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

Study Overview
=================
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).

Official Title
-----------------
A Double-Blind, Placebo-Controlled, Randomised, Phase II Study Evaluating the Efficacy and Safety of Addition of Continuous Multiple Line Bevacizumab Treatment to Lomustine in Second (2nd)-Line Followed by Standard of Care (SOC) in Third (3rd)-Line and Beyond Compared to Addition of Placebo, Following First Progression of Disease (PD1) in Patients With Glioblastoma (GBM) After First (1st)-Line Treatment With Radiotherapy, Temozolomide and Bevacizumab

Conditions
-----------------
Glioblastoma

Intervention / Treatment
-----------------
* Drug: Bevacizumab
* Drug: Lomustine
* Drug: Placebo
* Radiation: Radiotherapy
* Drug: Temozolomide
* Drug: SOC Agent


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria at Enrollment (before PD1): Newly diagnosed, histologically confirmed glioblastoma not previously treated with chemotherapy or radiotherapy If female and not postmenopausal (less than [<] 12 months of amenorrhea) or surgically sterile, must agree to use a highly effective contraceptive method during the treatment period and for at least 6 months after the last dose of study drug Karnofsky performance status (KPS) greater than or equal to (>/=) 60 Mandatory tissue collection during pre-study surgery or biopsy for confirmation of the diagnosis and pathology Craniotomy or intracranial biopsy site must be adequately healed. Study treatment should be initiated > 28 days following the last surgical procedure Inclusion Criteria at Randomization (following PD1): Documented PD1 according to RANO criteria Eligibility for second-line treatment with lomustine and bevacizumab as investigational medicinal products Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Bevacizumab well tolerated and not interrupted for longer than 60 days during first-line treatment Tissue submission among participants for whom operation/re-operation is indicated before second-line treatment starts; operation/re-operation performed >/=28 days after last bevacizumab administration and second-line treatment initiated >/=28 days after surgical wound healed Randomization within 28 days after PD1 among participants for whom operation/re-operation is not necessary First administration of second-line treatment no later than 2 days from randomization Exclusion Criteria at Enrollment (before PD1): Any prior chemotherapy for glioblastoma and low-grade astrocytomas Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field Prior or current anti-angiogenic treatment Treatment with any other investigational drug within 28 days or 2 investigational agent half-lives (whichever is longer) prior to first study treatment Inadequate hematological, renal, or liver function Inadequately controlled hypertension Prior history of gastrointestinal perforation or abscess Clinically significant cardiovascular disease History or evidence of central nervous system disease unrelated to cancer unless adequately treated with standard medical therapy History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding Serious non-healing wound, active ulcer, or untreated bone fracture Known hypersensitivity to any component of bevacizumab/placebo or any of the study drugs Active infection requiring IV antibiotics at start of study treatment Other malignancy within 5 years prior to study enrollment, except for carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ treated with curative intent Pregnant or lactating women Participation in any other study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First-Line Bevacizumab followed by Bevacizumab + Lomustine/SOC<br>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. | Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 10 milligrams per kilogram (mg/kg) intravenous (IV) every 2 weeks (Q2W) throughout the study, with the exception of bevacizumab monotherapy prior to PD1, which will be given as 15 mg/kg IV every 3 weeks (Q3W).<br>* Other names: Avastin;Drug: Lomustine<br>* Lomustine will be administered at a dose of 90 milligrams per square meter (mg/m^2) orally (PO) every 6 weeks (Q6W), with a cap of 160 milligrams (mg) per dose. In the absence of hematologic toxicity following the first dose, the second and subsequent doses may be increased to 110 mg/m^2 PO Q6W, with a cap of 200 mg per dose.<br>Radiation: Radiotherapy<br>* Radiotherapy will be administered for a total dose of 60 Gray (Gy), administered in 2-Gy fractions, 5 days per week for 6 weeks during first-line treatment.<br>Drug: Temozolomide<br>* Temozolomide will be administered orally (PO) as 75 mg/m^2 per day for the first 6 weeks of first-line treatment (concurrent treatment), followed by 6 cycles (28 days each) as follows: 150 mg/m^2 per day for the first 5 days of Cycle 1, then 200 mg/m^2 per day (if permitted by the participant's hematological and non-hematological toxicity profile) for the first 5 days of Cycles 2-6.<br>Drug: SOC Agent<br>* The choice of SOC agent will be at the discretion of investigator. The SOC agent will be administered during third-line treatment and subsequent lines, as per standard practice.<br>|
| Placebo Comparator: First-Line Bevacizumab followed by Placebo + Lomustine/SOC<br>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. | Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 10 milligrams per kilogram (mg/kg) intravenous (IV) every 2 weeks (Q2W) throughout the study, with the exception of bevacizumab monotherapy prior to PD1, which will be given as 15 mg/kg IV every 3 weeks (Q3W).<br>* Other names: Avastin;Drug: Lomustine<br>* Lomustine will be administered at a dose of 90 milligrams per square meter (mg/m^2) orally (PO) every 6 weeks (Q6W), with a cap of 160 milligrams (mg) per dose. In the absence of hematologic toxicity following the first dose, the second and subsequent doses may be increased to 110 mg/m^2 PO Q6W, with a cap of 200 mg per dose.<br>Drug: Placebo<br>* Placebo will be administered via IV infusion, in a formulation matched to bevacizumab, Q2W after randomization.<br>Radiation: Radiotherapy<br>* Radiotherapy will be administered for a total dose of 60 Gray (Gy), administered in 2-Gy fractions, 5 days per week for 6 weeks during first-line treatment.<br>Drug: Temozolomide<br>* Temozolomide will be administered orally (PO) as 75 mg/m^2 per day for the first 6 weeks of first-line treatment (concurrent treatment), followed by 6 cycles (28 days each) as follows: 150 mg/m^2 per day for the first 5 days of Cycle 1, then 200 mg/m^2 per day (if permitted by the participant's hematological and non-hematological toxicity profile) for the first 5 days of Cycles 2-6.<br>Drug: SOC Agent<br>* The choice of SOC agent will be at the discretion of investigator. The SOC agent will be administered during third-line treatment and subsequent lines, as per standard practice.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | From randomization at PD1 until death from any cause or end of study (overall approximately 35 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |