High Grade Glioma
Conditions
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.
Interventions
DRUGBevacizumab
10 milligrams per kilogram every 2 weeks during the study for up to 12 cycles, each cycle length of 28 days
RADIATIONRadiotherapy
Total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks during the chemoradiation phase.
DRUGTemozolomide (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.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 1-Year Survival | 1 year after end of treatment | 1-year 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 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) | — |
| 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. |
| 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. |
Countries
Australia, Austria, Belgium, Canada, Czechia, Denmark, France, Hungary, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom
Participant flow
Pre-assignment details
Chemoradiation + temozolomide (TMZ) and Chemoradiation + Bevacizumab + TMZ arms: 174 participants were screened; 121 were randomized; 116 received study treatment. Young Patient Cohort: 4 participants were screened; 3 were enrolled and received study treatment (these subjects were not randomized and are not included in efficacy analyses).
Participants by arm
| Arm | Count |
|---|---|
| Chemoradiation + TMZ Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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. | 59 |
| Chemoradiation + Bevacizumab + TMZ Participants received 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 was followed by an adjuvant treatment phase where participants received 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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 was given concomitantly at a dose of 10 mg/kg every 2 weeks throughout the entire treatment period. | 62 |
| Bevacizumab + TMZ Young Patient Cohort (YPC) Participants aged \>/= 6 months and \< 3 years received 10 mg/kg Bevacizumab every 2 weeks and 150 to 200 mg/m\^2 of TMZ daily on Days 1-5 of each cycle. TMZ was 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. | 3 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death during follow-up | 10 | 11 | 1 |
| Overall Study | End of Study | 1 | 0 | 0 |
| Overall Study | Progressive Disease | 2 | 5 | 0 |
| Overall Study | Withdrew consent | 2 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Bevacizumab + TMZ Young Patient Cohort (YPC) | Chemoradiation + Bevacizumab + TMZ | Chemoradiation + TMZ |
|---|---|---|---|---|
| Age, Customized >/= 13 years and < 18 years | 40 Participants | 0 Participants | 17 Participants | 23 Participants |
| Age, Customized < 3 years | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Age, Customized >/= 3 years and < 6 years | 16 Participants | 0 Participants | 10 Participants | 6 Participants |
| Age, Customized >/= 6 years and < 13 years | 65 Participants | 0 Participants | 35 Participants | 30 Participants |
| Sex: Female, Male Female | 51 Participants | 0 Participants | 28 Participants | 23 Participants |
| Sex: Female, Male Male | 73 Participants | 3 Participants | 34 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 56 / 56 | 60 / 60 | 3 / 3 |
| serious Total, serious adverse events | 27 / 56 | 35 / 60 | 0 / 3 |
Outcome results
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.
Time frame: From the time of randomization to the date of any defined event (up to 12 months)
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiation + TMZ | Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC) | 11.79 months |
| Chemoradiation + Bevacizumab + TMZ | Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC) | 8.21 months |
p-value: 0.129295% CI: [0.9, 2.3]Log Rank
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.
Time frame: Up to 12 months
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation + TMZ | Concordance Between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival | 96.6 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Concordance Between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival | 87.1 percentage of participants |
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.
Time frame: From the time of randomization to the date of any defined event (up to 12 months)
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiation + TMZ | EFS as Assessed by the Investigator | 11.79 months |
| Chemoradiation + Bevacizumab + TMZ | EFS as Assessed by the Investigator | 11.27 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.
Time frame: 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)
Population: Randomized participant population aged 5 years or older with a measure at the specified time point. Here, 'n' represents the number of participants with a measure at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Additional Safety Follow-Up (Visit 2) | 0.784 units on a scale | Standard Deviation 0.287 |
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Yearly Follow-Up 1 | 0.906 units on a scale | Standard Deviation 0.11 |
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Additional Safety Follow-Up (Visit 4) | 0.814 units on a scale | Standard Deviation 0.304 |
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | End of Treatment | 0.832 units on a scale | Standard Deviation 0.216 |
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Additional Safety Follow-Up (Visit 6) | 1.000 units on a scale | Standard Deviation 0 |
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Yearly Follow-up 2 | 0.737 units on a scale | Standard Deviation 0.326 |
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Cycle 6, Day 1 | 0.785 units on a scale | Standard Deviation 0.239 |
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | End of Study | 0.647 units on a scale | Standard Deviation 0.496 |
| Chemoradiation + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Baseline | 0.713 units on a scale | Standard Deviation 0.317 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Additional Safety Follow-Up (Visit 8) | 0.930 units on a scale | — |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | End of Study | 0.790 units on a scale | Standard Deviation 0.234 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Baseline | 0.730 units on a scale | Standard Deviation 0.274 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Cycle 6, Day 1 | 0.779 units on a scale | Standard Deviation 0.232 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | End of Treatment | 0.820 units on a scale | Standard Deviation 0.209 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Yearly Follow-Up 1 | 0.926 units on a scale | Standard Deviation 0.109 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Yearly Follow-up 2 | 0.793 units on a scale | Standard Deviation 0.219 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Additional Safety Follow-Up (Visit 2) | 0.901 units on a scale | Standard Deviation 0.147 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Additional Safety Follow-Up (Visit 4) | 0.830 units on a scale | Standard Deviation 0.143 |
| Chemoradiation + Bevacizumab + TMZ | Health Status as Measured by the Health Utility Index (HUI) | Additional Safety Follow-Up (Visit 6) | 0.490 units on a scale | Standard Deviation 0.537 |
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.
