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

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ClinicalTrials.gov Identifier: NCT00381797
Recruitment Status : Completed
First Posted : September 28, 2006
Results First Posted : January 15, 2013
Last Update Posted : November 28, 2017
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions: Childhood Cerebral Anaplastic Astrocytoma
Childhood Oligodendroglioma
Childhood Spinal Cord Neoplasm
Recurrent Childhood Brain Stem Glioma
Recurrent Childhood Ependymoma
Recurrent Childhood Medulloblastoma
Interventions: Biological: Bevacizumab
Radiation: Fludeoxyglucose F-18
Drug: Irinotecan Hydrochloride

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
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.

Participant Flow:   Overall Study
    High-grade Gliomas   Brain Stem Tumors   Medulloblastoma   Ependymoma   Low Grade Glioma
STARTED   18   17   10   15   37 
COMPLETED   17   16   10   14   35 
NOT COMPLETED   1   1   0   1   2 
Withdrawal by Subject                1                1                0                0                2 
Ineligible                0                0                0                1                0 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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.
Total Total of all reporting groups

Baseline Measures
   High-grade Gliomas   Brain Stem Tumors   Medulloblastoma   Ependymoma   Low Grade Glioma   Total 
Overall Participants Analyzed 
[Units: Participants]
 18   17   10   15   37   97 
Age 
[Units: Participants]
Count of Participants
           
<=18 years      14  77.8%      17 100.0%      9  90.0%      14  93.3%      37 100.0%      91  93.8% 
Between 18 and 65 years      4  22.2%      0   0.0%      1  10.0%      1   6.7%      0   0.0%      6   6.2% 
>=65 years      0   0.0%      0   0.0%      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Age 
[Units: Years]
Mean (Standard Deviation)
 15.07  (3.82)   8.45  (3.35)   10.56  (5.28)   10.16  (5.17)   8.58  (4.09)   10.21  (4.82) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
           
Female      7  38.9%      9  52.9%      5  50.0%      9  60.0%      19  51.4%      49  50.5% 
Male      11  61.1%      8  47.1%      5  50.0%      6  40.0%      18  48.6%      48  49.5% 
Region of Enrollment 
[Units: Participants]
           
United States   18   17   10   15   37   97 


  Outcome Measures

1.  Primary:   Objective Response Rate Sustained for ≥ 8 Weeks   [ Time Frame: From day 1 of treatment up to 24 weeks ]

2.  Primary:   Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E)   [ Time Frame: From day 1 of treatment up to 24 weeks ]

3.  Secondary:   Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity   [ Time Frame: From day 1 of treatment until off study ]

4.  Secondary:   Cumulative Incidence of Sustained Objective Responses   [ Time Frame: From the first imaging after treatment up to 2 years ]

5.  Secondary:   Progression-free Survival   [ Time Frame: From start of treatment up to 2 years ]

6.  Secondary:   Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging   [ Time Frame: Baseline and day 15 ]

7.  Secondary:   Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image   [ Time Frame: Baseline and day 15 ]

8.  Secondary:   Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study OR up to 2 years ]

9.  Secondary:   Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years ]

10.  Secondary:   Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years ]

11.  Secondary:   Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ]

12.  Secondary:   Association of Log-transformed Tumor Perfusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years ]

13.  Secondary:   Volume of Distribution   [ Time Frame: Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 ]

14.  Secondary:   Systemic Clearance   [ Time Frame: Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 ]

15.  Secondary:   Terminal Half-life   [ Time Frame: Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 ]

16.  Secondary:   Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15   [ Time Frame: Baseline and 24-48 hours after the 2nd dose of Bevacizumab in course 1 ]

17.  Secondary:   Descriptive Statistics for the Changes in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) Concurrently Measured With the Changes in Perfusion From Magnetic Resonance Imaging   [ Time Frame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 ]

18.  Secondary:   Descriptive Statistics for the Change of Perfusion in Magnetic Resonance Imaging Concurrently Measured With the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC)   [ Time Frame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 ]

19.  Secondary:   Correlation of the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline With the Change in Perfusion From Magnetic Resonance Imaging   [ Time Frame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 ]

20.  Secondary:   Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline   [ Time Frame: Baseline ]

21.  Secondary:   Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline   [ Time Frame: Baseline ]

22.  Secondary:   Number of Patients With High VEGF-A Expression at Baseline   [ Time Frame: Baseline ]

23.  Secondary:   Number of Patients With High VEGF-R2 Expression at Baseline   [ Time Frame: Baseline ]

24.  Secondary:   Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ]

25.  Secondary:   Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ]

26.  Secondary:   Progression-free Survival Hazard Ratio by VEGF-A Expression   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ]

27.  Secondary:   Progression-free Survival Hazard Ratio by VEGF-R2 Expression   [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Neuroimaging data capturing Volume Enhancing and Perfusion Ratio was so limited to run any statistical model. Similarly, due to limited data, some PK and Biology objectives were not able to be addressed.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Shengjie Wu
Organization: St. Jude Children's Research Hospital
phone: (901) 595-2859
e-mail: shengjie.wu@stjude.org


Publications:

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00381797     History of Changes
Other Study ID Numbers: NCI-2009-01090
NCI-2009-01090 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PBTC-022
CDR0000499832
PBTC-022 ( Other Identifier: Pediatric Brain Tumor Consortium )
PBTC-022 ( Other Identifier: CTEP )
U01CA081457 ( U.S. NIH Grant/Contract )
First Submitted: September 26, 2006
First Posted: September 28, 2006
Results First Submitted: January 17, 2012
Results First Posted: January 15, 2013
Last Update Posted: November 28, 2017