Trial Outcomes & Findings for A Study of Bevacizumab (Avastin) in Combination With Temozolomide (TMZ) and Radiotherapy in Paediatric and Adolescent Participants With High-Grade Glioma (NCT NCT01390948)

Last Updated: 2020-08-06

Results Overview

EFS was defined as the time from randomisation to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non- HGG malignancy or death attributable to any cause. Tumor assessments were conducted using magnetic resonance imaging (MRI) and reviewed by the site-independent CRRC using Response Assessment in Neuro-Oncology (RANO) criteria. Tumor progression was defined as clear clinical progression or \>/= 25% increase in the sum of the products of perpendicular diameters of the contrast enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease was observed) or best response and with the subject on stable or increasing doses of corticosteroids. Tumor recurrence was defined as recurrence after tumor was completely resected (no disease present at baseline). EFS was estimated using the Kaplan-Meier method.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

124 participants

Primary outcome timeframe

From the time of randomization to the date of any defined event (up to 12 months)

Results posted on

2020-08-06

Participant Flow

Chemoradiation + temozolomide (TMZ) and Chemoradiation + Bevacizumab + TMZ arms: 174 participants were screened; 121 were randomized; 116 received study treatment. Young Patient Cohort: 4 participants were screened; 3 were enrolled and received study treatment (these subjects were not randomized and are not included in efficacy analyses).

Participant milestones

Participant milestones
Measure	Chemoradiation + TMZ Participants received a total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 milligrams per meter squared (mg/m\^2) TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 milligrams per kilogram (mg/kg) every 2 weeks throughout the entire treatment period.	Bevacizumab + TMZ Young Patient Cohort (YPC) Participants aged \>/= 6 months and \< 3 years received 10 mg/kg Bevacizumab every 2 weeks and 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.
Overall Study STARTED	59	62	3
Overall Study Treated	56	60	3
Overall Study COMPLETED	44	44	2
Overall Study NOT COMPLETED	15	18	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Chemoradiation + TMZ Participants received a total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 milligrams per meter squared (mg/m\^2) TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 milligrams per kilogram (mg/kg) every 2 weeks throughout the entire treatment period.	Bevacizumab + TMZ Young Patient Cohort (YPC) Participants aged \>/= 6 months and \< 3 years received 10 mg/kg Bevacizumab every 2 weeks and 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.
Overall Study End of Study	1	0	0
Overall Study Withdrew consent	2	2	0
Overall Study Progressive Disease	2	5	0
Overall Study Death during follow-up	10	11	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.	Bevacizumab + TMZ Young Patient Cohort (YPC) n=3 Participants Participants aged \>/= 6 months and \< 3 years received 10 mg/kg Bevacizumab every 2 weeks and 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Total n=124 Participants Total of all reporting groups
Age, Customized < 3 years	0 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants
Age, Customized >/= 3 years and < 6 years	6 Participants n=5 Participants	10 Participants n=7 Participants	0 Participants n=5 Participants	16 Participants n=4 Participants
Age, Customized >/= 6 years and < 13 years	30 Participants n=5 Participants	35 Participants n=7 Participants	0 Participants n=5 Participants	65 Participants n=4 Participants
Age, Customized >/= 13 years and < 18 years	23 Participants n=5 Participants	17 Participants n=7 Participants	0 Participants n=5 Participants	40 Participants n=4 Participants
Sex: Female, Male Female	23 Participants n=5 Participants	28 Participants n=7 Participants	0 Participants n=5 Participants	51 Participants n=4 Participants
Sex: Female, Male Male	36 Participants n=5 Participants	34 Participants n=7 Participants	3 Participants n=5 Participants	73 Participants n=4 Participants

PRIMARY outcome

Timeframe: From the time of randomization to the date of any defined event (up to 12 months)

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC)	11.79 months Interval 7.85 to 16.39	8.21 months Interval 7.75 to 12.68

SECONDARY outcome

Timeframe: From the time of randomization to the date of death (up to approximately 60 months)

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

Overall Survival was defined as the time of diagnosis to the date of death due to any cause. Overall Survival was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Overall Survival	20.27 months Interval 14.75 to 33.77	18.30 months Interval 16.2 to 25.69

SECONDARY outcome

Timeframe: 1 year after end of treatment

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

1-year survival was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Percentage of Participants With 1-Year Survival	67.69 percentage of participants Interval 55.39 to 79.99	74.83 percentage of participants Interval 63.79 to 85.87

SECONDARY outcome

Timeframe: 6 months

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

EFS was defined as the time from randomisation to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non- HGG malignancy or death attributable to any cause. Tumor assessments were conducted using MRI and reviewed by the site-independent CRRC using RANO criteria. Tumor progression was defined as clear clinical progression or \>/= 25% increase in the sum of the products of perpendicular diameters of the contrast enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease was observed) or best response and with the subject on stable or increasing doses of corticosteroids. Tumor recurrence was defined as recurrence after tumor was completely resected (no disease present at baseline). EFS was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Percentage of Participants With EFS as Determined by the CRRC at 6 Months	66.46 percentage of participants Interval 52.58 to 77.13	68.43 percentage of participants Interval 55.06 to 78.58

SECONDARY outcome

Timeframe: 1 year

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

EFS was defined as the time from randomisation to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non- HGG malignancy or death attributable to any cause. Tumor assessments were conducted using MRI and reviewed by the site-independent CRRC using RANO criteria. Tumor progression was defined as clear clinical progression or \>/= 25% increase in the sum of the products of perpendicular diameters of the contrast enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease was observed) or best response and with the subject on stable or increasing doses of corticosteroids. Tumor recurrence was defined as recurrence after tumor was completely resected (no disease present at baseline). EFS was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Percentage of Participants With EFS as Determined by the CRRC at 1 Year	48.37 percentage of participants Interval 34.82 to 60.65	38.28 percentage of participants Interval 25.79 to 50.64

SECONDARY outcome

Timeframe: From the time of randomization to the date of any defined event (up to 12 months)

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

EFS was defined as the time from randomisation to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non-HGG malignancy or death attributable to any cause. Tumor assessments were conducted using MRI and reviewed by the investigator using RANO criteria. Tumor progression was defined as clear clinical progression or \>/= 25% increase in the sum of the products of perpendicular diameters of the contrast enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease was observed) or best response and with the participant on stable or increasing doses of corticosteroids. Tumor recurrence was defined as recurrence after tumor was completely resected (no disease present at baseline). EFS was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
EFS as Assessed by the Investigator	11.79 months Interval 8.51 to 20.53	11.27 months Interval 8.11 to 14.49

SECONDARY outcome

Timeframe: From the time of randomization to the date of any defined event (up to 12 months)

Population: Randomized participant population with a measurable lesion at baseline.

ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) determined on two consecutive occasions \>/= 4 weeks apart. Tumor assessments were conducted using MRI and reviewed by the site-independent CRRC using RANO criteria. The following were needed to qualify as CR: complete disappearance of all measurable enhancing lesions sustained for at least 4 weeks by MRI, no steroids above physiological levels, clinical status stable or improved compared to baseline. The following were needed to qualify as PR: ≥ 50% decrease from baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks by MRI, steroid dose not increased compared to baseline, clinical status stable or improved compared to baseline.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=15 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=12 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Objective Response Rate (ORR)	40 percentage of participants Interval 19.09 to 66.77	41.7 percentage of participants Interval 18.1 to 70.6

SECONDARY outcome

Timeframe: Up to 12 months

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

Concordance is presented as the percentage of participants with concordance between assessments. EFS concordance was defined as event Structural assessment and Diffusion Perfusion assessment occurs within 28 days or no event Structural and no Diffusion Perfusion.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Concordance Between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival	96.6 percentage of participants	87.1 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Cycle 6 of the adjuvant phase, end of treatment (approximately 58 weeks post-baseline), and yearly during the follow-up period (maximum 5 years in follow-up)

Population: Randomized participant population aged 5 years or older with a measure at the specified time point. Here, 'n' represents the number of participants with a measure at the specified time point.