Time frame: End of treatment (approximately 58 weeks post-baseline)
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chemoradiation + TMZ | Neurological Psychological Function as Measured by the Wechsler Scale | 92.0 units on a scale | Standard Deviation 9.8 |
| Chemoradiation + Bevacizumab + TMZ | Neurological Psychological Function as Measured by the Wechsler Scale | 97.0 units on a scale | Standard Deviation 18.4 |
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.
Time frame: Beginning of the concurrent phase to end of treatment break (10 weeks)
Population: Safety population included all participants that received study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Chemoradiation + TMZ | Number of Dose Administrations of TMZ and Bevacizumab in the Concurrent Phase | TMZ | 42.0 number of dose administrations |
| Chemoradiation + TMZ | Number of Dose Administrations of TMZ and Bevacizumab in the Concurrent Phase | Bevacizumab | NA number of dose administrations |
| Chemoradiation + Bevacizumab + TMZ | Number of Dose Administrations of TMZ and Bevacizumab in the Concurrent Phase | TMZ | 42.0 number of dose administrations |
| Chemoradiation + Bevacizumab + TMZ | Number of Dose Administrations of TMZ and Bevacizumab in the Concurrent Phase | Bevacizumab | 6.0 number of dose administrations |
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.
Time frame: Beginning of the concurrent phase to end of treatment break (10 weeks)
Population: Safety population included all participants that received study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiation + TMZ | Number of Radiotherapy Dose Administrations in the Concurrent Phase | 54.0 Grays |
| Chemoradiation + Bevacizumab + TMZ | Number of Radiotherapy Dose Administrations in the Concurrent Phase | 54.0 Grays |
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.
Time frame: From the time of randomization to the date of any defined event (up to 12 months)
Population: Randomized participant population with a measurable lesion at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation + TMZ | Objective Response Rate (ORR) | 40 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Objective Response Rate (ORR) | 41.7 percentage of participants |
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.
Time frame: From the time of randomization to the date of death (up to approximately 60 months)
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiation + TMZ | Overall Survival | 20.27 months |
| Chemoradiation + Bevacizumab + TMZ | Overall Survival | 18.30 months |
Secondary
Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations
Time frame: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)
Population: Safety population included all participants that received study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemoradiation + TMZ | Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations | Radiotherapy | 94.6 percentage of participants |
| Chemoradiation + TMZ | Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations | TMZ | 85.7 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations | Radiotherapy | 98.3 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Percentage of Participants Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations | TMZ | 88.3 percentage of participants |
Secondary
Percentage of Participants With 1-Year Survival
1-year survival was estimated using the Kaplan-Meier method.
Time frame: 1 year after end of treatment
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation + TMZ | Percentage of Participants With 1-Year Survival | 67.69 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Percentage of Participants With 1-Year Survival | 74.83 percentage of participants |
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.
Time frame: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)
Population: Safety population included all participants that received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation + TMZ | Percentage of Participants With an Adverse Event (AE) | 100 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Percentage of Participants With an Adverse Event (AE) | 98.3 percentage of participants |
Secondary
Percentage of Participants With a Treatment Delay or Discontinuation
Time frame: From the time of randomization of the first participant to the date of clinical cutoff (approximately 60 months)
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemoradiation + TMZ | Percentage of Participants With a Treatment Delay or Discontinuation | AE leading to dose modification/interruption | 60.7 percentage of participants |
| Chemoradiation + TMZ | Percentage of Participants With a Treatment Delay or Discontinuation | AE leading to withdrawal from treatment | 5.4 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Percentage of Participants With a Treatment Delay or Discontinuation | AE leading to dose modification/interruption | 71.7 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Percentage of Participants With a Treatment Delay or Discontinuation | AE leading to withdrawal from treatment | 21.7 percentage of participants |
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.
Time frame: 1 year
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation + TMZ | Percentage of Participants With EFS as Determined by the CRRC at 1 Year | 48.37 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Percentage of Participants With EFS as Determined by the CRRC at 1 Year | 38.28 percentage of participants |
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.
Time frame: 6 months
Population: Randomized participant population included all randomized participants regardless of whether they received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation + TMZ | Percentage of Participants With EFS as Determined by the CRRC at 6 Months | 66.46 percentage of participants |
| Chemoradiation + Bevacizumab + TMZ | Percentage of Participants With EFS as Determined by the CRRC at 6 Months | 68.43 percentage of participants |