A Comparison of Continuous Bevacizumab (Avastin) Treatment or Placebo in Addition to Lomustine Followed by Standard of Care After Disease Progression in Participants With Glioblastoma
Phase 2
Completed
- Conditions
- Glioblastoma
- Interventions
- Drug: PlaceboRadiation: RadiotherapyDrug: SOC Agent
- Registration Number
- NCT01860638
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This multicenter, double-blind, placebo-controlled, randomized study will evaluate the efficacy and safety of the addition of bevacizumab treatment to lomustine (in 2nd-line \[2L\] treatment) and SOC (in 3rd-line \[3L\] and subsequent lines of treatment) following first-line disease progression (PD1) in participants with newly diagnosed glioblastoma. All enrolled participants will receive 1L treatment with radiotherapy, temozolomide, and bevacizumab. At PD1, eligible participants will be randomized (1:1) to receive 2L treatment with either bevacizumab plus lomustine or placebo plus lomustine. After second-line disease progression (PD2), participants will receive 3L treatment and will continue blinded bevacizumab or placebo with the addition of an SOC agent. Following third-line disease progression (PD3), participants will receive subsequent lines of treatment and will either continue blinded bevacizumab or placebo (at the discretion of the investigator), or switch to open-label bevacizumab (at the choice of the participant).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 296
Inclusion Criteria
Not provided
Exclusion Criteria
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description First-Line Bevacizumab followed by Placebo + Lomustine/SOC Placebo Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to placebo will receive placebo plus lomustine until PD2. Following PD2, participants will continue with blinded placebo with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Placebo + Lomustine/SOC SOC Agent Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to placebo will receive placebo plus lomustine until PD2. Following PD2, participants will continue with blinded placebo with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Placebo + Lomustine/SOC Radiotherapy Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to placebo will receive placebo plus lomustine until PD2. Following PD2, participants will continue with blinded placebo with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Bevacizumab + Lomustine/SOC Radiotherapy Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to bevacizumab will receive bevacizumab plus lomustine until PD2. Following PD2, participants will continue with blinded bevacizumab with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Bevacizumab + Lomustine/SOC SOC Agent Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to bevacizumab will receive bevacizumab plus lomustine until PD2. Following PD2, participants will continue with blinded bevacizumab with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Bevacizumab + Lomustine/SOC Lomustine Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to bevacizumab will receive bevacizumab plus lomustine until PD2. Following PD2, participants will continue with blinded bevacizumab with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Bevacizumab + Lomustine/SOC Bevacizumab Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to bevacizumab will receive bevacizumab plus lomustine until PD2. Following PD2, participants will continue with blinded bevacizumab with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Bevacizumab + Lomustine/SOC Temozolomide Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to bevacizumab will receive bevacizumab plus lomustine until PD2. Following PD2, participants will continue with blinded bevacizumab with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Placebo + Lomustine/SOC Lomustine Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to placebo will receive placebo plus lomustine until PD2. Following PD2, participants will continue with blinded placebo with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Placebo + Lomustine/SOC Bevacizumab Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to placebo will receive placebo plus lomustine until PD2. Following PD2, participants will continue with blinded placebo with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant. First-Line Bevacizumab followed by Placebo + Lomustine/SOC Temozolomide Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to placebo will receive placebo plus lomustine until PD2. Following PD2, participants will continue with blinded placebo with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant.
