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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 124
- 试验地点
- 53
- 主要终点
- Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Bevacizumab (Drug)
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.
干预措施: Temozolomide (TMZ) (Drug)
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.
干预措施: Bevacizumab (Drug)
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.
干预措施: Radiotherapy (Radiation)
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.
干预措施: Temozolomide (TMZ) (Drug)
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.
干预措施: Radiotherapy (Radiation)
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.
干预措施: Temozolomide (TMZ) (Drug)
结局指标
主要结局
Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC)
时间窗: 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.
次要结局
- Objective Response Rate (ORR)(From the time of randomization to the date of any defined event (up to 12 months))
- 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))
- Number of Radiotherapy Dose Administrations in the Concurrent Phase(Beginning of the concurrent phase to end of treatment break (10 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))
- 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))
- Percentage of Participants With 1-Year Survival(1 year after end of treatment)
- Overall Survival(From the time of randomization to the date of death (up to approximately 60 months))
- Percentage of Participants With EFS as Determined by the CRRC at 6 Months(6 months)
- Neurological Psychological Function as Measured by the Wechsler Scale(End of treatment (approximately 58 weeks post-baseline))
- 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))
- Concordance Between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival(Up to 12 months)
- 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))