Childhood Cerebral Anaplastic Astrocytoma, Childhood Oligodendroglioma, Childhood Spinal Cord Neoplasm, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Ependymoma, Recurrent Childhood Medulloblastoma
Conditions
Brief summary
This phase II trial is studying how well giving bevacizumab together with irinotecan works in treating young patients with recurrent, progressive, or refractory glioma, medulloblastoma, ependymoma, or low grade glioma. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of glioma by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with irinotecan may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in pediatric patients with recurrent, progressive, or refractory malignant glioma (Stratum A \[closed to accrual as of 4/21/2009\]) or recurrent/progressive/refractory intrinsic brain stem glioma (Stratum B \[closed to accrual as of 4/21/2009\]). II. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in patients with recurrent or progressive medulloblastoma (Stratum C \[closed to accrual as of 10/27/2009\]) or recurrent or progressive ependymoma (Stratum D \[closed to accrual as of 7/29/2010\]). III. Estimate the sustained disease stabilization rate associated with bevacizumab and irinotecan in patients with recurrent or progressive low grade glioma (Stratum E \[closed to accrual as of 7/29/2010\]). SECONDARY OBJECTIVES: I. Estimate the rate of treatment-related toxicity of this regimen in these patients. II. Estimate the cumulative incidence of sustained objective responses as a function of this regimen in these patients. III. Estimate the distributions of survival and event-free survival of these patients. IV. Correlate functional changes in tumor with progression-free survival and response using MR perfusion/diffusion imaging and fludeoxyglucose F 18 positron emission tomography. OUTLINE: This is a multicenter study. Patients are stratified according to tumor type (high-grade glioma \[closed to accrual as of 4/21/2009\] vs intrinsic brain stem tumor \[closed to accrual as of 4/21/2009\] vs medulloblastoma \[closed to accrual as of 10/27/2010\] vs ependymoma \[closed to accrual as of 7/29/2010\] vs low grade glioma \[closed to accrual as of 7/29/2010\]). Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment. After completion of study treatment, patients are followed for 30 days and then every 3 months for up to 2 years.
Interventions
BIOLOGICALBevacizumab
Given IV
RADIATIONFludeoxyglucose F-18
Undergo fludeoxyglucose F18 PET
DRUGIrinotecan Hydrochloride
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed high-grade glioma (WHO grade III or IV) at any site within the brain, including the following: * Anaplastic astrocytoma * Glioblastoma multiforme (including giant cell and gliosarcoma subtypes) * Anaplastic oligodendroglioma * Anaplastic ganglioglioma * Anaplastic oligoastrocytoma * Diffuse brain stem glioma * Histologic confirmation not required * Histologically confirmed medulloblastoma * Histologically confirmed ependymoma * Primary spinal cord malignant glioma with measurable metastatic disease within the brain * Histologic confirmation required * Neuraxis dissemination allowed provided there is bidimensionally measurable disease within the brain and spinal cord * Low grade glioma at any site within the brain with or without spinal cord disease * Recurrent, progressive, or refractory disease (must have received prior chemoradiotherapy) * No more than 2 prior chemotherapy regimens following relapse * Bidimensionally measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 2 planes * If there is spinal cord disease as well, response assessment will be based only upon the measurable tumor in the brain * No diffuse gliomatosis cerebri with \< 1 discrete, measurable lesion * No evidence of new symptomatic CNS hemorrhage (\> grade 2) within the past 2 weeks * No central non-cerebellar PNET's (e.g., cerebral PNET or pineoblastoma) * No spinal cord tumors only * Karnofsky performance status (PS) 50-100% (\> 16 years of age) OR Lansky PS 50-100% (≤ 16 years of age) * Absolute neutrophil count ≥ 1,500/mm³ (unsupported) * Platelet count ≥ 100,000/mm³ (unsupported) * Hemoglobin \> 8 g/dL (support allowed) * Creatinine normal * BUN \< 25 mg/dL * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * ALT and AST ≤ 3 times ULN * Neurological deficits must be stable for ≥ 1 week prior to study entry * No active renal, cardiac (congestive cardiac failure, myocarditis), or pulmonary disease * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment * No clinically significant unrelated systemic illness that would preclude study treatment, including any of the following: * Serious infections * Significant cardiac, pulmonary, hepatic, or other organ dysfunction * No uncontrolled systemic hypertension, defined as systolic blood pressure (BP) and/or diastolic BP \> 95th percentile for age * No stroke, myocardial infarction, or unstable angina within the past 6 months * No clinically significant peripheral vascular disease * No significant traumatic injury within the past 6 weeks * No evidence of bleeding diathesis, coagulopathy, or PT INR \> 1.5 * Urine protein/creatinine ratio ≤ 1.0 * No abdominal fistula or gastrointestinal perforation within the past 6 months * No serious nonhealing wound, ulcer, or bone fracture * At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas) * At least 7 days since prior investigational or biologic agents (3 weeks if patient experienced ≥ grade 2 myelosuppression or if agent has a prolonged half-life) * More than 7 days since prior minor surgery * More than 12 weeks since prior craniospinal or focal irradiation to primary tumor or other sites * At least 4 weeks since prior major surgery and recovered * At least 3 months since prior autologous bone marrow or stem cell transplantation * At least 2 weeks since prior colony-forming growth factors (i.e., filgrastim \[G-CSF\], sargramostim \[GM-CSF\], epoetin alfa) * No prior bevacizumab or irinotecan hydrochloride * No anticipated surgery during treatment * No concurrent prophylactic G-CSF, GM-CSF, or epoetin alfa * Concurrent dexamethasone allowed provided the dose is stable or decreasing over the past week * No other concurrent anticancer or investigational drugs * No concurrent medications that may interfere with study (e.g., immunosuppressive agents other than corticosteroids) * No concurrent therapeutic anticoagulation * No concurrent nonsteroidal anti-inflammatory drugs, clopidogrel bisulfate, dipyridamole, or acetylsalicylic acid (aspirin) \> 81 mg/day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate Sustained for ≥ 8 Weeks | From day 1 of treatment up to 24 weeks | Objective response is either a complete response or a partial response observed during the first four courses of treatment and sustained for 8 weeks. The objective response rate will be reported separately for patients with recurrent/progressive malignant glioma(Stratum A), recurrent/progressive instrinsic brain stem tumors(Stratum B), recurrent/progressive medulloblastoma(Stratum C), and recurrent/progressive ependymoma(Stratum D). CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size. This outcome measures is not defined for the Stratum E in the protocol. |
| Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E) | From day 1 of treatment up to 24 weeks | Disease stabilization is defined as a complete response(CR) or partial response(PR) observed during the first four courses and sustained for 8 weeks; or stable disease (SD) sustained for 6 courses characterized by SD at the end of course 2, at the end of course 4 and at the end of course 6. CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size. SD is at least stable and maintenance corticosteroid dose not increased in neurologic examination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From start of treatment up to 2 years | Progression-Free survival is the interval of time between of protocol treatment and minimum date of documentation of progressive Disease,second malignancy,death due to any cause, or date of last follow-up. Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression,OR the appearance of new tumor OR a \> 25% increase in the sum of the products of two longest perpendicular diameters of all measurable tumors. K-M method was used to estimate progression-free survival. |
| Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging | Baseline and day 15 | Perfusion ratio obtained from magnetic resonance(MR) diffusion imaging may explain changes in the tumor after therapy. Changes in the perfusion ratio will be reported for those strata that have a sufficient number of participants with MR diffusion imaging. The change was calculated from perfusion ratio at Baseline to perfusion ratio at Day 15(values of perfusion ratio at Day 15 - values of perfusion ratio at baseline). The higher of perfusion ratio is worse. MR perfusion ratio is perfusion solid part of tumor from CBV divided by perfusion frontal while matter. There is no a unit available. |
| Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image | Baseline and day 15 | Diffusion ratio obtained from magnetic resonance (MR) diffusion imaging may explain changes in the tumor after therapy. Changes in the diffusion ratio will be reported for those strata that have a sufficient number of participants with MR diffusion imaging. The change was calculated from diffusion ratio at Baseline to diffusion ratio at Day 15 (values of diffusion ratio at Day 15 -values of diffusion ration at baseline). The higher of diffusion ratio is better. MR diffusion ratio is the diffusion solid part of tumor divided by the diffusion frontal white matter. There is no a unit available. |
| Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | The association of CA9 expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with CA9 measurements. |
| Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates | From start of treatment until the earliest of progressive disease, death, second malignancy or off study OR up to 2 years | Using Cox proportional hazards models, the association of tumor volume based on FLAIR images with PFS will be investigated for those strata that have a sufficient number of participants with volume FLAIR measurements. Volumetric magnetic resonance imaging is performed to investigate surrogate markers of tumor growth. Volume FLAIR measurements were longitudinal. As we are not comparing the strata, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. We consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume based on FLAIR. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. |
| Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates | From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years | Using Cox Proportional hazards Models, the association of Log-transformed tumor enhancing volume with progression-free survival will be investigated. Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth. Tumor enhancing volumes were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section and we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor enhancing volume. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. |
| Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates | From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years | Using Cox Proportional Hazards Models, the association of cystic necrosis with progression-free survival will be investigated. Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth. Volumes of cystic necrosis were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section and we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume based on cystic necrosis. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. |
| Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | Using Cox Proportional Hazards Models, the association of tumor diffusion ratios with progression-free survival will be investigated. Magnetic resonance (MR) diffusion imaging is performed to investigate surrogate markers of tumor growth. Tumor diffusion ratios were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. And we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor diffusion ratio. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. |
| Association of Log-transformed Tumor Perfusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates | From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years | Using Cox Proportional Hazards Models, the association of tumor perfusion ratio with progression-free survival will be investigated. Magnetic resonance (MR) perfusion imaging is performed to investigate surrogate markers of tumor growth. Tumor perfusion ratios were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. We consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume perfusion ratio. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. |
| Progression-free Survival Hazard Ratio by VEGF-A Expression | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | The association of VEGF-A expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-A measurements. |
| Progression-free Survival Hazard Ratio by VEGF-R2 Expression | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | The association of VEGF-R2 expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-R2 measurements. |
| Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity | From day 1 of treatment until off study | Adverse events are monitored and graded according to the Common Terminology Criteria for Adverse Events. The grade 1 = mild, grade 2=moderate, grade 3 =severe, grade 4=life threatening/disabling, grade 5=death. |
| Systemic Clearance | Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 | Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the systemic clearance. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology, 2016 volume 81(1):148-160. The estimates of the systemic clearance were calculated by the model described in the paper. |
| Terminal Half-life | Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 | Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the PK parameters. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology,2016 volume 81(1):148-160. The estimates of the terminal half-life were calculated by the method described in the paper. |
| Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15 | Baseline and 24-48 hours after the 2nd dose of Bevacizumab in course 1 | The change in VEGF-R2 was calculated from baseline to the time of the 2nd dose (values of 24-48 hours after the 2nd dose at Day 15 - values of pre-dose 1 Day1, i.e., baseline). VEGF-R2 is measured in the relative phosphorylation score which is generated as a ratio of normalized phosphorylated VEGF-R2 versus normalized total VEGF-R2 protein. |
| Descriptive Statistics for the Changes in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) Concurrently Measured With the Changes in Perfusion From Magnetic Resonance Imaging | Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 | The changes in VEGF-R2 are calculated by values at Day 15 minus values at baseline for the patients who had the changes in perfusion from magnetic resonance perfusion imaging. The purpose of reporting descriptive statistics of changes of VEGF-R2 is to provide the information for the correlation coefficients in Section 19. |
| Descriptive Statistics for the Change of Perfusion in Magnetic Resonance Imaging Concurrently Measured With the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) | Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 | The change of perfusion in magnetic resonance imaging is calculated by taking the difference between the Day-15 measurements and the Baseline measurements for patients who had the changes of VEGF-R2. The purpose of reporting the descriptive statistics is to provide the information for the correlation coefficients reported in the next section, Section 19. MR perfusion ratio is the ratio of the perfusion measurements in the tumor and the perfusion measurerement in comparative frontal while matter, which is the comparative healthy part of the brain. |
