Overview

This trial is active, not recruiting.

Conditions childhood high-grade cerebral astrocytoma, childhood oligodendroglioma, childhood spinal cord neoplasm, recurrent childhood brain stem glioma, recurrent childhood ependymoma, recurrent childhood medulloblastoma
Treatments bevacizumab, irinotecan hydrochloride, fludeoxyglucose f 18
Phase phase 2
Target VEGF
Sponsor National Cancer Institute (NCI)
Start date August 2006
End date December 2010
Trial size 97 participants
Trial identifier NCT00381797, CDR0000499832, NCI-2009-01090, PBTC-022, U01CA081457

Summary

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

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
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.
bevacizumab anti-VEGF humanized monoclonal antibody
Given IV
irinotecan hydrochloride Campto
Given IV
fludeoxyglucose f 18 18FDG
Undergo fludeoxyglucose F18 PET

Primary Outcomes

Measure
Objective Response Rate Sustained for ≥ 8 Weeks
time frame: From day 1 of treatment up to 24 weeks
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

Secondary Outcomes

Measure
Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity
time frame: From day 1 of treatment until off study
Cumulative Incidence of Sustained Objective Responses
time frame: From the first imaging after treatment up to 2 years
Progression-free Survival
time frame: From start of treatment up to 2 years
Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging
time frame: Baseline and day 15
Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image
time frame: Baseline and day 15
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
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
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
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
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
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
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
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
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
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
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
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
Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline
time frame: Baseline
Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline
time frame: Baseline
Number of Patients With High VEGF-A Expression at Baseline
time frame: Baseline
Number of Patients With High VEGF-R2 Expression at Baseline
time frame: Baseline
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
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
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
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

Eligibility Criteria

Male or female participants up to 21 years old.

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

Additional Information

Official title Phase II Study of Bevacizumab Plus Irinotecan (Camptosar™) in Children With Recurrent, Progressive, or Refractory Malignant Gliomas, Diffuse/Intrinsic Brain Stem Gliomas, Medulloblastomas, Ependymomas and Low Grade Gliomas
Principal investigator Sridharan Gururangan
Description PRIMARY OBJECTIVES: I. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in pediatric patients with recurrent, progressive, or refractory malignant glioma (Stratum A [closed to accrual as of 4/21/2009]) or recurrent/progressive/refractory intrinsic brain stem glioma (Stratum B [closed to accrual as of 4/21/2009]). II. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in patients with recurrent or progressive medulloblastoma (Stratum C [closed to accrual as of 10/27/2009]) or recurrent or progressive ependymoma (Stratum D [closed to accrual as of 7/29/2010]). III. Estimate the sustained disease stabilization rate associated with bevacizumab and irinotecan in patients with recurrent or progressive low grade glioma (Stratum E [closed to accrual as of 7/29/2010]). SECONDARY OBJECTIVES: I. Estimate the rate of treatment-related toxicity of this regimen in these patients. II. Estimate the cumulative incidence of sustained objective responses as a function of this regimen in these patients. III. Estimate the distributions of survival and event-free survival of these patients. IV. Correlate functional changes in tumor with progression-free survival and response using MR perfusion/diffusion imaging and fludeoxyglucose F 18 positron emission tomography. OUTLINE: This is a multicenter study. Patients are stratified according to tumor type (high-grade glioma [closed to accrual as of 4/21/2009] vs intrinsic brain stem tumor [closed to accrual as of 4/21/2009] vs medulloblastoma [closed to accrual as of 10/27/2010] vs ependymoma [closed to accrual as of 7/29/2010] vs low grade glioma [closed to accrual as of 7/29/2010]). Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment. After completion of study treatment, patients are followed for 30 days and then every 3 months for up to 2 years.
Trial information was received from ClinicalTrials.gov and was last updated in April 2014.
Information provided to ClinicalTrials.gov by National Cancer Institute (NCI).