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

Sponsor:	Pediatric Brain Tumor Consortium
Collaborator:	National Cancer Institute (NCI)
Information provided by:	Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00381797

Purpose

RATIONALE: 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.

PURPOSE: 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.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	Biological: bevacizumab Drug: irinotecan hydrochloride	Phase II

Study Type:	Interventional
Study Design:	Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
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

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Irinotecan U 101440E Irinotecan hydrochloride Bevacizumab

U.S. FDA Resources

Further study details as provided by Pediatric Brain Tumor Consortium:

Primary Outcome Measures:

Objective response rate sustained for ≥ 8 weeks [ Time Frame: First four courses of treatment ] [ Designated as safety issue: No ]
Objective response is either a complete response or a partial reponse. Brain imaging to assess objective response is performed every 8 weeks for the first 6 months, every 12 weeks up to 2 years, at the time of disease progression and at completion or discontinuation of treatment. The objective response rate will be reported separately for patients with recurrent/progressive/refractory malignant glioma (Stratum A), recurrent/progressive/refractory instrinsic brain stem glioma (Stratum B), recurrent or progressive medulloblastoma (Stratum C), and recurrent or progressive ependymoma (Stratum D).
Sustained disease stabilization rate associated with bevacizumab and irinotecan in patients with recurrent or progressive low-grade glioma (Stratum E) [ Time Frame: First six courses of treatment ] [ Designated as safety issue: No ]
Disease stabilization is defined as a complete response or partial response observed during the first four courses and sustained for 8 weeks or stable disease observed at the end of course two and sustained until at least the end of course six. Brain imaging to assess tumor response to the treatment is performed every 8 weeks for the first 6 months, every 12 weeks thereafter up to 2 years, at the time of disease progression and completion or discontinuation of treatment.

Secondary Outcome Measures:

Number of study participants with grade 3 or 4 treatment-related toxicity [ Time Frame: From day 1 of treatment until off study ] [ Designated as safety issue: Yes ]
Cumulative incidence of sustained objective responses [ Time Frame: From the initial image brain image documenting the objective response until the earliest of progressive disease, death, second malignancy, or off study ] [ Designated as safety issue: No ]
Cumulative incidence of sustained objective responses provides an estimate of the timing of the responses as a function of the number of months on treatment. Estimates of the cumulative incidence of sustained objective reponses will be reported separately for each stratum.
Progression-free survival [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ] [ Designated as safety issue: No ]
Progression-free survival estimates will be reported separately for each stratum.
Change in perfusion ratio between the baseline and day 15 brain image [ Time Frame: Baseline and day 15 ] [ Designated as safety issue: No ]
Perfusion ratio obtained from magenetic resonance (MR) perfusion 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 perfusion imaging.
Change in diffusion ratio between the baseline and day 15 brain image [ Time Frame: Baseline and day 15 ] [ Designated as safety issue: No ]
Diffusion ratio obtained from magenetic 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.
Progression-free survival hazard ratio by tumor volume based on FLAIR [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ] [ Designated as safety issue: No ]
Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth and to see if these imaging markers are associated with treatment outcome. The association of tumor volume based on FLAIR images with progression-free survival will be investigated for those strata that have a sufficient number of participants with volume FLAIR measurements.
Progression-free survival hazard ratio by tumor enhancing volume [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ] [ Designated as safety issue: No ]
Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth and to see if these imaging markers are associated with treatment outcome. The association of tumor enhancing volume with progression-free survival will be investigated for those strata that have a sufficient number of participants with enhancing volume measurements.
Progression-free survival hazard ratio by volume of cystic necrosis [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ] [ Designated as safety issue: No ]
Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth and to see if these imaging markers are associated with treatment outcome. The association of cystic necrosis with progression-free survival will be investigated for those strata that have a sufficient number of participants with cystic necrosis measurements.
Progression-free survival hazard ratio by tumor diffusion ratio [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ] [ Designated as safety issue: No ]
Magnetic resonance (MR) diffusion imaging is performed to investigate surrogate markers of tumor growth and to see if these imaging markers are associated with treatment outcome. The association of tumor diffusion ratios with progression-free survival will be investigated for those strata that have a sufficient number of participants with tumor diffusion ratio measurements.
Progression-free survival hazard ratio by tumor perfusion ratio [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ] [ Designated as safety issue: No ]
Magnetic resonance (MR) perfusion imaging is performed to investigate surrogate markers of tumor growth and to see if these imaging markers are associated with treatment outcome. The association of tumor perfusion ratios with progression-free survival will be investigated for those strata that have a sufficient number of participants with tumor perfusion ratio measurements.
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 ] [ Designated as safety issue: No ]
Blood specimens will be collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens will be analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data will be analyzed to provide an estimate of the volume of distribution. Estimates of the volume of distribution will be reported separately for each stratum.
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 ] [ Designated as safety issue: No ]
Blood specimens will be collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens will be analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data will be analyzed to provide an estimate of the systemic clearance. Estimates of the systemic clearance will be reported separately for each stratum.
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 ] [ Designated as safety issue: No ]
Blood specimens will be collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens will be analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data will be analyzed to provide an estimate of the terminal half-life. Estimates of the terminal half-life will be reported separately for each stratum.
Change in vascular endothelial growth factor receptor-2 (VEGF-R2) expression in peripheral blood mononuclear cells (PBMC) from baseline [ Time Frame: Baseline and 24-48 hours after the 2nd dose of Bevacizumab in course 1 ] [ Designated as safety issue: No ]
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 permeability from magnetic resonance perfusion imaging [ Time Frame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 ] [ Designated as safety issue: No ]
Number of patients with high hypoxia inducible factor-2alpha expression at baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Reported separately for each stratum.
Number of patients with high carbonic anhydrase 9 expression at baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Reported separately for each stratum.
Number of patients with high VEGF-A expression at baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Reported separately for each stratum.
Number of patients with high VEGF-R2 expression at baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Reported separately for each stratum.
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 ] [ Designated as safety issue: No ]
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.
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 ] [ Designated as safety issue: No ]
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.
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 ] [ Designated as safety issue: No ]
The association of VEGF-A expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-A measurements.
Progression-free survival hazard ratio by VEGF-R2 expression [ Time Frame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study ] [ Designated as safety issue: No ]
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.