| Correlation of the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline With the Change in Perfusion From Magnetic Resonance Imaging | Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 | Spearman correlation coefficient is used to measure the correlation of the changes in VEGF-R2 with the changes in perfusion ratios. The changes are calculated by values at Day 15 minus values at baseline for VEGF-2 in Section 17 above and perfusion in Section 18 above, respectively. The correlation coefficients are reported in each stratum separately. |
| Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline | Baseline | The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum. |
| Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline | Baseline | The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum. |
| Number of Patients With High VEGF-A Expression at Baseline | Baseline | The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum. |
| Number of Patients With High VEGF-R2 Expression at Baseline | Baseline | The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum. |
| Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | The association of hypoxia inducible factor-2alpha expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with hypoxia inducible factor-2alpha measurements. The hazard ratio was reported for patients who had hypoxia inducible factor-2alpha expression. |
| Volume of Distribution | Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 | Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the volume of distribution. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology ,2016 volume 81(1):148-160. The estimates of the volume of distribution were calculated by the model described in the paper. |
| Cumulative Incidence of Sustained Objective Responses | From the first imaging after treatment up to 2 years | Cumulative incidence of sustained objective response provides a percentage of participants experiencing the event of interest at a given follow-up time point (for example, 6-months, 1-year, etc.) in the presence of competing events such as progressive disease or death, and it is estimated using the event data for both the event of interest and the competing events experienced by the study participants. In this sense, it is different than the incidence rates estimated in epidemiological studies in terms of 'incidences per 1000 person years. 6-month Cumulative incidence of sustained objective responses will be reported separately for each stratum. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High-grade Gliomas Recurrent, progressive or refractory high-grade gliomas (Stratum A): The only patients with Recurrent, progressive or refractory high-grade gliomas were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\
80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2. | 18 |
| Brain Stem Tumors Recurrent,progressive or refractory intrinsic brain stem tumors (Stratum B): The only patients with Recurrent,progressive or refractory intrinsic brain stem tumors were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\
80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2. | 17 |
| Medulloblastoma Recurrent or progressive medulloblastoma(Stratum C): The only patients with recurrent or progressive medulloblastoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\
80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2. | 10 |
| Ependymoma Recurrent or progressive ependymoma (Stratum D):The only patients with recurrent or progressive ependymoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\
80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2. | 15 |
| Low Grade Glioma Recurrent low grade glioma (Stratum E): The only patients with recurrent low grade glioma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\
80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2. | 37 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Ineligible | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Brain Stem Tumors | Medulloblastoma | Ependymoma | High-grade Gliomas | Low Grade Glioma | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 17 Participants | 9 Participants | 14 Participants | 14 Participants | 37 Participants | 91 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 6 Participants |
| Age, Continuous | 8.45 years STANDARD_DEVIATION 3.35 | 10.56 years STANDARD_DEVIATION 5.28 | 10.16 years STANDARD_DEVIATION 5.17 | 15.07 years STANDARD_DEVIATION 3.82 | 8.58 years STANDARD_DEVIATION 4.09 | 10.21 years STANDARD_DEVIATION 4.82 |
| Region of Enrollment United States | 17 participants | 10 participants | 15 participants | 18 participants | 37 participants | 97 participants |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 9 Participants | 7 Participants | 19 Participants | 49 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 6 Participants | 11 Participants | 18 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 91 / 92 |
| serious Total, serious adverse events | 37 / 92 |
Outcome results
Primary
Objective Response Rate Sustained for ≥ 8 Weeks
Objective response is either a complete response or a partial response observed during the first four courses of treatment and sustained for 8 weeks. The objective response rate will be reported separately for patients with recurrent/progressive malignant glioma(Stratum A), recurrent/progressive instrinsic brain stem tumors(Stratum B), recurrent/progressive medulloblastoma(Stratum C), and recurrent/progressive ependymoma(Stratum D). CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size. This outcome measures is not defined for the Stratum E in the protocol.
