Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01390948




Trial ID
NCT01390948
Ethics application status
Date submitted
7/07/2011
Date registered
7/07/2011
Date last updated
22/05/2018

Titles & IDs
Public title
A Study of Bevacizumab (Avastin) in Combination With Temozolomide (TMZ) and Radiotherapy in Paediatric and Adolescent Participants With High-Grade Glioma
Scientific title
A Phase II Open-Label, Randomized, Multi-Centre Comparative Study Of Bevacizumab-Based Therapy In Paediatric Patients With Newly Diagnosed Supratentorial, Infratentorial Cerebellar, or Peduncular High-Grade Glioma
Secondary ID [1] 0 0
2010-022189-28
Secondary ID [2] 0 0
BO25041
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High Grade Glioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Bevacizumab
Treatment: Other - Radiotherapy
Treatment: Drugs - Temozolomide (TMZ)

Experimental: Bevacizumab + TMZ Young Patient Cohort (YPC) - 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.

Experimental: Main Cohort: Chemoradiation + Bevacizumab + TMZ - 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.

Active Comparator: Main Cohort: Chemoradiation + TMZ - 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: Drugs: Bevacizumab
10 milligrams per kilogram every 2 weeks during the study for up to 12 cycles, each cycle length of 28 days

Treatment: Other: Radiotherapy
Total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks during the chemoradiation phase.

Treatment: Drugs: Temozolomide (TMZ)
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 code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC) - EFS was defined as the time from diagnosis to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non-high-grade glioma (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 a greater than or equal to (>/=) 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.
Timepoint [1] 0 0
From the time of randomization to the date of any defined event (up to approximately 52 months)
Secondary outcome [1] 0 0
Overall Survival - 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.
Timepoint [1] 0 0
From the time of randomization to the date of death (up to approximately 52 months)
Secondary outcome [2] 0 0
Percentage of Participants With 1-Year Survival - 1-year survival was estimated using the Kaplan-Meier method.
Timepoint [2] 0 0
1 year
Secondary outcome [3] 0 0
Percentage of Participants With EFS as Determined by the CRRC at 6 Months - EFS was defined as the time from diagnosis 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 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.
Timepoint [3] 0 0
6 months
Secondary outcome [4] 0 0
Percentage of Participants With EFS as Determined by the CRRC at 1 Year - EFS was defined as the time from diagnosis 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 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.
Timepoint [4] 0 0
1 year
Secondary outcome [5] 0 0
EFS as Assessed by the Investigator - EFS was defined as the time from diagnosis 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.
Timepoint [5] 0 0
From the time of randomization to the date of any defined event (up to approximately 52 months)
Secondary outcome [6] 0 0
Objective Response Rate (ORR) - 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.
Timepoint [6] 0 0
From the time of randomization of the first participant to the date of clinical cutoff (approximately 52 months)
Secondary outcome [7] 0 0
Concordance Between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival - 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.
Timepoint [7] 0 0
From the time of randomization of the first participant to the date of clinical cutoff (approximately 52 months)
Secondary outcome [8] 0 0
Health Status as Measured by the Health Utility Index (HUI) - 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.
Timepoint [8] 0 0
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)
Secondary outcome [9] 0 0
Neurological Psychological Function as Measured by the Wechsler Scale - 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.
Timepoint [9] 0 0
End of treatment (approximately 58 weeks post-baseline)
Secondary outcome [10] 0 0
Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations
Timepoint [10] 0 0
From the time of randomization of the first participant to the date of clinical cutoff (approximately 52 months)
Secondary outcome [11] 0 0
Percentage of Participants With a Treatment Delay or Discontinuation
Timepoint [11] 0 0
From the time of randomization of the first participant to the date of clinical cutoff (approximately 52 months)
Secondary outcome [12] 0 0
Number of Dose Administrations of Study Treatment in the Concurrent Phase - 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.
Timepoint [12] 0 0
Beginning of the concurrent phase to end of treatment break (10 weeks)
Secondary outcome [13] 0 0
Percentage of Participants With an Adverse Event (AE) - 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.
Timepoint [13] 0 0
From the time of randomization of the first participant to the date of clinical cutoff (approximately 52 months)

