Trial Outcomes & Findings for Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma (NCT NCT00381797)

Last Updated: 2017-11-28

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

97 participants

Primary outcome timeframe

From day 1 of treatment up to 24 weeks

Results posted on

2017-11-28

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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.	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.	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.	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.
Overall Study STARTED	18	17	10	15	37
Overall Study COMPLETED	17	16	10	14	35
Overall Study NOT COMPLETED	1	1	0	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.	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.	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.
Overall Study Withdrawal by Subject	1	1	0	0	2
Overall Study Ineligible	0	0	0	1	0

Baseline Characteristics

Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	High-grade Gliomas n=18 Participants 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.	Brain Stem Tumors n=17 Participants 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.	Medulloblastoma n=10 Participants 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.	Ependymoma n=15 Participants 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.	Low Grade Glioma n=37 Participants 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.	Total n=97 Participants Total of all reporting groups
Age, Categorical <=18 years	14 Participants n=5 Participants	17 Participants n=7 Participants	9 Participants n=5 Participants	14 Participants n=4 Participants	37 Participants n=21 Participants	91 Participants n=8 Participants
Age, Categorical Between 18 and 65 years	4 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	6 Participants n=8 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Age, Continuous	15.07 years STANDARD_DEVIATION 3.82 • n=5 Participants	8.45 years STANDARD_DEVIATION 3.35 • n=7 Participants	10.56 years STANDARD_DEVIATION 5.28 • n=5 Participants	10.16 years STANDARD_DEVIATION 5.17 • n=4 Participants	8.58 years STANDARD_DEVIATION 4.09 • n=21 Participants	10.21 years STANDARD_DEVIATION 4.82 • n=8 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	9 Participants n=7 Participants	5 Participants n=5 Participants	9 Participants n=4 Participants	19 Participants n=21 Participants	49 Participants n=8 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	8 Participants n=7 Participants	5 Participants n=5 Participants	6 Participants n=4 Participants	18 Participants n=21 Participants	48 Participants n=8 Participants
Region of Enrollment United States	18 participants n=5 Participants	17 participants n=7 Participants	10 participants n=5 Participants	15 participants n=4 Participants	37 participants n=21 Participants	97 participants n=8 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=15 Participants 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.	Brain Stem Tumors n=16 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=9 Participants 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.	Ependymoma n=13 Participants 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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Objective Response Rate Sustained for ≥ 8 Weeks	0 participants	0 participants	0 participants	0 participants	—

PRIMARY outcome

Timeframe: From day 1 of treatment up to 24 weeks

Population: Patients with recurrent or progressive low grade glioma were treated with any courses.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=35 Participants 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.	Brain Stem Tumors Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E)	23 participants Interval 17.0 to 28.0	—	—	—	—

SECONDARY outcome

Timeframe: From day 1 of treatment until off study

Population: The patients were treated with any dose treatment.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=17 Participants 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.	Brain Stem Tumors n=16 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=10 Participants 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.	Ependymoma n=14 Participants 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.	Low Grade Glioma n=35 Participants Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity	8 participants	4 participants	4 participants	6 participants	22 participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=15 Participants 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.	Brain Stem Tumors n=16 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=9 Participants 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.	Ependymoma n=13 Participants 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.	Low Grade Glioma n=35 Participants Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Cumulative Incidence of Sustained Objective Responses	0 Percentage of Participants 0	0 Percentage of Participants 0	0 Percentage of Participants 0	0 Percentage of Participants 0	0.058 Percentage of Participants 0.0405

SECONDARY outcome

Timeframe: From start of treatment up to 2 years

Population: The patients were treated with any dose treatment.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=17 Participants 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.	Brain Stem Tumors n=16 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=10 Participants 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.	Ependymoma n=14 Participants 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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Progression-free Survival	4.20 Months 95% Confidence Interval 1.57 • Interval 1.82 to 7.44	2.35 Months Interval 1.85 to 4.17	2.48 Months Interval 0.43 to 16.66	2.15 Months Interval 1.85 to 6.15	—

SECONDARY outcome

Timeframe: Baseline and day 15

Population: There are no sufficient data for the analyses in the Medulloblastoma arm and Ependymoma arm.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=9 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=19 Participants 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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging	-0.14 Ratio Full Range 0.705 • Interval -3.95 to 3.37	-1.98 Ratio Interval -4.34 to -0.018	-0.42 Ratio Interval -2.34 to 2.55	—	—

