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

NCT01390948 | Completed Phase 2 Results DMC

• 4 other identifiers: BO250412010-022189-28ITCC-019HGG-01
• Study Type: interventional
• Target: 124
• Locations: 13 countries
• Sites: 51

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.

Conditions

High Grade Glioma

Outcome Measures

Primary Outcomes (1)

• Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC)

  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.

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

Secondary Outcomes (14)

• Overall Survival

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

• Percentage of Participants With 1-Year Survival

  1 year after end of treatment

• Percentage of Participants With EFS as Determined by the CRRC at 6 Months

  6 months

• Percentage of Participants With EFS as Determined by the CRRC at 1 Year

  1 year

• EFS as Assessed by the Investigator

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

Study Arms (3)

Bevacizumab + TMZ Young Patient Cohort (YPC)

EXPERIMENTAL

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.

Drug: Bevacizumab; Drug: Temozolomide (TMZ)

Main Cohort: Chemoradiation + Bevacizumab + TMZ

EXPERIMENTAL

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.

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

Main Cohort: Chemoradiation + TMZ

ACTIVE COMPARATOR

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.

Radiation: Radiotherapy; Drug: Temozolomide (TMZ)

Interventions

Bevacizumab DRUG

10 milligrams per kilogram every 2 weeks during the study for up to 12 cycles, each cycle length of 28 days

Also known as: Avastin

Bevacizumab + TMZ Young Patient Cohort (YPC); Main Cohort: Chemoradiation + Bevacizumab + TMZ

Radiotherapy RADIATION

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

Main Cohort: Chemoradiation + Bevacizumab + TMZ; Main Cohort: Chemoradiation + TMZ

Temozolomide (TMZ) DRUG

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.

Bevacizumab + TMZ Young Patient Cohort (YPC); Main Cohort: Chemoradiation + Bevacizumab + TMZ; Main Cohort: Chemoradiation + TMZ

Eligibility Criteria

• Age: 6 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (53)

The Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Lady Cilento Children's Hospital; Oncology Services Group, Level 12b

South Brisbane, Queensland, QLD 4101, Australia

Location

Kepler Universitätskliniken GmbH - Med Campus IV.

Linz, 4020, Austria

Location

Medizinische Universität Wien

Vienna, 1090, Austria

Location

UZ Leuven Gasthuisberg

Leuven, 3000, Belgium

Location

Alberta Children'S Hospital

Calgary, Alberta, T3B 6A8, Canada

Location

Hospital For Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Fakultni nemocnice Brno; 2. detska klinika, pracoviste Detska nemocnice

Brno, 62500, Czechia

Location

Fakultni Nemocnice V Motole, S.P.

Prague, 15060, Czechia

Location

Skejby Sygehus - Aarhus University Hospital; CF Center, Børneafdeling A

Aarhus N, 8200, Denmark

Location

Rigshospitalet; Onkologisk Klinik

København Ø, 2100, Denmark

Location

Centre Hospitalier d'Angers; Service de cancérologie pédiatrique

Angers, 49033, France

Location

CHU ESTAING; Centre Regional de Cancérologie et Thérapie Cellulaire Pédiatrique (CRCTCP)

Clermont-Ferrand, 63003, France

Location

Centre Oscar Lambret; Service de Pediatrie

Lille, 59020, France

Location

Centre Leon Berard

Lyon, 69008, France

Location

Hopital Timone Enfants; Onco Pediatrie

Marseille, 13385, France

Location

Hopital Lenval; Service Hématologie Infantile

Nice, 06200, France

Location

Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris; Service d Oncologie Pediatrique

Paris, 75248, France

Location

CHRU de Rennes - Hôpital Sud- Service d'Hématologie Pédiatrique

Rennes, 35056, France

Location

Hopital Nord;Consult Pediatrie

Saint-Priest-en-Jarez, 42777, France

Location

Hôpital Hautepierre

Strasbourg, 67200, France

Location

Hopital Des Enfants; Service d Hemato-Oncologie

Toulouse, 31059, France

Location

CHRU de Tours - Centre de Pédiatrie Clocheville; Service d'Oncopédiatrie

Tours, 37044, France

Location

Hopital Brabois Enfants

Vandœuvre-lès-Nancy, 54511, France

Location

Institut Gustave Roussy; Service Pediatrique

Villejuif, 94805, France

Location

Semmelweis University, 2nd Dept of Pediatrics Neurooncology Unit

Budapest, 1094, Hungary

Location

Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpigh

Bologna, Emilia-Romagna, 40138, Italy

Location

Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS; U.O.S. Neuroncologia

Genoa, Liguria, 16147, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Lombardy, 20133, Italy

Location

Azienda Ospedaliera di Padova

Padua, Veneto, 35128, Italy

Location

UMC St Radboud

Nijmegen, 6525 GA, Netherlands

Location

Erasmus Mc/Sophia's Childrens Hospital; Dept. of Pediatric Oncology

Rotterdam, 3015 GJ, Netherlands

Location

Instytut Pomnik-Centrum Zdrowia Dziecka; Klinika Onkologii

Warsaw, 04-746, Poland

Location

Hospital Sant Joan De Deu

Esplugues de Llobregas, Barcelona, 08950, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario La Fe

Valencia, 46014, Spain

Location

Sahlgrenska Universitetssjukhuset, Östra Sjukhus; Drottning Silvias Barnsjukhus

Gothenburg, 416 85, Sweden

Location

Universitetssjukhuset Linköping; Barn och Ungdomskliniken

Linköping, 581 85, Sweden

Location

Skånes Universitetssjukhus

Lund, 221 85, Sweden

Location

Karolinska Universitetssjukhuset, Solna; Astrid Lindgrens Barnsjukhus, Barcanceravdelningen

Solna, 171 76, Sweden

Location

Birmingham Childrens Hospital; Oncology Dept

Birmingham, B4 6NH, United Kingdom

Location

Bristol Royal Hospital for Children; Paediatric Haematology, Oncology, BMT

Bristol, BS2 8BJ, United Kingdom

Location

Addenbrookes Hospital; Paediatric Oncology Ward C2

Cambridge, CB2 0QQ, United Kingdom

Location

Royal Hospital for Sick Children

Edinburgh, EH91LF, United Kingdom

Location

Leeds General Infirmary; Ward 35

Leeds, LS1 3EX, United Kingdom

Location

Alder Hey Children's NHS Foundation Trust

Liverpool, L12 2AP, United Kingdom

Location

University College London NHS Foundation Trust

London, NW1 2PG, United Kingdom

Location

Great Ormond Street Hospital; Dept. Of Pediatric Oncology

London, WC1N 3JH, United Kingdom

Location

Royal Manchester Childrens Hospital

Manchester, M13 9WL, United Kingdom

Location

Newcastle University & The Newcastle upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Queens Medical Centre

Nottingham, NG7 2UH, United Kingdom

Location

Southampton General Hospital

Southampton, SO16 6YD, United Kingdom

Location

Royal Marsden Hospital; Pediatric Unit

Surrey, SM2 5PT, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 35412366 DERIVED

• 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.

  PMID: 31419298 DERIVED

• 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.

  PMID: 30819765 DERIVED

• 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.

  PMID: 29763623 DERIVED

• 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.

  PMID: 29412784 DERIVED

MeSH Terms

Conditions

Glioma

Interventions

Bevacizumab; Radiotherapy; Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Therapeutics; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

1-800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2011
• First Posted: July 11, 2011
• Study Start: October 18, 2011
• Primary Completion: February 5, 2016
• Study Completion: January 29, 2020
• Last Updated: August 6, 2020
• Results First Posted: August 4, 2017

Record last verified: 2020-07

Locations

AU (2); ES (3); FR (14); IT (4); CA (2); CZ (2); BE (1); HU (1); DK (2); NL (2); PL (1); SE (4); GB (13)