Time frame: From day 1 of treatment up to 24 weeks
Population: Two patients in the Stratum A,one patient in the Stratum C, and one patient in the Stratum D were inevaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Objective Response Rate Sustained for ≥ 8 Weeks | 0 participants |
| Brain Stem Tumors | Objective Response Rate Sustained for ≥ 8 Weeks | 0 participants |
| Medulloblastoma | Objective Response Rate Sustained for ≥ 8 Weeks | 0 participants |
| Ependymoma | Objective Response Rate Sustained for ≥ 8 Weeks | 0 participants |
Primary
Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E)
Disease stabilization is defined as a complete response(CR) or partial response(PR) observed during the first four courses and sustained for 8 weeks; or stable disease (SD) sustained for 6 courses characterized by SD at the end of course 2, at the end of course 4 and at the end of course 6. CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size. SD is at least stable and maintenance corticosteroid dose not increased in neurologic examination.
Time frame: From day 1 of treatment up to 24 weeks
Population: Patients with recurrent or progressive low grade glioma were treated with any courses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E) | 23 participants |
Secondary
Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates
Using Cox Proportional Hazards Models, the association of tumor diffusion ratios with progression-free survival will be investigated. Magnetic resonance (MR) diffusion imaging is performed to investigate surrogate markers of tumor growth. Tumor diffusion ratios were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. And we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor diffusion ratio. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
Population: Patients had diffusion ratio at pre-treatment scans and at least one on treatment scans.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| High-grade Gliomas | Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates | 4.41 Hazard Ratio |
| Brain Stem Tumors | Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates | 1.82 Hazard Ratio |
Secondary
Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates
Using Cox Proportional hazards Models, the association of Log-transformed tumor enhancing volume with progression-free survival will be investigated. Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth. Tumor enhancing volumes were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section and we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor enhancing volume. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years
Population: Patients had tumor enhancing volume at Pre-treatment and at least one on treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| High-grade Gliomas | Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates | 1.65 Hazard Ratio |
| Brain Stem Tumors | Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates | 1.16 Hazard Ratio |
Secondary
Association of Log-transformed Tumor Perfusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates
Using Cox Proportional Hazards Models, the association of tumor perfusion ratio with progression-free survival will be investigated. Magnetic resonance (MR) perfusion imaging is performed to investigate surrogate markers of tumor growth. Tumor perfusion ratios were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. We consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume perfusion ratio. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years
Population: The analyses cannot be performed with the Cox proportional hazard model since there are no sufficient measurements of perfusion ratio and events.
Secondary
Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates
Using Cox proportional hazards models, the association of tumor volume based on FLAIR images with PFS will be investigated for those strata that have a sufficient number of participants with volume FLAIR measurements. Volumetric magnetic resonance imaging is performed to investigate surrogate markers of tumor growth. Volume FLAIR measurements were longitudinal. As we are not comparing the strata, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. We consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume based on FLAIR. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study OR up to 2 years
Population: Patients had Flair volume at Pre-treatment and at least one on treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| High-grade Gliomas | Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates | 1.47 Hazard Ratio |
| Brain Stem Tumors | Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates | 1.76 Hazard Ratio |
Secondary
Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates
Using Cox Proportional Hazards Models, the association of cystic necrosis with progression-free survival will be investigated. Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth. Volumes of cystic necrosis were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section and we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume based on cystic necrosis. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years
Population: Patients had volume of cystic necrosis at Pre-treatment and at least one on treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| High-grade Gliomas | Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates | 2.56 Hazard Ratio |
| Brain Stem Tumors | Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates | 1.09 Hazard Ratio |
Secondary
Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image
Diffusion ratio obtained from magnetic resonance (MR) diffusion imaging may explain changes in the tumor after therapy. Changes in the diffusion ratio will be reported for those strata that have a sufficient number of participants with MR diffusion imaging. The change was calculated from diffusion ratio at Baseline to diffusion ratio at Day 15 (values of diffusion ratio at Day 15 -values of diffusion ration at baseline). The higher of diffusion ratio is better. MR diffusion ratio is the diffusion solid part of tumor divided by the diffusion frontal white matter. There is no a unit available.
