Clinical trial NCT00381797: Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Childhood Cerebral Anaplastic Astrocytoma
Childhood Oligodendroglioma
Childhood Spinal Cord Neoplasm
Recurrent Childhood Brain Stem Glioma
Recurrent Childhood Ependymoma
Recurrent Childhood Medulloblastoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-09-28
Enrollment: 97
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective Response Rate Sustained for ≥ 8 Weeks
timeFrame: From day 1 of treatment up to 24 weeks
measure: Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E)
timeFrame: From day 1 of treatment up to 24 weeks
Secondary outcomes:
measure: Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity
timeFrame: From day 1 of treatment until off study
measure: Cumulative Incidence of Sustained Objective Responses
timeFrame: From the first imaging after treatment up to 2 years
measure: Progression-free Survival
timeFrame: From start of treatment up to 2 years
measure: Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging
timeFrame: Baseline and day 15
measure: Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image
timeFrame: Baseline and day 15
measure: Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study OR up to 2 years
measure: Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years
measure: Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years
measure: Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
measure: Association of Log-transformed Tumor Perfusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years
measure: Volume of Distribution
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
measure: Systemic Clearance
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
measure: Terminal Half-life
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
measure: Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15
timeFrame: Baseline and 24-48 hours after the 2nd dose of Bevacizumab in course 1
measure: 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
timeFrame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1
measure: 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)
timeFrame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1
measure: 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
timeFrame: Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1
measure: Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline
timeFrame: Baseline
measure: Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline
timeFrame: Baseline
measure: Number of Patients With High VEGF-A Expression at Baseline
timeFrame: Baseline
measure: Number of Patients With High VEGF-R2 Expression at Baseline
timeFrame: Baseline
measure: Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
measure: Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
measure: Progression-free Survival Hazard Ratio by VEGF-A Expression
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
measure: Progression-free Survival Hazard Ratio by VEGF-R2 Expression
timeFrame: From start of treatment until the earliest of progressive disease, death, second malignancy or off study
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Medical Center-Mount Zion
state: California
city: Washington, D.C.
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: Pediatric Brain Tumor Consortium
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Pediatric Brain Tumor Consortium
name: Sridharan Gururangan
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.