SECONDARY outcome

Timeframe: Baseline and day 15

Population: There are no sufficient data for the analyses in the Medulloblastoma arm.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=17 Participants 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.	Brain Stem Tumors n=10 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=11 Participants 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.	Ependymoma n=29 Participants 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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image	-0.34 Ratio Full Range 0.085 • Interval -0.91 to 0.26	-0.17 Ratio Interval -0.6 to 0.51	0.11 Ratio Interval -0.23 to 1.38	-0.11 Ratio Interval -0.89 to 0.52	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=13 Participants 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.	Brain Stem Tumors n=12 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates	1.47 Hazard Ratio Interval 0.79 to 2.77	1.76 Hazard Ratio Interval 0.65 to 4.75	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=15 Participants 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.	Brain Stem Tumors n=16 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates	1.65 Hazard Ratio Interval 0.802 to 3.39	1.16 Hazard Ratio Interval 0.597 to 2.27	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=15 Participants 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.	Brain Stem Tumors n=16 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates	2.56 Hazard Ratio Interval 0.89 to 7.41	1.09 Hazard Ratio Interval 0.28 to 4.21	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=17 Participants 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.	Brain Stem Tumors n=14 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates	4.41 Hazard Ratio Interval 0.15 to 131.0	1.82 Hazard Ratio Interval 0.21 to 15.9	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=76 Participants 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.	Brain Stem Tumors Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Volume of Distribution	1729 ml Standard Deviation 736.9	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=39 Participants 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.	Brain Stem Tumors Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Systemic Clearance	9.43 ml/h Standard Deviation 4.70	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=39 Participants 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.	Brain Stem Tumors Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Terminal Half-life	125.2 hours Standard Deviation 5.80	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=4 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=3 Participants 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.	Ependymoma n=5 Participants 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.	Low Grade Glioma n=4 Participants Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
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 Interval -2.62 to 0.82	-0.21 Ratio Interval -5.11 to 0.12	-0.003 Ratio Interval -0.136 to 0.937	0.24 Ratio Interval -8.87 to 0.36	1.70 Ratio Interval -0.89 to 20.55

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=3 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
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	-1.20 Ratio Standard Error 0.99	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=3 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
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	-1.54 Ratio Standard Error 0.87	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=3 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
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	-0.50 Correlation Coefficient 0.27	—	—	—

SECONDARY outcome

Timeframe: Baseline

Population: Only strata were reported, in which the patients had tissue samples available.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=4 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=17 Participants 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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline	0 participants	3 participants	7 participants	—	—

SECONDARY outcome

Timeframe: Baseline

Population: Only strata were reported, in which the patients had tissue samples available.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=4 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=17 Participants 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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline	0 participants	4 participants	2 participants	—	—

SECONDARY outcome

Timeframe: Baseline

Population: Only strata were reported, in which the patients had tissue samples available.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=4 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=18 Participants 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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Number of Patients With High VEGF-A Expression at Baseline	2 participants	5 participants	16 participants	—	—

SECONDARY outcome

Timeframe: Baseline

Population: Only strata were reported, in which the patients had tissue samples available.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=4 Participants 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.	Brain Stem Tumors n=5 Participants Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	Medulloblastoma n=18 Participants 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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Number of Patients With High VEGF-R2 Expression at Baseline	4 participants	4 participants	13 participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=17 Participants 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.	Brain Stem Tumors Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression	1.36 Hazard Ratio Interval 0.364 to 5.083	—	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=17 Participants 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.	Brain Stem Tumors Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression	0.705 Hazard Ratio Interval 0.089 to 5.598	—	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=18 Participants 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.	Brain Stem Tumors Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Progression-free Survival Hazard Ratio by VEGF-A Expression	0.091 Hazard Ratio Interval 0.006 to 1.51	—	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High-grade Gliomas n=18 Participants 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.	Brain Stem Tumors Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory 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.	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.	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.	Low Grade Glioma Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive 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.
Progression-free Survival Hazard Ratio by VEGF-R2 Expression	0.632 Hazard Ratio Interval 0.161 to 2.482	—	—	—	—