HUI is a preference-based, multi-attitude, health-related instrument specifically developed for use with children. HUI consists of eight attributes of health status: vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain. Each attribute had 5 or 6 levels varying from highly impaired to normal. Each of the eight health dimensions was tested separately and a composite score ranging between 1 (perfect health) and 0 (death) was obtained for participants aged 5 years or older.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=36 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=45 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Health Status as Measured by the Health Utility Index (HUI) Baseline	0.713 units on a scale Standard Deviation 0.317	0.730 units on a scale Standard Deviation 0.274
Health Status as Measured by the Health Utility Index (HUI) Yearly Follow-Up 1	0.906 units on a scale Standard Deviation 0.110	0.926 units on a scale Standard Deviation 0.109
Health Status as Measured by the Health Utility Index (HUI) Additional Safety Follow-Up (Visit 6)	1.000 units on a scale Standard Deviation 0.000	0.490 units on a scale Standard Deviation 0.537
Health Status as Measured by the Health Utility Index (HUI) Cycle 6, Day 1	0.785 units on a scale Standard Deviation 0.239	0.779 units on a scale Standard Deviation 0.232
Health Status as Measured by the Health Utility Index (HUI) End of Treatment	0.832 units on a scale Standard Deviation 0.216	0.820 units on a scale Standard Deviation 0.209
Health Status as Measured by the Health Utility Index (HUI) Yearly Follow-up 2	0.737 units on a scale Standard Deviation 0.326	0.793 units on a scale Standard Deviation 0.219
Health Status as Measured by the Health Utility Index (HUI) Additional Safety Follow-Up (Visit 2)	0.784 units on a scale Standard Deviation 0.287	0.901 units on a scale Standard Deviation 0.147
Health Status as Measured by the Health Utility Index (HUI) Additional Safety Follow-Up (Visit 4)	0.814 units on a scale Standard Deviation 0.304	0.830 units on a scale Standard Deviation 0.143
Health Status as Measured by the Health Utility Index (HUI) Additional Safety Follow-Up (Visit 8)	—	0.930 units on a scale Standard Deviation NA A single participant was analyzed
Health Status as Measured by the Health Utility Index (HUI) End of Study	0.647 units on a scale Standard Deviation 0.496	0.790 units on a scale Standard Deviation 0.234

SECONDARY outcome

Timeframe: End of treatment (approximately 58 weeks post-baseline)

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

The Wechsler Intelligence Scale for Children version IV (WISC-IV) was used to generate a full scale intelligence quotient (IQ) which represents a child's general intellectual ability. The average IQ score is 100, with lower scores representing lower intellectual ability.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Neurological Psychological Function as Measured by the Wechsler Scale	92.0 units on a scale Standard Deviation 9.8	97.0 units on a scale Standard Deviation 18.4

SECONDARY outcome

Timeframe: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)

Population: Safety population included all participants that received study treatment.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=56 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=60 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations Radiotherapy	94.6 percentage of participants	98.3 percentage of participants
Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations TMZ	85.7 percentage of participants	88.3 percentage of participants

SECONDARY outcome

Timeframe: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)

Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=59 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=62 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Percentage of Participants With a Treatment Delay or Discontinuation AE leading to dose modification/interruption	60.7 percentage of participants	71.7 percentage of participants
Percentage of Participants With a Treatment Delay or Discontinuation AE leading to withdrawal from treatment	5.4 percentage of participants	21.7 percentage of participants

SECONDARY outcome

Timeframe: Beginning of the concurrent phase to end of treatment break (10 weeks)

Population: Safety population included all participants that received study drug.

Number of doses were assessed for the concurrent phase, which is the treatment period after the initial treatment phase and including the subsequent treatment break of approximately 4 weeks.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=56 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=60 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Number of Radiotherapy Dose Administrations in the Concurrent Phase	54.0 Grays Interval 4.0 to 60.0	54.0 Grays Interval 2.0 to 56.0

SECONDARY outcome

Timeframe: Beginning of the concurrent phase to end of treatment break (10 weeks)

Population: Safety population included all participants that received study drug.

Number of doses were assessed for the concurrent phase, which is the treatment period after the initial treatment phase and including the subsequent treatment break of approximately 4 weeks.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=56 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=60 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Number of Dose Administrations of TMZ and Bevacizumab in the Concurrent Phase Bevacizumab	NA number of dose administrations Bevacizumab not administered for this arm	6.0 number of dose administrations Interval 1.0 to 10.0
Number of Dose Administrations of TMZ and Bevacizumab in the Concurrent Phase TMZ	42.0 number of dose administrations Interval 1.0 to 50.0	42.0 number of dose administrations Interval 3.0 to 49.0

SECONDARY outcome

Timeframe: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)

Population: Safety population included all participants that received study drug.

An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Outcome measures

Outcome measures
Measure	Chemoradiation + TMZ n=56 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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.	Chemoradiation + Bevacizumab + TMZ n=60 Participants Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period.
Percentage of Participants With an Adverse Event (AE)	100 percentage of participants	98.3 percentage of participants

Adverse Events

Chemoradiation + TMZ

Serious events: 27 serious events

Other events: 56 other events

Deaths: 0 deaths

Chemoradiation + Bevacizumab + TMZ

Serious events: 35 serious events

Other events: 60 other events

Deaths: 0 deaths

Bevacizumab + TMZ Young Patient Cohort (YPC)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 1-800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER