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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

97 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-08-31

Study Completion Date

2015-10-31

Brief Summary

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This phase II trial is studying how well giving bevacizumab together with irinotecan works in treating young patients with recurrent, progressive, or refractory glioma, medulloblastoma, ependymoma, or low grade glioma. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of glioma by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with irinotecan may kill more tumor cells.

Detailed Description

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PRIMARY OBJECTIVES:

I. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in pediatric patients with recurrent, progressive, or refractory malignant glioma (Stratum A \[closed to accrual as of 4/21/2009\]) or recurrent/progressive/refractory intrinsic brain stem glioma (Stratum B \[closed to accrual as of 4/21/2009\]).

II. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in patients with recurrent or progressive medulloblastoma (Stratum C \[closed to accrual as of 10/27/2009\]) or recurrent or progressive ependymoma (Stratum D \[closed to accrual as of 7/29/2010\]).

III. Estimate the sustained disease stabilization rate associated with bevacizumab and irinotecan in patients with recurrent or progressive low grade glioma (Stratum E \[closed to accrual as of 7/29/2010\]).

SECONDARY OBJECTIVES:

I. Estimate the rate of treatment-related toxicity of this regimen in these patients.

II. Estimate the cumulative incidence of sustained objective responses as a function of this regimen in these patients.

III. Estimate the distributions of survival and event-free survival of these patients.

IV. Correlate functional changes in tumor with progression-free survival and response using MR perfusion/diffusion imaging and fludeoxyglucose F 18 positron emission tomography.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor type (high-grade glioma \[closed to accrual as of 4/21/2009\] vs intrinsic brain stem tumor \[closed to accrual as of 4/21/2009\] vs medulloblastoma \[closed to accrual as of 10/27/2010\] vs ependymoma \[closed to accrual as of 7/29/2010\] vs low grade glioma \[closed to accrual as of 7/29/2010\]).

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment.

After completion of study treatment, patients are followed for 30 days and then every 3 months for up to 2 years.

Conditions

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Childhood Cerebral Anaplastic Astrocytoma Childhood Oligodendroglioma Childhood Spinal Cord Neoplasm Recurrent Childhood Brain Stem Glioma Recurrent Childhood Ependymoma Recurrent Childhood Medulloblastoma

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm I

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment.

Group Type EXPERIMENTAL

Bevacizumab

Intervention Type BIOLOGICAL

Given IV

Fludeoxyglucose F-18

Intervention Type RADIATION

Undergo fludeoxyglucose F18 PET

Irinotecan Hydrochloride

Intervention Type DRUG

Given IV

Interventions

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Bevacizumab

Given IV

Intervention Type BIOLOGICAL

Fludeoxyglucose F-18

Undergo fludeoxyglucose F18 PET

Intervention Type RADIATION

Irinotecan Hydrochloride

Given IV

Intervention Type DRUG

Other Intervention Names

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Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar FKB238 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF 18FDG FDG fludeoxyglucose F 18 Fludeoxyglucose F18 Fluorine-18 2-Fluoro-2-deoxy-D-Glucose Fluorodeoxyglucose F18 Campto Camptosar Camptothecin 11 Camptothecin-11 CPT 11 CPT-11 Irinomedac U-101440E

Eligibility Criteria

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Inclusion Criteria

* Histologically confirmed high-grade glioma (WHO grade III or IV) at any site within the brain, including the following:

* Anaplastic astrocytoma
* Glioblastoma multiforme (including giant cell and gliosarcoma subtypes)
* Anaplastic oligodendroglioma
* Anaplastic ganglioglioma
* Anaplastic oligoastrocytoma
* Diffuse brain stem glioma

* Histologic confirmation not required
* Histologically confirmed medulloblastoma
* Histologically confirmed ependymoma
* Primary spinal cord malignant glioma with measurable metastatic disease within the brain