Adverse Events

PBTC-022

Serious events: 37 serious events

Other events: 91 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	PBTC-022 n=92 participants at risk Children with recurrent,progressive,or refractory malignant gliomas, diffuse/intrinsic brain stem gliomas, medulloblastomas and low grade gliomas
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	1.1% 1/92 • Number of events 1 • 2 Years
Investigations Alanine aminotransferase increased	2.2% 2/92 • Number of events 3 • 2 Years
Metabolism and nutrition disorders Alkalosis	1.1% 1/92 • Number of events 1 • 2 Years
Metabolism and nutrition disorders Anorexia	1.1% 1/92 • Number of events 1 • 2 Years
Investigations Aspartate aminotransferase increased	2.2% 2/92 • Number of events 2 • 2 Years
Musculoskeletal and connective tissue disorders Avascular necrosis	2.2% 2/92 • Number of events 2 • 2 Years
Respiratory, thoracic and mediastinal disorders Bronchospasm	1.1% 1/92 • Number of events 1 • 2 Years
Gastrointestinal disorders Constipation	1.1% 1/92 • Number of events 1 • 2 Years
Metabolism and nutrition disorders Dehydration	1.1% 1/92 • Number of events 1 • 2 Years
Nervous system disorders Depressed level of consciousness	1.1% 1/92 • Number of events 1 • 2 Years
Nervous system disorders Dysphasia	1.1% 1/92 • Number of events 1 • 2 Years
Vascular disorders Flushing	1.1% 1/92 • Number of events 1 • 2 Years
Vascular disorders Hematoma	1.1% 1/92 • Number of events 1 • 2 Years
Nervous system disorders Hydrocephalus	3.3% 3/92 • Number of events 3 • 2 Years
Metabolism and nutrition disorders Hyperglycemia	2.2% 2/92 • Number of events 2 • 2 Years
Metabolism and nutrition disorders Hyperkalemia	1.1% 1/92 • Number of events 1 • 2 Years
Vascular disorders Hypertension	2.2% 2/92 • Number of events 2 • 2 Years
Metabolism and nutrition disorders Hypoalbuminemia	3.3% 3/92 • Number of events 3 • 2 Years
Metabolism and nutrition disorders Hypocalcemia	3.3% 3/92 • Number of events 3 • 2 Years
Metabolism and nutrition disorders Hyponatremia	4.3% 4/92 • Number of events 4 • 2 Years
Metabolism and nutrition disorders Hypophosphatemia	1.1% 1/92 • Number of events 1 • 2 Years
Respiratory, thoracic and mediastinal disorders Hypoxia	2.2% 2/92 • Number of events 2 • 2 Years
Psychiatric disorders Insomnia	1.1% 1/92 • Number of events 1 • 2 Years
Musculoskeletal and connective tissue disorders Joint effusion	1.1% 1/92 • Number of events 1 • 2 Years
Nervous system disorders Leukoencephalopathy	1.1% 1/92 • Number of events 1 • 2 Years
Investigations Lipase increased	1.1% 1/92 • Number of events 1 • 2 Years
Investigations Lymphocyte count decreased	2.2% 2/92 • Number of events 2 • 2 Years
Skin and subcutaneous tissue disorders Nail loss	1.1% 1/92 • Number of events 1 • 2 Years
Gastrointestinal disorders Nausea	1.1% 1/92 • Number of events 1 • 2 Years
Nervous system disorders Nervous system disorders - Other, specify	2.2% 2/92 • Number of events 2 • 2 Years
Investigations Neutrophil count decreased	3.3% 3/92 • Number of events 3 • 2 Years
Psychiatric disorders Personality change	1.1% 1/92 • Number of events 1 • 2 Years
Investigations Platelet count decreased	3.3% 3/92 • Number of events 3 • 2 Years
Respiratory, thoracic and mediastinal disorders Pneumonitis	1.1% 1/92 • Number of events 1 • 2 Years
Renal and urinary disorders Proteinuria	1.1% 1/92 • Number of events 1 • 2 Years
Psychiatric disorders Psychosis	1.1% 1/92 • Number of events 1 • 2 Years
Nervous system disorders Seizure	5.4% 5/92 • Number of events 8 • 2 Years
Skin and subcutaneous tissue disorders Skin ulceration	2.2% 2/92 • Number of events 2 • 2 Years
Renal and urinary disorders Urinary retention	1.1% 1/92 • Number of events 1 • 2 Years
Gastrointestinal disorders Vomiting	2.2% 2/92 • Number of events 3 • 2 Years
Investigations Weight loss	2.2% 2/92 • Number of events 3 • 2 Years

