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NCT00943826

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

Completed Phase 3 Results posted Last updated 25 September 2017
What this trial tests

Phase 3 trial testing Bevacizumab in Glioblastoma in 921 participants. Completed in 9 September 2015.

Timeline
29 June 2009
Primary endpoint
28 February 2013
9 September 2015

Quick facts

Lead sponsorHoffmann-La Roche
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment921
Start date29 June 2009
Primary completion28 February 2013
Estimated completion9 September 2015
Sites133 locations across Hong Kong, Italy, Japan, Poland, South Korea, Denmark, New Zealand, Netherlands

Drugs / interventions tested

Conditions studied

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

18 and older, any sex, with Glioblastoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator Primary · Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months)

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 (n

GroupValue95% CI
Bevacizumab + RT + Temozolomide10.610.0 – 11.4
Placebo + RT + Temozolomide6.26.0 – 7.5
Co-Primary: Overall Survival (OS) Primary · Randomization until OS Event (Until data cutoff= 28 February 2013 [up to 42.2 months])

Overall Survival was defined as the time from randomization to death due to any cause.

GroupValue95% CI
Bevacizumab + RT + Temozolomide16.815.5 – 18.5
Placebo + RT + Temozolomide16.715.4 – 18.4
PFS as Assessed by an Independent Review Facility Secondary · Randomization until PFS Event (Until data cutoff= 31 March 2012 [up to 29.5 months])

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 (no

GroupValue95% CI
Bevacizumab + RT +Temozolomide8.47.9 – 9.7
Placebo + RT + Temozolomide4.34.1 – 5.1
Kaplan-Meier (KM) Estimate of One Year Overall Survival Secondary · Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months])

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.

GroupValue95% CI
Bevacizumab + RT + Temozolomide0.720.68 – 0.77
Placebo + RT + Temozolomide0.660.62 – 0.71
Kaplan-Meier (KM) Estimate of Two Year Overall Survival Secondary · Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months])

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.

GroupValue95% CI
Bevacizumab + RT + Temozolomide0.340.29 – 0.38
Placebo + RT + Temozolomide0.300.26 – 0.34
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) Secondary · Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months)

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

Global health status (n=354, 309)
GroupValue95% CI
Bevacizumab + RT + Temozolomide80 – 26
Placebo + RT + Temozolomide41 – 29
Physical functioning (n=353, 318)
GroupValue95% CI
Bevacizumab + RT + Temozolomide70 – 27
Placebo + RT + Temozolomide51 – 29
Social functioning (n=352, 327)
GroupValue95% CI
Bevacizumab + RT + Temozolomide80 – 26
Placebo + RT + Temozolomide40 – 27
Motor dysfunction (n=361, 314)
GroupValue95% CI
Bevacizumab + RT + Temozolomide71 – 27
Placebo + RT + Temozolomide40 – 26
Communication deficit (n=365, 329)
GroupValue95% CI
Bevacizumab + RT + Temozolomide80 – 27
Placebo + RT + Temozolomide41 – 24
Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death Secondary · Randomization until study completion (Until data cutoff= 09 Sep 2015 [up to 64 months])

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

Non-SAEs
GroupValue95% CI
Bevacizumab + RT + Temozolomide437
Placebo + RT + Temozolomide412
SAEs
GroupValue95% CI
Bevacizumab + RT + Temozolomide179
Placebo + RT + Temozolomide115
Death
GroupValue95% CI
Bevacizumab + RT + Temozolomide335
Placebo + RT + Temozolomide337

Adverse events — posted to ClinicalTrials.gov

Time frame: Randomization until study completion (Until data cutoff= 09 Sep 2015 [up to 64 months]). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Bevacizumab + RT+Temozolomide
Serious: 179/461 (39%)
Deaths:
Placebo + RT+Temozolomide
Serious: 115/450 (26%)
Deaths:

Serious adverse events (199 terms)