Time frame: Baseline and day 15
Population: There are no sufficient data for the analyses in the Medulloblastoma arm.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image | -0.34 Ratio | Full Range 0.085 |
| Brain Stem Tumors | Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image | -0.17 Ratio | — |
| Medulloblastoma | Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image | 0.11 Ratio | — |
| Ependymoma | Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image | -0.11 Ratio | — |
Secondary
Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging
Perfusion ratio obtained from magnetic resonance(MR) diffusion imaging may explain changes in the tumor after therapy. Changes in the perfusion ratio will be reported for those strata that have a sufficient number of participants with MR diffusion imaging. The change was calculated from perfusion ratio at Baseline to perfusion ratio at Day 15(values of perfusion ratio at Day 15 - values of perfusion ratio at baseline). The higher of perfusion ratio is worse. MR perfusion ratio is perfusion solid part of tumor from CBV divided by perfusion frontal while matter. There is no a unit available.
Time frame: Baseline and day 15
Population: There are no sufficient data for the analyses in the Medulloblastoma arm and Ependymoma arm.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging | -0.14 Ratio | Full Range 0.705 |
| Brain Stem Tumors | Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging | -1.98 Ratio | — |
| Medulloblastoma | Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging | -0.42 Ratio | — |
Secondary
Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15
The change in VEGF-R2 was calculated from baseline to the time of the 2nd dose (values of 24-48 hours after the 2nd dose at Day 15 - values of pre-dose 1 Day1, i.e., baseline). VEGF-R2 is measured in the relative phosphorylation score which is generated as a ratio of normalized phosphorylated VEGF-R2 versus normalized total VEGF-R2 protein.
Time frame: Baseline and 24-48 hours after the 2nd dose of Bevacizumab in course 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High-grade Gliomas | Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15 | -0.37 Ratio |
| Brain Stem Tumors | Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15 | -0.21 Ratio |
| Medulloblastoma | Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15 | -0.003 Ratio |
| Ependymoma | Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15 | 0.24 Ratio |
| Low Grade Glioma | Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15 | 1.70 Ratio |
Secondary
Correlation of the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline With the Change in Perfusion From Magnetic Resonance Imaging
Spearman correlation coefficient is used to measure the correlation of the changes in VEGF-R2 with the changes in perfusion ratios. The changes are calculated by values at Day 15 minus values at baseline for VEGF-2 in Section 17 above and perfusion in Section 18 above, respectively. The correlation coefficients are reported in each stratum separately.
Time frame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1
Population: The analyses are performed for the patients who had the changes in both VEGF-R2 and perfusion.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Correlation of the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline With the Change in Perfusion From Magnetic Resonance Imaging | 0.5 Correlation Coefficient | 0.61 |
| Brain Stem Tumors | Correlation of the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline With the Change in Perfusion From Magnetic Resonance Imaging | -0.50 Correlation Coefficient | 0.27 |
Secondary
Cumulative Incidence of Sustained Objective Responses
Cumulative incidence of sustained objective response provides a percentage of participants experiencing the event of interest at a given follow-up time point (for example, 6-months, 1-year, etc.) in the presence of competing events such as progressive disease or death, and it is estimated using the event data for both the event of interest and the competing events experienced by the study participants. In this sense, it is different than the incidence rates estimated in epidemiological studies in terms of 'incidences per 1000 person years. 6-month Cumulative incidence of sustained objective responses will be reported separately for each stratum.