Other adverse events

Other adverse events
Measure	PBTC-022 n=92 participants at risk Children with recurrent,progressive,or refractory malignant gliomas, diffuse/intrinsic brain stem gliomas, medulloblastomas and low grade gliomas
Metabolism and nutrition disorders Acidosis	12.0% 11/92 • Number of events 22 • 2 Years
Investigations Alanine aminotransferase increased	30.4% 28/92 • Number of events 37 • 2 Years
Investigations Alkaline phosphatase increased	6.5% 6/92 • Number of events 13 • 2 Years
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	14.1% 13/92 • Number of events 16 • 2 Years
Skin and subcutaneous tissue disorders Alopecia	8.7% 8/92 • Number of events 8 • 2 Years
Metabolism and nutrition disorders Anorexia	20.7% 19/92 • Number of events 25 • 2 Years
Investigations Aspartate aminotransferase increased	34.8% 32/92 • Number of events 50 • 2 Years
Nervous system disorders Ataxia	12.0% 11/92 • Number of events 16 • 2 Years
Investigations Blood bilirubin increased	7.6% 7/92 • Number of events 13 • 2 Years
Gastrointestinal disorders Constipation	17.4% 16/92 • Number of events 21 • 2 Years
Respiratory, thoracic and mediastinal disorders Cough	14.1% 13/92 • Number of events 15 • 2 Years
Investigations Creatinine increased	6.5% 6/92 • Number of events 11 • 2 Years
Gastrointestinal disorders Diarrhea	48.9% 45/92 • Number of events 113 • 2 Years
Nervous system disorders Dizziness	10.9% 10/92 • Number of events 13 • 2 Years
Eye disorders Extraocular muscle paresis	5.4% 5/92 • Number of events 5 • 2 Years
General disorders Fever	17.4% 16/92 • Number of events 23 • 2 Years
Investigations GGT increased	6.5% 6/92 • Number of events 8 • 2 Years
Metabolism and nutrition disorders Hyperglycemia	18.5% 17/92 • Number of events 24 • 2 Years
Metabolism and nutrition disorders Hyperkalemia	9.8% 9/92 • Number of events 10 • 2 Years
Metabolism and nutrition disorders Hypermagnesemia	18.5% 17/92 • Number of events 30 • 2 Years
Metabolism and nutrition disorders Hypernatremia	7.6% 7/92 • Number of events 8 • 2 Years
Vascular disorders Hypertension	40.2% 37/92 • Number of events 74 • 2 Years
Metabolism and nutrition disorders Hypoalbuminemia	16.3% 15/92 • Number of events 22 • 2 Years
Metabolism and nutrition disorders Hypocalcemia	20.7% 19/92 • Number of events 38 • 2 Years
Metabolism and nutrition disorders Hypoglycemia	10.9% 10/92 • Number of events 14 • 2 Years
Metabolism and nutrition disorders Hypokalemia	26.1% 24/92 • Number of events 32 • 2 Years
Metabolism and nutrition disorders Hypomagnesemia	12.0% 11/92 • Number of events 22 • 2 Years
Metabolism and nutrition disorders Hyponatremia	12.0% 11/92 • Number of events 20 • 2 Years
Metabolism and nutrition disorders Hypophosphatemia	22.8% 21/92 • Number of events 41 • 2 Years
Nervous system disorders Intracranial hemorrhage	10.9% 10/92 • Number of events 10 • 2 Years
Investigations Lymphocyte count decreased	45.7% 42/92 • Number of events 92 • 2 Years
Gastrointestinal disorders Nausea	56.5% 52/92 • Number of events 129 • 2 Years
Investigations Neutrophil count decreased	29.3% 27/92 • Number of events 57 • 2 Years
Investigations Platelet count decreased	12.0% 11/92 • Number of events 25 • 2 Years
Renal and urinary disorders Proteinuria	21.7% 20/92 • Number of events 61 • 2 Years
Skin and subcutaneous tissue disorders Rash acneiform	6.5% 6/92 • Number of events 8 • 2 Years
Skin and subcutaneous tissue disorders Rash maculo-papular	17.4% 16/92 • Number of events 21 • 2 Years
Skin and subcutaneous tissue disorders Skin hyperpigmentation	5.4% 5/92 • Number of events 5 • 2 Years
Nervous system disorders Tremor	6.5% 6/92 • Number of events 6 • 2 Years
Renal and urinary disorders Urinary retention	5.4% 5/92 • Number of events 5 • 2 Years
Gastrointestinal disorders Vomiting	60.9% 56/92 • Number of events 282 • 2 Years
Investigations White blood cell decreased	47.8% 44/92 • Number of events 85 • 2 Years

Additional Information

Shengjie Wu

St. Jude Children's Research Hospital

Phone: (901) 595-2859

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60