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

High Grade Glioma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01390948
• Other study ID #: BO25041
• Secondary ID: 2010-022189-28IT
• Status: Completed
• Phase: Phase 2
• Start date: October 18, 2011
• Est. completion date: January 29, 2020

Study information

• Verified date: July 2020
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 124
• Est. completion date: January 29, 2020
• Est. primary completion date: February 5, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Glioma
• High Grade Glioma

Intervention

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

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

Drug:
• 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.

Locations

Country	Name	City	State
Australia	Lady Cilento Children's Hospital; Oncology Services Group, Level 12b	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Austria	Kepler Universitätskliniken GmbH - Med Campus IV.	Linz
Austria	Medizinische Universität Wien	Wien
Belgium	UZ Leuven Gasthuisberg	Leuven
Canada	Alberta Children'S Hospital	Calgary	Alberta
Canada	Hospital For Sick Children	Toronto	Ontario
Czechia	Fakultni nemocnice Brno; 2. detska klinika, pracoviste Detska nemocnice	Brno
Czechia	Fakultni Nemocnice V Motole, S.P.	Prague
Denmark	Skejby Sygehus - Aarhus University Hospital; CF Center, Børneafdeling A	Aarhus N
Denmark	Rigshospitalet; Onkologisk Klinik	København Ø
France	Centre Hospitalier d'Angers; Service de cancérologie pédiatrique	Angers
France	CHU ESTAING; Centre Regional de Cancérologie et Thérapie Cellulaire Pédiatrique (CRCTCP)	Clermont Ferrand
France	Centre Oscar Lambret; Service de Pediatrie	Lille
France	Centre Leon Berard	Lyon
France	Hopital Timone Enfants; Onco Pediatrie	Marseille
France	Hopital Lenval; Service Hématologie Infantile	Nice
France	Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris; Service d Oncologie Pediatrique	Paris
France	CHRU de Rennes - Hôpital Sud- Service d'Hématologie Pédiatrique	Rennes
France	Hopital Nord;Consult Pediatrie	St Priest En Jarez
France	Hôpital Hautepierre	Strasbourg
France	Hopital Des Enfants; Service d Hemato-Oncologie	Toulouse
France	CHRU de Tours - Centre de Pédiatrie Clocheville; Service d'Oncopédiatrie	Tours
France	Hopital Brabois Enfants	Vandoeuvre-les-Nancy cedex
France	Institut Gustave Roussy; Service Pediatrique	Villejuif
Hungary	Semmelweis University, 2nd Dept of Pediatrics Neurooncology Unit	Budapest
Italy	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpigh	Bologna	Emilia-Romagna
Italy	Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS; U.O.S. Neuroncologia	Genova	Liguria
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia
Italy	Azienda Ospedaliera di Padova	Padova	Veneto
Netherlands	UMC St Radboud	Nijmegen
Netherlands	Erasmus Mc/Sophia's Childrens Hospital; Dept. of Pediatric Oncology	Rotterdam
Poland	Instytut Pomnik-Centrum Zdrowia Dziecka; Klinika Onkologii	Warsaw
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Sant Joan De Deu	Esplugues De Llobregas	Barcelona
Spain	Hospital Universitario La Fe	Valencia
Sweden	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
United Kingdom	Birmingham Childrens Hospital; Oncology Dept	Birmingham
United Kingdom	Bristol Royal Hospital for Children; Paediatric Haematology, Oncology, BMT	Bristol
United Kingdom	Addenbrookes Hospital; Paediatric Oncology Ward C2	Cambridge
United Kingdom	Royal Hospital for Sick Children	Edinburgh
United Kingdom	Leeds General Infirmary; Ward 35	Leeds
United Kingdom	Alder Hey Children's NHS Foundation Trust	Liverpool
United Kingdom	Great Ormond Street Hospital; Dept. Of Pediatric Oncology	London
United Kingdom	University College London NHS Foundation Trust	London
United Kingdom	Royal Manchester Childrens Hospital	Manchester
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

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Canada,  Czechia,  Denmark,  France,  Hungary,  Italy,  Netherlands,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	From the time of randomization to the date of death (up to approximately 60 months)
Secondary	Percentage of Participants With 1-Year Survival	1-year survival was estimated using the Kaplan-Meier method.	1 year after end of treatment
Secondary	Percentage of Participants With EFS as Determined by the CRRC at 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.	6 months
Secondary	Percentage of Participants With EFS as Determined by the CRRC at 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.	1 year
Secondary	EFS as Assessed by the Investigator	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.	From the time of randomization to the date of any defined event (up to 12 months)
Secondary	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.	From the time of randomization to the date of any defined event (up to 12 months)
Secondary	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.	Up to 12 months
Secondary	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.	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	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.	End of treatment (approximately 58 weeks post-baseline)
Secondary	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)
Secondary	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)
Secondary	Number of Radiotherapy Dose Administrations 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.	Beginning of the concurrent phase to end of treatment break (10 weeks)
Secondary	Number of Dose Administrations of TMZ and Bevacizumab 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.	Beginning of the concurrent phase to end of treatment break (10 weeks)
Secondary	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.	From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)