Eligibility
Key inclusion 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)
Minimum age
6 Months
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
John Hunter Hospital - New Lambton
Recruitment hospital [2] 0 0
Sydney Children's Hospital; Centre for Children's Cancer and Blood Disorders - Sydney
Recruitment hospital [3] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 0 0
Lady Cilento Children's Hospital; Oncology Services Group, Level 12b - South Brisbane
Recruitment hospital [5] 0 0
Royal Children's Hospital; Childrens Cancer Centre - Melbourne
Recruitment hospital [6] 0 0
Princess Margaret Hospital for Children - Subiaco
Recruitment postcode(s) [1] 0 0
2305 - New Lambton
Recruitment postcode(s) [2] 0 0
2031 - Sydney
Recruitment postcode(s) [3] 0 0
2145 - Westmead
Recruitment postcode(s) [4] 0 0
QLD 4101 - South Brisbane
Recruitment postcode(s) [5] 0 0
3052 - Melbourne
Recruitment postcode(s) [6] 0 0
6008 - Subiaco
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Linz
Country [2] 0 0
Austria
State/province [2] 0 0
Wien
Country [3] 0 0
Belgium
State/province [3] 0 0
Bruxelles
Country [4] 0 0
Belgium
State/province [4] 0 0
Gent
Country [5] 0 0
Belgium
State/province [5] 0 0
Leuven
Country [6] 0 0
Belgium
State/province [6] 0 0
Liège
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Canada
State/province [7] 0 0
Alberta
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Canada
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Ontario
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Canada
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Quebec
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Czechia
State/province [10] 0 0
Brno
Country [11] 0 0
Czechia
State/province [11] 0 0
Prague
Country [12] 0 0
Denmark
State/province [12] 0 0
Aarhus N
Country [13] 0 0
Denmark
State/province [13] 0 0
København Ø
Country [14] 0 0
Finland
State/province [14] 0 0
Turku
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France
State/province [15] 0 0
Angers
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France
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Bordeaux
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France
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Clermont Ferrand
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France
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Grenoble
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France
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Lille
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France
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Lyon
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France
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Marseille
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France
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Montpellier
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France
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Nantes
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France
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Nice
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France
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Paris
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France
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Poitiers
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France
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Rennes
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France
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St Priest En Jarez
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France
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Strasbourg
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France
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Toulouse
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France
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Tours
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France
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Vandoeuvre-les-Nancy cedex
Country [33] 0 0
France
State/province [33] 0 0
Villejuif
Country [34] 0 0
Hungary
State/province [34] 0 0
Budapest
Country [35] 0 0
Italy
State/province [35] 0 0
Emilia-Romagna
Country [36] 0 0
Italy
State/province [36] 0 0
Lazio
Country [37] 0 0
Italy
State/province [37] 0 0
Liguria
Country [38] 0 0
Italy
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Lombardia
Country [39] 0 0
Italy
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Piemonte
Country [40] 0 0
Italy
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Toscana
Country [41] 0 0
Italy
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Veneto
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Netherlands
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Amsterdam
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Netherlands
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Nijmegen
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Netherlands
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Rotterdam
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Poland
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Warsaw
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Spain
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Barcelona
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Spain
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Vizcaya
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Spain
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Alicante
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Spain
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Madrid
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Spain
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Malaga
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Spain
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Murcia
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Spain
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Sevilla
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Spain
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Valencia
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Sweden
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Göteborg
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Sweden
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Linkoeping
Country [56] 0 0
Sweden
State/province [56] 0 0
Lund
Country [57] 0 0
Sweden
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Solna
Country [58] 0 0
United Kingdom
State/province [58] 0 0
Birmingham
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United Kingdom
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Bristol
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United Kingdom
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Cambridge
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United Kingdom
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Cardiff
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United Kingdom
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Edinburgh
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United Kingdom
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Glasgow
Country [64] 0 0
United Kingdom
State/province [64] 0 0
Leeds
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United Kingdom
State/province [65] 0 0
Liverpool
Country [66] 0 0
United Kingdom
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London
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United Kingdom
State/province [67] 0 0
Manchester
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United Kingdom
State/province [68] 0 0
Newcastle upon Tyne
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United Kingdom
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Nottingham
Country [70] 0 0
United Kingdom
State/province [70] 0 0
Southampton
Country [71] 0 0
United Kingdom
State/province [71] 0 0
Surrey

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/show/NCT01390948
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries