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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


Phase 2
N/A
21 Years
Open (Enrolling)
Both
Brain and Central Nervous System Tumors

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Trial Information

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


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Objective Response Rate Sustained for ≥ 8 Weeks

Outcome Description:

Objective response is either a complete response or a partial response observed during the first four courses of treatment and sustained for 8 weeks. The objective response rate will be reported separately for patients with recurrent/progressive malignant glioma(Stratum A), recurrent/progressive instrinsic brain stem tumors(Stratum B), recurrent/progressive medulloblastoma(Stratum C), and recurrent/progressive ependymoma(Stratum D). CR is complete disappearance of all enhancing tumor. PR is >= 50% reduction in tumor size. This outcome measures is not defined for the Stratum E in the protocol.

Outcome Time Frame:

From day 1 of treatment up to 24 weeks

Safety Issue:

No

Principal Investigator

Sri Gururangan, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Duke University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-01090

NCT ID:

NCT00381797

Start Date:

August 2006

Completion Date:

July 2015

Related Keywords:

  • Brain and Central Nervous System Tumors
  • childhood high-grade cerebral astrocytoma
  • childhood spinal cord neoplasm
  • childhood oligodendroglioma
  • recurrent childhood medulloblastoma
  • recurrent childhood ependymoma
  • Ependymoma
  • Glioma
  • Medulloblastoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115
Dan L. Duncan Cancer Center at Baylor College of MedicineHouston, Texas  77030