A Study of Bevacizumab (Avastin) in Combination With Temozolomide (TMZ) and Radiotherapy in Paediatric and Adolescent Participants With High-Grade Glioma
Condition: High Grade Glioma
MeSH terms: Glioma
Intervention: Bevacizumab; Radiotherapy; Temozolomide (TMZ)
Intervention description: 10 milligrams per kilogram every 2 weeks during the study for up to 12 cycles, each cycle length of 28 days; Total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks during the chemoradiation phase.; 75 milligrams per square meter (mg/m^2) daily continuous starting concomitantly with the first radiation fraction and ending with the last radiation fraction for a maximum number of treatment days = 49 days. During the TMZ adjuvant treatment phase and for participants from YPC: TMZ (150 to 200 mg/m^2/day) x 12 cycles, 1st cycle 150 mg/m^2/days 1-5, escalated to 200 mg/m^2 on Days 1-5 from Cycle 2 onwards depending on the tolerance during the 1st cycle. Cycle length = 28 days.
Intervention MeSH terms: Bevacizumab; Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 124.0
Sex: All
Minimum age: 6 Months
Maximum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility 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