* Histologic confirmation required
* Neuraxis dissemination allowed provided there is bidimensionally measurable disease within the brain and spinal cord
* Low grade glioma at any site within the brain with or without spinal cord disease
* Recurrent, progressive, or refractory disease (must have received prior chemoradiotherapy)
* No more than 2 prior chemotherapy regimens following relapse
* Bidimensionally measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 2 planes
* If there is spinal cord disease as well, response assessment will be based only upon the measurable tumor in the brain
* No diffuse gliomatosis cerebri with \< 1 discrete, measurable lesion
* No evidence of new symptomatic CNS hemorrhage (\> grade 2) within the past 2 weeks
* No central non-cerebellar PNET's (e.g., cerebral PNET or pineoblastoma)
* No spinal cord tumors only
* Karnofsky performance status (PS) 50-100% (\> 16 years of age) OR Lansky PS 50-100% (≤ 16 years of age)
* Absolute neutrophil count ≥ 1,500/mm³ (unsupported)
* Platelet count ≥ 100,000/mm³ (unsupported)
* Hemoglobin \> 8 g/dL (support allowed)
* Creatinine normal
* BUN \< 25 mg/dL
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* ALT and AST ≤ 3 times ULN
* Neurological deficits must be stable for ≥ 1 week prior to study entry
* No active renal, cardiac (congestive cardiac failure, myocarditis), or pulmonary disease
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment
* No clinically significant unrelated systemic illness that would preclude study treatment, including any of the following:

* Serious infections
* Significant cardiac, pulmonary, hepatic, or other organ dysfunction
* No uncontrolled systemic hypertension, defined as systolic blood pressure (BP) and/or diastolic BP \> 95th percentile for age
* No stroke, myocardial infarction, or unstable angina within the past 6 months
* No clinically significant peripheral vascular disease
* No significant traumatic injury within the past 6 weeks
* No evidence of bleeding diathesis, coagulopathy, or PT INR \> 1.5
* Urine protein/creatinine ratio ≤ 1.0
* No abdominal fistula or gastrointestinal perforation within the past 6 months
* No serious nonhealing wound, ulcer, or bone fracture
* At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas)
* At least 7 days since prior investigational or biologic agents (3 weeks if patient experienced ≥ grade 2 myelosuppression or if agent has a prolonged half-life)
* More than 7 days since prior minor surgery
* More than 12 weeks since prior craniospinal or focal irradiation to primary tumor or other sites
* At least 4 weeks since prior major surgery and recovered
* At least 3 months since prior autologous bone marrow or stem cell transplantation
* At least 2 weeks since prior colony-forming growth factors (i.e., filgrastim \[G-CSF\], sargramostim \[GM-CSF\], epoetin alfa)
* No prior bevacizumab or irinotecan hydrochloride
* No anticipated surgery during treatment
* No concurrent prophylactic G-CSF, GM-CSF, or epoetin alfa
* Concurrent dexamethasone allowed provided the dose is stable or decreasing over the past week
* No other concurrent anticancer or investigational drugs
* No concurrent medications that may interfere with study (e.g., immunosuppressive agents other than corticosteroids)
* No concurrent therapeutic anticoagulation
* No concurrent nonsteroidal anti-inflammatory drugs, clopidogrel bisulfate, dipyridamole, or acetylsalicylic acid (aspirin) \> 81 mg/day

Maximum Eligible Age

21 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Sridharan Gururangan

Role: PRINCIPAL_INVESTIGATOR

Pediatric Brain Tumor Consortium

Locations

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UCSF Medical Center-Mount Zion

San Francisco, California, United States

Site Status

Children's National Medical Center

Washington D.C., District of Columbia, United States

Site Status

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

Site Status

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Site Status

Duke University Medical Center

Durham, North Carolina, United States

Site Status

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Site Status

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Site Status

Pediatric Brain Tumor Consortium

Memphis, Tennessee, United States

Site Status

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Site Status

Texas Children's Hospital

Houston, Texas, United States

Site Status

Seattle Children's Hospital

Seattle, Washington, United States

Site Status

Countries

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United States

References

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Han K, Peyret T, Quartino A, Gosselin NH, Gururangan S, Casanova M, Merks JH, Massimino M, Grill J, Daw NC, Navid F, Jin J, Allison DE. Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation. Br J Clin Pharmacol. 2016 Jan;81(1):148-60. doi: 10.1111/bcp.12778. Epub 2015 Dec 10.

Reference Type BACKGROUND

PMID: 26345283 (View on PubMed)