Time frame: From the first imaging after treatment up to 2 years
Population: Two patients in the Stratum A,one patient in the Stratum C, and one patient in the Stratum D were inevaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Cumulative Incidence of Sustained Objective Responses | 0 Percentage of Participants | 0 |
| Brain Stem Tumors | Cumulative Incidence of Sustained Objective Responses | 0 Percentage of Participants | 0 |
| Medulloblastoma | Cumulative Incidence of Sustained Objective Responses | 0 Percentage of Participants | 0 |
| Ependymoma | Cumulative Incidence of Sustained Objective Responses | 0 Percentage of Participants | 0 |
| Low Grade Glioma | Cumulative Incidence of Sustained Objective Responses | 0.058 Percentage of Participants | 0.0405 |
Secondary
Descriptive Statistics for the Change of Perfusion in Magnetic Resonance Imaging Concurrently Measured With the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC)
The change of perfusion in magnetic resonance imaging is calculated by taking the difference between the Day-15 measurements and the Baseline measurements for patients who had the changes of VEGF-R2. The purpose of reporting the descriptive statistics is to provide the information for the correlation coefficients reported in the next section, Section 19. MR perfusion ratio is the ratio of the perfusion measurements in the tumor and the perfusion measurerement in comparative frontal while matter, which is the comparative healthy part of the brain.
Time frame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1
Population: The analyses are performed for the patients who had the changes in both VEGF-R2 and perfusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Descriptive Statistics for the Change of Perfusion in Magnetic Resonance Imaging Concurrently Measured With the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) | -1.60 Ratio | Standard Error 1.18 |
| Brain Stem Tumors | Descriptive Statistics for the Change of Perfusion in Magnetic Resonance Imaging Concurrently Measured With the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) | -1.54 Ratio | Standard Error 0.87 |
Secondary
Descriptive Statistics for the Changes in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) Concurrently Measured With the Changes in Perfusion From Magnetic Resonance Imaging
The changes in VEGF-R2 are calculated by values at Day 15 minus values at baseline for the patients who had the changes in perfusion from magnetic resonance perfusion imaging. The purpose of reporting descriptive statistics of changes of VEGF-R2 is to provide the information for the correlation coefficients in Section 19.
Time frame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1
Population: The analyses are performed for the patients who had the changes in both VEGF-R2 and perfusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Descriptive Statistics for the Changes in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) Concurrently Measured With the Changes in Perfusion From Magnetic Resonance Imaging | -1.12 Ratio | Standard Error 0.78 |
| Brain Stem Tumors | Descriptive Statistics for the Changes in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) Concurrently Measured With the Changes in Perfusion From Magnetic Resonance Imaging | -1.20 Ratio | Standard Error 0.99 |
Secondary
Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline
The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum.
Time frame: Baseline
Population: Only strata were reported, in which the patients had tissue samples available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline | 0 participants |
| Brain Stem Tumors | Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline | 4 participants |
| Medulloblastoma | Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline | 2 participants |
Secondary
Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline
The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum.
Time frame: Baseline
Population: Only strata were reported, in which the patients had tissue samples available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline | 0 participants |
| Brain Stem Tumors | Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline | 3 participants |
| Medulloblastoma | Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline | 7 participants |
Secondary
Number of Patients With High VEGF-A Expression at Baseline
The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum.
Time frame: Baseline
Population: Only strata were reported, in which the patients had tissue samples available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Number of Patients With High VEGF-A Expression at Baseline | 2 participants |
| Brain Stem Tumors | Number of Patients With High VEGF-A Expression at Baseline | 5 participants |
| Medulloblastoma | Number of Patients With High VEGF-A Expression at Baseline | 16 participants |
Secondary
Number of Patients With High VEGF-R2 Expression at Baseline
The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum.
Time frame: Baseline
Population: Only strata were reported, in which the patients had tissue samples available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Number of Patients With High VEGF-R2 Expression at Baseline | 4 participants |
| Brain Stem Tumors | Number of Patients With High VEGF-R2 Expression at Baseline | 4 participants |
| Medulloblastoma | Number of Patients With High VEGF-R2 Expression at Baseline | 13 participants |
Secondary
Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity
Adverse events are monitored and graded according to the Common Terminology Criteria for Adverse Events. The grade 1 = mild, grade 2=moderate, grade 3 =severe, grade 4=life threatening/disabling, grade 5=death.
