A Study of Bevacizumab (Avastin) in Combination With Temozolomide (TMZ) and Radiotherapy in Paediatric and Adolescent Participants With High-Grade Glioma

Roche

Status and phase: Completed; Phase 2

Conditions: High Grade Glioma

Treatments: Radiation: Radiotherapy; Drug: Bevacizumab; Drug: Temozolomide (TMZ)

Study type: Interventional

Funder types: Industry

Identifiers

NCT01390948

2010-022189-28 (EudraCT Number)

HGG-01 (Other Identifier)

BO25041

ITCC-019 (Other Identifier)

Details and patient eligibility

About

This randomized, open-label, multicenter, 2-arm study will investigate the efficacy, safety, tolerability and pharmacokinetics of bevacizumab when added to postoperative radiotherapy with concomitant and adjuvant TMZ as compared to postoperative radiotherapy with concomitant and adjuvant TMZ alone in paediatric participants with newly diagnosed histologically confirmed World Health Organization (WHO) Grade III or IV localized supratentorial or infratentorial cerebellar or peduncular high grade glioma (HGG). Participants will be randomly assigned to one of two treatment arms.

Upon approval by the Health Authorities/Ethics Committees in the participating countries, an additional young participant cohort (YPC) (children >/= 6 months and < 3 years of age with progressive or relapsed metastatic or localized, supra- or infratentorial, non-brain stem WHO Grade III or IV HGG) was included in the study. Children in the YPC will receive bevacizumab and TMZ without radiation therapy. The anticipated time on study treatment is over 1 year.

Enrollment: 124 patients

Sex: All

Ages: 6 months to 18 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria - Main cohort :

• Paediatric participants, aged >= 3 years and < 18 years
• Written informed consent obtained from the participant/parents or legally acceptable representative
• Newly diagnosed localised, supratentorial or infratentorial cerebellar or peduncular, WHO Grade III or IV gliomas
• Local histological diagnosis confirmed by a designated central reference neuropathologist
• Availability of the baseline magnetic resonance imaging (MRI) performed according to imaging guidelines
• Able to commence trial treatment not before 4 weeks after cranial surgery and no later than 6 weeks following the last major surgery
• Adequate bone marrow, coagulation, liver, and renal function

Young Participant Cohort

• Written informed consent obtained from parents or legal representative
• Age at enrollment: from >= 6 months to < 3 years of age
• Progressive or relapsed metastatic or localised, supra- or infratentorial, non-brain stem WHO Grade III or IV glioma (local pathology confirmation made either at initial diagnosis or at relapse)
• Availability of a baseline MRI performed according to imaging guidelines
• Adequate organ function (bone marrow, coagulation, liver, kidney)

Exclusion Criteria - Main cohort:

• Metastatic HGG defined as evidence of neuraxis dissemination by MRI or positive cerebrospinal fluid (CSF) cytology
• WHO-defined Gliomatosis cerebri (multifocal HGG)
• Any disease or condition that contraindicates the use of the study medication/treatment or places the patient at an unacceptable risk of experiencing treatment-related complications
• Radiological evidence of surgically related intracranial bleeding
• Prior diagnosis of a malignancy and disease-free for 5 years
• Prior systemic anti-cancer therapy
• Previous cranial irradiation

Young Participant Cohort

• WHO-defined Gliomatosis cerebri (multifocal HGG)
• Newly diagnosed HGG below the age of 3 years
• Relapsed HGG below the age of 6 months or above the age of 3 years regardless of the age at first onset
• Indication for concomitant cranial irradiation, regardless of age
• Any disease or condition that contraindicates the use of the study medication/treatment or places the child at an unacceptable risk of experiencing treatment-related complications
• Any specific contraindication to MRI

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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124 participants in 3 patient groups

Bevacizumab + TMZ Young Patient Cohort (YPC)

Experimental group

Description:

Participants aged greater than or equal to (\>/=) 6 months and less than (\<) 3 years will receive 10 milligrams per kilogram (mg/kg) Bevacizumab every 2 weeks and 150 to 200 milligrams per meter squared (mg/m\^2) of TMZ daily on Days 1-5 of each cycle. TMZ will be given at a dose of 150 mg/m\^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m\^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.

Treatment:

Drug: Bevacizumab

Drug: Temozolomide (TMZ)

Main Cohort: Chemoradiation + Bevacizumab + TMZ

Experimental group

Description:

Participants will receive a total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 mg/m\^2 TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break will be followed by an adjuvant treatment phase where participants will receive 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ will be given at a dose of 150 mg/m\^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m\^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle. Bevacizumab will be given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.

Treatment:

Drug: Bevacizumab

Drug: Temozolomide (TMZ)

Radiation: Radiotherapy

Main Cohort: Chemoradiation + TMZ

Active Comparator group

Description:

Participants will receive a total dose of 54 Gy units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 mg/m\^2 TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break will be followed by an adjuvant treatment phase where participants will receive 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ will be given at a dose of 150 mg/m\^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m\^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.

Treatment:

Drug: Temozolomide (TMZ)

Radiation: Radiotherapy