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

Roche

Status and phase: Completed; Phase 2

Conditions: Glioblastoma

Treatments: Drug: Placebo; Drug: Bevacizumab; Drug: Temozolomide; Radiation: Radiotherapy; Drug: SOC Agent; Drug: Lomustine

Study type: Interventional

Funder types: Industry

Identifiers

NCT01860638

MO28347

2012-003138-17 (EudraCT Number)

Details and patient eligibility

About

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).

Enrollment: 296 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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296 participants in 2 patient groups, including a placebo group

First-Line Bevacizumab followed by Bevacizumab + Lomustine/SOC

Experimental group

Description:

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.

Treatment:

Drug: Temozolomide

Drug: Lomustine

Drug: SOC Agent

Drug: Bevacizumab

Radiation: Radiotherapy

First-Line Bevacizumab followed by Placebo + Lomustine/SOC

Placebo Comparator group

Description:

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.

Treatment:

Drug: Temozolomide

Drug: Placebo

Drug: Lomustine

Drug: SOC Agent

Drug: Bevacizumab

Radiation: Radiotherapy