- Primary Outcome Measures
Name Time Method Overall Survival (OS) From randomization at PD1 until death from any cause or end of study (overall approximately 35 months)
- Secondary Outcome Measures
Name Time Method Percentage of Participants Alive at 6, 12, and 18 Months from Randomization At 6, 12, and 18 months after randomization/PD1 (overall up to approximately 35 months) Progression-Free Survival (PFS) on 2L Treatment According to Modified Response Assessment in Neuro-Oncology (RANO) Criteria From first administration of randomized treatment until PD2 or death from any cause (overall approximately 18 months) PFS on 3L Treatment According to Modified RANO Criteria From first administration of randomized treatment until PD3 or death from any cause (overall approximately 35 months) Restricted PFS on 3L Treatment According to Modified RANO Criteria From first administration of treatment after PD2 until PD3 or death from any cause (overall approximately 26 months) Percentage of Participants with 2L Objective Response of Complete Response (CR) or Partial Response (PR) According to Modified RANO Criteria From randomization/PD1 until PD2, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 2L-treatment, whichever occurs first (approximately 18 months overall) Percentage of Participants with 3L Objective Response of CR or PR According to Modified RANO Criteria From PD2 until PD3, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of study treatment, whichever occurs first (approximately 26 months overall) Percentage of Participants with 2L Disease Control as CR, PR, or Stable Disease According to Modified RANO Criteria From randomization/PD1 until PD2, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 2L-treatment, whichever occurs first (approximately 18 months overall) Percentage of Participants with 3L Disease Control as CR, PR, or SD According to Modified RANO Criteria From PD2/start of 3L-treatment until PD3, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 3L-treatment, whichever occurs first (approximately 26 months overall) Duration of 2L Objective Response Assessed According to Modified RANO Criteria From first occurrence of CR/PR after randomization/PD1 until PD2, death from any cause, subsequent anticancer therapy, whichever occurs first (approximately 18 months overall) Duration of 3L Objective Response According to Modified RANO Criteria From first occurrence of CR/PR after PD2 until PD3, subsequent anticancer therapy, or death from any cause, whichever occurs first (approximately 26 months overall) Percentage of Participants with Adverse Events (AEs) From baseline up to 30 days after last dose (up to 41 months overall) 1L Treatment: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Global Health Status/Global QoL Scale Score Baseline;Week(Wk)3,5;end of Wk6;Maintenance:Day(D)1 (Visit[V]1), D15 (V2) Cycles(C)1-6 Q4W;Monotherapy:V1-V44 Q3W;Safety Follow-up(FU) (30 days after last 1L dose);PD FUs(8 Wk after Safety FU [PD FU1],then every 12 Wk until PD1) (up to 41 months overall) 2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ C30 Global Health Status/Global QoL Scale Score 2L Baseline (2L treatment V1); 2L treatment: V2-V41 (Q2W) until PD2; 3L treatment: V1-V61 (Q2W) until PD3; Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall) 1L Treatment: Change From Baseline in EORTC QLQ Brain Cancer Module 20 (BN20) Multiple Item Score Baseline; Wk 3, 5; end of Wk6; Maintenance: D1(V1), D15(V2) of C1-6 (Q4W); Monotherapy: V1-V44 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall) 2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ BN20 Multiple Item Score 2L Baseline (2L treatment V1); 2L treatment: V2-V41 (Q2W) until PD2; 3L treatment: V1-V61 (Q2W) until PD3; Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall) Percentage of Participants with Mini Mental Status Examination (MMSE) Score <27 or >/=27 Baseline and 2L Baseline 1L Treatment: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) z-score Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall) 2L and 3L Treatment: Change From 2L Baseline in HVLT-R z-score 2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall) 1L Treatment: Change From Baseline in Controlled Oral Word Association (COWA) z-score Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall) 2L and 3L Treatment: Change From 2L Baseline in COWA z-score 2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall) 1L Treatment: Change From Baseline in Trail-Making Test (TMT) Part A and B z-score Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall) 2L and 3L Treatment: Change From 2L Baseline in TMT Part A and Part B z-score 2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall) Number of Participants with Hospitalizations According to Type of Hospitalizations From Baseline up to death or study withdrawal/study end (up to 41 months overall) Duration of Hospitalizations According to Type of Hospitalizations From Baseline up to death or study withdrawal/study end (up to 41 months overall) EuroQol Five-Dimension Questionnaire (EQ-5D) Score From Baseline up to death or study withdrawal/study end (up to 41 months overall)
Trial Locations
- Locations (64)
Medizinische Universität Graz; Universitätsklinik für Neurologie
🇦🇹Graz, Austria
Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck; Department fuer Neurologie
🇦🇹Innsbruck, Austria
Kepler Universitätsklinikum GmbH - Neuromed Campus; Innere Medizin mit Neuroonkologie
🇦🇹Linz, Austria
Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.
🇦🇹Salzburg, Austria
Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie
🇦🇹Wien, Austria
Kaiser-Franz-Josef-Spital; Neurologische Abteilung
🇦🇹Wien, Austria
MBAL Serdika EOOD
🇧🇬Sofia, Bulgaria
Tom Baker Cancer Centre; Dept of Medicine
🇨🇦Calgary, Alberta, Canada
McGill University; Montreal Neurological Institute; Oncology
🇨🇦Montreal, Quebec, Canada
Clinical Hospital Centre Zagreb
🇭🇷Zagreb, Croatia
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