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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01860638
• Date of registration: 21/05/2013
• Prospective Registration: Yes
• Primary sponsor: Hoffmann-La Roche
• Public title: 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
• Scientific 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
• Date of first enrolment: August 19, 2013
• Target sample size: 296
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01860638
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

Albania, Argentina, Austria, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Croatia, Egypt, Estonia, France, Greece, Ireland, Italy, Latvia, Lithuania, Mexico, Netherlands, Portugal, Romania, Serbia, Spain, Sweden, Turkey, United Kingdom

Contacts

• Name: Clinical Trials
• Affiliation: Hoffmann-La Roche

Key inclusion & exclusion 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



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Glioblastoma

Intervention(s)

Radiation: Radiotherapy

Drug: Bevacizumab

Drug: Placebo

Drug: Lomustine

Drug: SOC Agent

Drug: Temozolomide

Primary Outcome(s)

Overall Survival (OS) [Time Frame: From randomization at PD1 until death from any cause or end of study (overall approximately 35 months)]

Secondary Outcome(s)

EuroQol Five-Dimension Questionnaire (EQ-5D) Score [Time Frame: From Baseline up to death or study withdrawal/study end (up to 41 months overall)]

Percentage of Participants with Adverse Events (AEs) [Time Frame: From baseline up to 30 days after last dose (up to 41 months overall)]

1L Treatment: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) z-score [Time Frame: 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)]

Percentage of Participants with 2L Disease Control as CR, PR, or Stable Disease According to Modified RANO Criteria [Time Frame: 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)]

Progression-Free Survival (PFS) on 2L Treatment According to Modified Response Assessment in Neuro-Oncology (RANO) Criteria [Time Frame: From first administration of randomized treatment until PD2 or death from any cause (overall approximately 18 months)]

Restricted PFS on 3L Treatment According to Modified RANO Criteria [Time Frame: From first administration of treatment after PD2 until PD3 or death from any cause (overall approximately 26 months)]

2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ C30 Global Health Status/Global QoL Scale Score [Time Frame: 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)]

2L and 3L Treatment: Change From 2L Baseline in HVLT-R z-score [Time Frame: 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)]

Duration of 2L Objective Response Assessed According to Modified RANO Criteria [Time Frame: 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 [Time Frame: 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)]

Duration of Hospitalizations According to Type of Hospitalizations [Time Frame: From Baseline up to death or study withdrawal/study end (up to 41 months overall)]

1L Treatment: Change From Baseline in Trail-Making Test (TMT) Part A and B z-score [Time Frame: 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)]

1L Treatment: Change From Baseline in Controlled Oral Word Association (COWA) z-score [Time Frame: 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)]

Percentage of Participants with 3L Disease Control as CR, PR, or SD According to Modified RANO Criteria [Time Frame: 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)]

Percentage of Participants Alive at 6, 12, and 18 Months from Randomization [Time Frame: At 6, 12, and 18 months after randomization/PD1 (overall up to approximately 35 months)]

1L Treatment: Change From Baseline in EORTC QLQ Brain Cancer Module 20 (BN20) Multiple Item Score [Time Frame: 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)]

Percentage of Participants with 2L Objective Response of Complete Response (CR) or Partial Response (PR) According to Modified RANO Criteria [Time Frame: 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)]

2L and 3L Treatment: Change From 2L Baseline in COWA z-score [Time Frame: 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 [Time Frame: From Baseline up to death or study withdrawal/study end (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 [Time Frame: 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)]

Percentage of Participants with Mini Mental Status Examination (MMSE) Score <27 or >/=27 [Time Frame: Baseline and 2L Baseline]

2L and 3L Treatment: Change From 2L Baseline in TMT Part A and Part B z-score [Time Frame: 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)]

Percentage of Participants with 3L Objective Response of CR or PR According to Modified RANO Criteria [Time Frame: 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)]

PFS on 3L Treatment According to Modified RANO Criteria [Time Frame: From first administration of randomized treatment until PD3 or death from any cause (overall approximately 35 months)]

2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ BN20 Multiple Item Score [Time Frame: 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)]

Secondary ID(s)

2012-003138-17

MO28347

Source(s) of Monetary Support

Please refer to primary and secondary sponsors