ReactionSystemBevacizumab + RT+Temozolom…Placebo + RT+Temozolomide
ThrombocytopeniaBlood and lymphatic system disorders
Pulmonary embolismRespiratory, thoracic and mediastinal disorders
Deep vein thrombosisVascular disorders
PneumoniaInfections and infestations
Cerebrovascular accidentNervous system disorders
PyrexiaGeneral disorders
SepsisInfections and infestations
ConvulsionNervous system disorders
PancytopeniaBlood and lymphatic system disorders
VomitingGastrointestinal disorders
HyperglycaemiaMetabolism and nutrition disorders
Brain oedemaNervous system disorders
HeadacheNervous system disorders
NeutropeniaBlood and lymphatic system disorders
Abdominal painGastrointestinal disorders
HypertensionVascular disorders
Urinary tract infectionInfections and infestations
Brain abscessInfections and infestations
Lower respiratory tract infectionInfections and infestations
Postoperative wound infectionInfections and infestations
Wound infectionInfections and infestations
Cerebral ischaemiaNervous system disorders
EpilepsyNervous system disorders
SomnolenceNervous system disorders
AnaemiaBlood and lymphatic system disorders
Other adverse events (48 terms — click to expand)

ReactionSystemBevacizumab + RT+Temozolom…Placebo + RT+Temozolomide
NauseaGastrointestinal disorders
FatigueGeneral disorders
AlopeciaSkin and subcutaneous tissue disorders
ConstipationGastrointestinal disorders
HypertensionVascular disorders
HeadacheNervous system disorders
ThrombocytopeniaBlood and lymphatic system disorders
VomitingGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
DiarrhoeaGastrointestinal disorders
AstheniaGeneral disorders
RashSkin and subcutaneous tissue disorders
ProteinuriaRenal and urinary disorders
ArthralgiaMusculoskeletal and connective tissue disorders
NeutropeniaBlood and lymphatic system disorders
NasopharyngitisInfections and infestations
LeukopeniaBlood and lymphatic system disorders
CoughRespiratory, thoracic and mediastinal disorders
PruritusSkin and subcutaneous tissue disorders
DizzinessNervous system disorders
InsomniaPsychiatric disorders
Urinary tract infectionInfections and infestations
Pain in extremityMusculoskeletal and connective tissue disorders
DepressionPsychiatric disorders
DysphoniaRespiratory, thoracic and mediastinal disorders
Radiation skin injuryInjury, poisoning and procedural complications
PyrexiaGeneral disorders
DysgeusiaNervous system disorders
ConvulsionNervous system disorders
LymphopeniaBlood and lymphatic system disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders
Back painMusculoskeletal and connective tissue disorders
Gingival bleedingGastrointestinal disorders
Oedema peripheralGeneral disorders
Weight decreasedInvestigations
Abdominal pain upperGastrointestinal disorders
Dry skinSkin and subcutaneous tissue disorders
AnaemiaBlood and lymphatic system disorders
Abdominal painGastrointestinal disorders

Most-reported serious reactions: Thrombocytopenia, Pulmonary embolism, Deep vein thrombosis, Pneumonia, Cerebrovascular accident, Pyrexia, Sepsis, Convulsion.

Data from ClinicalTrials.gov NCT00943826 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.
    Chinot OL, Wick W, Mason W, Henriksson R, et al · · 2014 · cited 1859× · PMID 24552318 · DOI 10.1056/nejmoa1308345
  2. Glioma targeted therapy: insight into future of molecular approaches.
    Yang K, Wu Z, Zhang H, Zhang N, et al · · 2022 · cited 518× · PMID 35135556 · DOI 10.1186/s12943-022-01513-z
  3. Emerging therapies for glioblastoma: current state and future directions.
    Rong L, Li N, Zhang Z. · · 2022 · cited 351× · PMID 35428347 · DOI 10.1186/s13046-022-02349-7
  4. Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme.
    Lai A, Tran A, Nghiemphu PL, Pope WB, et al · · 2011 · cited 343× · PMID 21135282 · DOI 10.1200/jco.2010.30.2729
  5. Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial.
    Sandmann T, Bourgon R, Garcia J, Li C, et al · · 2015 · cited 223× · PMID 26124478 · DOI 10.1200/jco.2015.61.5005
  6. Combination therapy to checkmate Glioblastoma: clinical challenges and advances.
    Ghosh D, Nandi S, Bhattacharjee S. · · 2018 · cited 171× · PMID 30327965 · DOI 10.1186/s40169-018-0211-8
  7. Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma.
    Happold C, Gorlia T, Chinot O, Gilbert MR, et al · · 2016 · cited 156× · PMID 26786929 · DOI 10.1200/jco.2015.63.6563
  8. Glioblastoma Therapy: Past, Present and Future.
    Obrador E, Moreno-Murciano P, Oriol-Caballo M, López-Blanch R, et al · · 2024 · cited 147× · PMID 38473776 · DOI 10.3390/ijms25052529

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing