A Study of Bevacizumab (Avastin) in Combination With Temozolomide (TMZ) and Radiotherapy in Paediatric and Adolescent Participants With High-Grade Glioma
- Conditions
- High Grade Glioma
- Interventions
- Registration Number
- NCT01390948
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 124
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Bevacizumab + TMZ Young Patient Cohort (YPC) Temozolomide (TMZ) 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. Main Cohort: Chemoradiation + Bevacizumab + TMZ Temozolomide (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. Main Cohort: Chemoradiation + TMZ Radiotherapy 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. Main Cohort: Chemoradiation + TMZ Temozolomide (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. Main Cohort: Chemoradiation + Bevacizumab + TMZ Radiotherapy 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. Main Cohort: Chemoradiation + Bevacizumab + TMZ Bevacizumab 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. Bevacizumab + TMZ Young Patient Cohort (YPC) Bevacizumab 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.
- Primary Outcome Measures
Name Time Method Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC) From the time of randomization to the date of any defined event (up to 12 months) 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.
- Secondary Outcome Measures
Name Time Method Objective Response Rate (ORR) From the time of randomization to the date of any defined event (up to 12 months) 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.
Health Status as Measured by the Health Utility Index (HUI) 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) 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.
Number of Radiotherapy Dose Administrations in the Concurrent Phase Beginning of the concurrent phase to end of treatment break (10 weeks) 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.
Number of Dose Administrations of TMZ and Bevacizumab in the Concurrent Phase Beginning of the concurrent phase to end of treatment break (10 weeks) 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.
Percentage of Participants With an Adverse Event (AE) From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months) 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.
Percentage of Participants With 1-Year Survival 1 year after end of treatment 1-year survival was estimated using the Kaplan-Meier method.
Overall Survival From the time of randomization to the date of death (up to approximately 60 months) 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.
Percentage of Participants With EFS as Determined by the CRRC at 6 Months 6 months 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.
Neurological Psychological Function as Measured by the Wechsler Scale End of treatment (approximately 58 weeks post-baseline) 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.
Percentage of Participants With EFS as Determined by the CRRC at 1 Year 1 year 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.
EFS as Assessed by the Investigator From the time of randomization to the date of any defined event (up to 12 months) 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.
Concordance Between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival Up to 12 months 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.
Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months) Percentage of Participants With a Treatment Delay or Discontinuation From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)
Trial Locations
- Locations (53)
The Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Lady Cilento Children's Hospital; Oncology Services Group, Level 12b
🇦🇺South Brisbane, Queensland, Australia
Fakultni nemocnice Brno; 2. detska klinika, pracoviste Detska nemocnice
🇨🇿Brno, Czechia
Fakultni Nemocnice V Motole, S.P.
🇨🇿Prague, Czechia
Hopital Timone Enfants; Onco Pediatrie
🇫🇷Marseille, France
Hopital Nord;Consult Pediatrie
🇫🇷St Priest En Jarez, France
Hopital Brabois Enfants
🇫🇷Vandoeuvre-les-Nancy cedex, France
Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpigh
🇮🇹Bologna, Emilia-Romagna, Italy
Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS; U.O.S. Neuroncologia
🇮🇹Genova, Liguria, Italy
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario La Fe
🇪🇸Valencia, Spain
Sahlgrenska Universitetssjukhuset, Östra Sjukhus; Drottning Silvias Barnsjukhus
🇸🇪Göteborg, Sweden
Universitetssjukhuset Linköping; Barn och Ungdomskliniken
🇸🇪Linkoeping, Sweden
Skånes Universitetssjukhus
🇸🇪Lund, Sweden
Karolinska Universitetssjukhuset, Solna; Astrid Lindgrens Barnsjukhus, Barcanceravdelningen
🇸🇪Solna, Sweden
Birmingham Childrens Hospital; Oncology Dept
🇬🇧Birmingham, United Kingdom
Addenbrookes Hospital; Paediatric Oncology Ward C2
🇬🇧Cambridge, United Kingdom
Bristol Royal Hospital for Children; Paediatric Haematology, Oncology, BMT
🇬🇧Bristol, United Kingdom
Leeds General Infirmary; Ward 35
🇬🇧Leeds, United Kingdom
Royal Hospital for Sick Children
🇬🇧Edinburgh, United Kingdom
Alder Hey Children's NHS Foundation Trust
🇬🇧Liverpool, United Kingdom
University College London NHS Foundation Trust
🇬🇧London, United Kingdom
Royal Manchester Childrens Hospital
🇬🇧Manchester, United Kingdom
Great Ormond Street Hospital; Dept. Of Pediatric Oncology
🇬🇧London, United Kingdom
Newcastle University & The Newcastle upon Tyne Hospitals NHS Foundation Trust
🇬🇧Newcastle upon Tyne, United Kingdom
Queens Medical Centre
🇬🇧Nottingham, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Royal Marsden Hospital; Pediatric Unit
🇬🇧Surrey, United Kingdom
Medizinische Universität Wien
🇦🇹Wien, Austria
Alberta Children'S Hospital
🇨🇦Calgary, Alberta, Canada
Hospital For Sick Children
🇨🇦Toronto, Ontario, Canada
Centre Oscar Lambret; Service de Pediatrie
🇫🇷Lille, France
CHRU de Rennes - Hôpital Sud- Service d'Hématologie Pédiatrique
🇫🇷Rennes, France
Kepler Universitätskliniken GmbH - Med Campus IV.
🇦🇹Linz, Austria
UZ Leuven Gasthuisberg
🇧🇪Leuven, Belgium
Centre Hospitalier d'Angers; Service de cancérologie pédiatrique
🇫🇷Angers, France
CHRU de Tours - Centre de Pédiatrie Clocheville; Service d'Oncopédiatrie
🇫🇷Tours, France
Instytut Pomnik-Centrum Zdrowia Dziecka; Klinika Onkologii
🇵🇱Warsaw, Poland
Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris; Service d Oncologie Pediatrique
🇫🇷Paris, France
CHU ESTAING; Centre Regional de Cancérologie et Thérapie Cellulaire Pédiatrique (CRCTCP)
🇫🇷Clermont Ferrand, France
Centre Leon Berard
🇫🇷Lyon, France
Semmelweis University, 2nd Dept of Pediatrics Neurooncology Unit
🇭🇺Budapest, Hungary
Azienda Ospedaliera di Padova
🇮🇹Padova, Veneto, Italy
Institut Gustave Roussy; Service Pediatrique
🇫🇷Villejuif, France
Fondazione IRCCS Istituto Nazionale dei Tumori
🇮🇹Milano, Lombardia, Italy
Erasmus Mc/Sophia's Childrens Hospital; Dept. of Pediatric Oncology
🇳🇱Rotterdam, Netherlands
Hopital Des Enfants; Service d Hemato-Oncologie
🇫🇷Toulouse, France
Hopital Lenval; Service Hématologie Infantile
🇫🇷Nice, France
UMC St Radboud
🇳🇱Nijmegen, Netherlands
Hospital Sant Joan De Deu
🇪🇸Esplugues De Llobregas, Barcelona, Spain
Skejby Sygehus - Aarhus University Hospital; CF Center, Børneafdeling A
🇩🇰Aarhus N, Denmark
Rigshospitalet; Onkologisk Klinik
🇩🇰København Ø, Denmark
Hôpital Hautepierre
🇫🇷Strasbourg, France