Clinical trial NCT01390948: A Study of Bevacizumab (Avastin) in Combination With Temozolomide (TMZ) and Radiotherapy in Paediatric and Adolescent Participants With High-Grade Glioma
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: High Grade Glioma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2011-07-11
Enrollment: 124
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC)
timeFrame: From the time of randomization to the date of any defined event (up to 12 months)
Secondary outcomes:
measure: Overall Survival
timeFrame: From the time of randomization to the date of death (up to approximately 60 months)
measure: Percentage of Participants With 1-Year Survival
timeFrame: 1 year after end of treatment
measure: Percentage of Participants With EFS as Determined by the CRRC at 6 Months
timeFrame: 6 months
measure: Percentage of Participants With EFS as Determined by the CRRC at 1 Year
timeFrame: 1 year
measure: EFS as Assessed by the Investigator
timeFrame: From the time of randomization to the date of any defined event (up to 12 months)
measure: Objective Response Rate (ORR)
timeFrame: From the time of randomization to the date of any defined event (up to 12 months)
measure: Concordance Between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival
timeFrame: Up to 12 months
measure: Health Status as Measured by the Health Utility Index (HUI)
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)
measure: Neurological Psychological Function as Measured by the Wechsler Scale
timeFrame: End of treatment (approximately 58 weeks post-baseline)
measure: Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations
timeFrame: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)
measure: Percentage of Participants With a Treatment Delay or Discontinuation
timeFrame: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)
measure: Number of Radiotherapy Dose Administrations in the Concurrent Phase
timeFrame: Beginning of the concurrent phase to end of treatment break (10 weeks)
measure: Number of Dose Administrations of TMZ and Bevacizumab in the Concurrent Phase
timeFrame: Beginning of the concurrent phase to end of treatment break (10 weeks)
measure: Percentage of Participants With an Adverse Event (AE)
timeFrame: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)
Other outcomes:
Locations:
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: South Brisbane
country: Australia
facility: Lady Cilento Children's Hospital; Oncology Services Group, Level 12b
state: Queensland
city: Linz
country: Austria
facility: Kepler Universitätskliniken GmbH - Med Campus IV.
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Calgary
country: Canada
facility: Alberta Children'S Hospital
state: Alberta
city: Toronto
country: Canada
facility: Hospital For Sick Children
state: Ontario
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno; 2. detska klinika, pracoviste Detska nemocnice
city: Prague
country: Czechia
facility: Fakultni Nemocnice V Motole, S.P.
city: Aarhus N
country: Denmark
facility: Skejby Sygehus - Aarhus University Hospital; CF Center, Børneafdeling A
city: København Ø
country: Denmark
facility: Rigshospitalet; Onkologisk Klinik
city: Angers
country: France
facility: Centre Hospitalier d'Angers; Service de cancérologie pédiatrique
city: Clermont Ferrand
country: France
facility: CHU ESTAING; Centre Regional de Cancérologie et Thérapie Cellulaire Pédiatrique (CRCTCP)
city: Lille
country: France
facility: Centre Oscar Lambret; Service de Pediatrie
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Hopital Timone Enfants; Onco Pediatrie
city: Nice
country: France
facility: Hopital Lenval; Service Hématologie Infantile
city: Paris
country: France
facility: Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris; Service d Oncologie Pediatrique
city: Rennes
country: France
facility: CHRU de Rennes - Hôpital Sud- Service d'Hématologie Pédiatrique
city: St Priest En Jarez
country: France
facility: Hopital Nord;Consult Pediatrie
city: Strasbourg
country: France
facility: Hôpital Hautepierre
city: Toulouse
country: France
facility: Hopital Des Enfants; Service d Hemato-Oncologie
city: Tours
country: France
facility: CHRU de Tours - Centre de Pédiatrie Clocheville; Service d'Oncopédiatrie
city: Vandoeuvre-les-Nancy cedex
country: France
facility: Hopital Brabois Enfants
city: Villejuif
country: France
facility: Institut Gustave Roussy; Service Pediatrique
city: Budapest
country: Hungary
facility: Semmelweis University, 2nd Dept of Pediatrics Neurooncology Unit
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpigh
state: Emilia-Romagna
city: Genova
country: Italy
facility: Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS; U.O.S. Neuroncologia
state: Liguria
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: Lombardia
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
state: Veneto
city: Nijmegen
country: Netherlands
facility: UMC St Radboud
city: Rotterdam
country: Netherlands
facility: Erasmus Mc/Sophia's Childrens Hospital; Dept. of Pediatric Oncology
city: Warsaw
country: Poland
facility: Instytut Pomnik-Centrum Zdrowia Dziecka; Klinika Onkologii
city: Esplugues De Llobregas
country: Spain
facility: Hospital Sant Joan De Deu
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset, Östra Sjukhus; Drottning Silvias Barnsjukhus
city: Linkoeping
country: Sweden
facility: Universitetssjukhuset Linköping; Barn och Ungdomskliniken
city: Lund
country: Sweden
facility: Skånes Universitetssjukhus
city: Solna
country: Sweden
facility: Karolinska Universitetssjukhuset, Solna; Astrid Lindgrens Barnsjukhus, Barcanceravdelningen
city: Birmingham
country: United Kingdom
facility: Birmingham Childrens Hospital; Oncology Dept
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children; Paediatric Haematology, Oncology, BMT
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital; Paediatric Oncology Ward C2
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Sick Children
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary; Ward 35
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London NHS Foundation Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital; Dept. Of Pediatric Oncology
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle University & The Newcastle upon Tyne Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Queens Medical Centre
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Surrey
country: United Kingdom
facility: Royal Marsden Hospital; Pediatric Unit
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Rodriguez D, Calmon R, Aliaga ES, Warren D, Warmuth-Metz M, Jones C, Mackay A, Varlet P, Le Deley MC, Hargrave D, Canete A, Massimino M, Azizi AA, Saran F, Zahlmann G, Garcia J, Vassal G, Grill J, Peet A, Dineen RA, Morgan PS, Jaspan T. MRI and Molecular Characterization of Pediatric High-Grade Midline Thalamic Gliomas: The HERBY Phase II Trial. Radiology. 2022 Jul;304(1):174-182. doi: 10.1148/radiol.211464. Epub 2022 Apr 12.
citation: Varlet P, Le Teuff G, Le Deley MC, Giangaspero F, Haberler C, Jacques TS, Figarella-Branger D, Pietsch T, Andreiuolo F, Deroulers C, Jaspan T, Jones C, Grill J. WHO grade has no prognostic value in the pediatric high-grade glioma included in the HERBY trial. Neuro Oncol. 2020 Jan 11;22(1):116-127. doi: 10.1093/neuonc/noz142.
citation: Rodriguez D, Chambers T, Warmuth-Metz M, Aliaga ES, Warren D, Calmon R, Hargrave D, Garcia J, Vassal G, Grill J, Zahlmann G, Morgan PS, Jaspan T. Evaluation of the Implementation of the Response Assessment in Neuro-Oncology Criteria in the HERBY Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas. AJNR Am J Neuroradiol. 2019 Mar;40(3):568-575. doi: 10.3174/ajnr.A5982. Epub 2019 Feb 28.
citation: Mackay A, Burford A, Molinari V, Jones DTW, Izquierdo E, Brouwer-Visser J, Giangaspero F, Haberler C, Pietsch T, Jacques TS, Figarella-Branger D, Rodriguez D, Morgan PS, Raman P, Waanders AJ, Resnick AC, Massimino M, Garre ML, Smith H, Capper D, Pfister SM, Wurdinger T, Tam R, Garcia J, Thakur MD, Vassal G, Grill J, Jaspan T, Varlet P, Jones C. Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer Cell. 2018 May 14;33(5):829-842.e5. doi: 10.1016/j.ccell.2018.04.004.
citation: Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Canete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, Open-Label, Randomized, Multicenter Trial (HERBY) of Bevacizumab in Pediatric Patients With Newly Diagnosed High-Grade Glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. doi: 10.1200/JCO.2017.76.0611. Epub 2018 Feb 7.