate of two year overall survival was reported (probability to survive for at least 2 years). Corresponding 95% CI was calculated using Greenwood's formula.	Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months])
Secondary	PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20)	EORTC QLQ-C30: 30 items; 5 functional scales; 9 symptom scales; & global health status. Most questions used 4-point scale (1:Not at all, 4:Very much), 2 questions used 7-point scale (1:very poor, 7:Excellent). EORTC QLQ-BN20: 20 items rated on a 4 point scale (1:not at all, 4:very much). EORTC QLQ-C30 and BN20 scores were transformed to a 0-100 scale, higher score=better functioning/global health (C30) or more severe symptoms (BN20). Stable HRQoL: change from baseline (BL) within 10 points. Improved HRQoL: an increase from BL >/=10 points for functioning/global health status, & decrease of >/=10 points for symptoms. PFS is reported for participants with Stable/Improved global health; physical, social functioning (C30); motor dysfunction & communication deficit (BN20). PFS: randomization to PD or death. PD: >=25% increase in sum of products of longest diameters of index lesions; or progression of existing non-index lesions; or appearance of new lesions; or neurological worsening.	Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months)
Secondary	Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death	An adverse event (AE) was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as AE.A serious adverse event (SAE) is any experience that suggests a significant hazard,contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Non-serious adverse events (Non-SAEs) included all AEs except SAEs (non-SAEs = all AEs - SAEs). Nine participants randomized to the Placebo+RT+Temozolomide arm incorrectly received at least 1 dose of bevacizumab and were added to the Bevacizumab+RT+Temozolomide arm for Safety.	Randomization until study completion (Until data cutoff= 09 Sep 2015 [up to 64 months])