Estimated Enrollment:	140
Study Start Date:	August 2006
Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Intervention Details:

10 mg/kg IV (in the vein) on day 1 and day 15 of each 28 day course. In the absence of unacceptable toxicity or disease progression, treatment may continue for 26 courses (approximately 2 years).

Other Names:

rhuMAb VEGF
Avastin

Patients will receive a starting dose of either 250 mg/m2 (if on enzyme-inducing anticonvulsant drug (EIACD)) or 125 mg/m2 (if not on EIACD) infused through a free-flowing intravenous catheter on day 15 of course 1. Subsequently, irinotecan will be given on day 1 and day 15 of each 28 day course. In the absence of toxicity to irinotecan, the irinotecan dose can be increased by 25 mg/m2 every 2 weeks up to a maximum of 150 mg/m2 for patients not on EIACD and 350 mg/m2 for patients on EIACD. In the absence of unacceptable toxicity or disease progression, treatment may continue for 26 courses (approximately 2 years).

Other Names:

Camptosar
NSC# 616348

Detailed Description:

OBJECTIVES:

Primary

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]).
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]).
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

Estimate the rate of treatment-related toxicity of this regimen in these patients.
Estimate the cumulative incidence of sustained objective responses as a function of this regimen in these patients.
Estimate the distributions of survival and event-free survival of these patients.
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.

PROJECTED ACCRUAL: A total of 140 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	up to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Diagnosis of 1 of the following:
- 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

PATIENT CHARACTERISTICS:

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

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
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
No other concurrent anticancer or investigational drugs
Concurrent dexamethasone allowed provided the dose is stable or decreasing over the past week
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

United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Dan L. Duncan Cancer Center at Baylor College of Medicine
Houston, Texas, United States, 77030

Responsible Party:	James M. Boyett, Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00381797 History of Changes
Other Study ID Numbers:	CDR0000499832, U01CA081457, PBTC-022
Study First Received:	September 26, 2006
Last Updated:	August 10, 2011
Health Authority:	United States: Food and Drug Administration