Time frame: From day 1 of treatment until off study
Population: The patients were treated with any dose treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity | 8 participants |
| Brain Stem Tumors | Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity | 4 participants |
| Medulloblastoma | Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity | 4 participants |
| Ependymoma | Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity | 6 participants |
| Low Grade Glioma | Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity | 22 participants |
Secondary
Progression-free Survival
Progression-Free survival is the interval of time between of protocol treatment and minimum date of documentation of progressive Disease,second malignancy,death due to any cause, or date of last follow-up. Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression,OR the appearance of new tumor OR a \> 25% increase in the sum of the products of two longest perpendicular diameters of all measurable tumors. K-M method was used to estimate progression-free survival.
Time frame: From start of treatment up to 2 years
Population: The patients were treated with any dose treatment.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Progression-free Survival | 4.20 Months | 95% Confidence Interval 1.57 |
| Brain Stem Tumors | Progression-free Survival | 2.35 Months | — |
| Medulloblastoma | Progression-free Survival | 2.48 Months | — |
| Ependymoma | Progression-free Survival | 2.15 Months | — |
Secondary
Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression
The association of CA9 expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with CA9 measurements.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
Population: Only the number of patients in strata E was sufficient to perform the analysis exploring the association of carbonic anhydrase 9 (CA9) expression with progression-free survival.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression | 0.705 Hazard Ratio |
Secondary
Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression
The association of hypoxia inducible factor-2alpha expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with hypoxia inducible factor-2alpha measurements. The hazard ratio was reported for patients who had hypoxia inducible factor-2alpha expression.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
Population: The number of patients in strata C and D was not sufficient to perform the analysis exploring the association of hypoxia inducible factor-2alpha expression with progression-free survival. Thus the association analysis was performed for the patients in Stratum E only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression | 1.36 Hazard Ratio |
Secondary
Progression-free Survival Hazard Ratio by VEGF-A Expression
The association of VEGF-A expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-A measurements.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
Population: Only the number of patients in strata E was sufficient to perform the analysis exploring the association of VEGF-A expression with progression-free survival.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Progression-free Survival Hazard Ratio by VEGF-A Expression | 0.091 Hazard Ratio |
Secondary
Progression-free Survival Hazard Ratio by VEGF-R2 Expression
The association of VEGF-R2 expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-R2 measurements.
Time frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
Population: Only the number of patients in strata E was sufficient to perform the analysis exploring the association of VEGF-R2 expression with progression-free survival.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-grade Gliomas | Progression-free Survival Hazard Ratio by VEGF-R2 Expression | 0.632 Hazard Ratio |
Secondary
Systemic Clearance
Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the systemic clearance. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology, 2016 volume 81(1):148-160. The estimates of the systemic clearance were calculated by the model described in the paper.
Time frame: Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1
Population: The study participants across the strata (stratum A, stratum B, stratum C, stratum D, and stratum E) were combined for this secondary objective. The number of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Systemic Clearance | 9.43 ml/h | Standard Deviation 4.7 |
Secondary
Terminal Half-life
Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the PK parameters. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology,2016 volume 81(1):148-160. The estimates of the terminal half-life were calculated by the method described in the paper.
Time frame: Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1
Population: The study participants across the strata (stratum A, stratum B, stratum C, stratum D, and stratum E) were combined for this secondary objective. The number of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Terminal Half-life | 125.2 hours | Standard Deviation 5.8 |
Secondary
Volume of Distribution
Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the volume of distribution. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology ,2016 volume 81(1):148-160. The estimates of the volume of distribution were calculated by the model described in the paper.
Time frame: Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1
Population: The study participants across the strata (stratum A, stratum B, stratum C, stratum D, and stratum E) were combined for this secondary objective. The number of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High-grade Gliomas | Volume of Distribution | 1729 ml | Standard Deviation 736.9 |