Sunitinib Malate in Treating Younger Patients With Recurrent, Refractory, or Progressive Malignant Glioma or Ependymoma

Phase 2

Completed

Conditions: Childhood Cerebral Anaplastic Astrocytoma
Childhood Infratentorial Ependymoma
Childhood Oligodendroglioma
Recurrent Childhood Cerebellar Astrocytoma
Recurrent Childhood Ependymoma
Recurrent Childhood Subependymal Giant Cell Astrocytoma
Childhood Cerebral Astrocytoma
Childhood Cerebellar Anaplastic Astrocytoma
Recurrent Childhood Cerebral Astrocytoma
Childhood Mixed Glioma

Interventions: Other: Diagnostic Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Sunitinib Malate

Registration Number: NCT01462695

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies how well sunitinib malate works in treating younger patients with recurrent, refractory, or progressive malignant glioma or ependymoma. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description: PRIMARY OBJECTIVES:

I. To estimate the objective response rate (partial response \[PR\] or complete response \[CR\] ≥ 8 weeks) to sunitinib in 2 strata (recurrent/progressive/refractory high-grade glioma vs ependymoma) of recurrent or progressive brain tumors in pediatric and young adult patients.

SECONDARY OBJECTIVES:

I. To explore and report descriptively the safety and tolerability of sunitinib in pediatric and young adult brain tumor patients who have not received prior anthracycline or radiotherapy involving the heart.

II. To describe the pharmacokinetic profile of pediatric and young adult patients taking sunitinib malate.

III. To describe the cumulative toxicities of sunitinib when administered over multiple courses to pediatric and young adult patients.

IV. To estimate progression-free survival (PFS) distributions for these cohorts of patients.

V. To evaluate changes in phosphorylation of PDGFR-α and -β, MEK/ERK, S6 kinase, and AKT in peripheral blood mononuclear cells and explore possible associations between these changes and outcome measures.

VI. To evaluate plasma levels of soluble isoforms of VEGFR-1 and -2 prior to initiation of therapy and at points during therapy as an exploration of possible biomarkers of clinical response.

VII. To evaluate and report descriptively the expression and ratio of VEGF isoforms in tumor tissue, as available.

VIII. To evaluate and report descriptively the genotype, expression, and possible amplification of KIT and PDGFR-α and -β in tumor tissue, as available.

OUTLINE: This is a multicenter study.

Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Treatment repeats every 42 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

Patients may undergo blood sample collection at baseline and during courses 1 and 2 for pharmacokinetic and pharmacodynamic studies. Tissue samples from diagnosis and surgical resection may be also collected.

After completion of study treatment, patients are followed up for up to 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Patients must be diagnosed with ependymoma or high-grade glioma (World Health Organization [WHO] grade III/IV):
- Stratum A: recurrent/progressive/refractory malignant glioma (i.e., anaplastic astrocytoma, glioblastoma multiforme [including giant cell and gliosarcoma types], anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or anaplastic ganglioglioma) within the brain with or without spinal cord disease
- Stratum B: recurrent/progressive/refractory ependymoma (including ependymoma variants) within the brain with or without spinal cord disease
- Patients with diffuse intrinsic pontine glioma are not eligible
A histological diagnosis from either the initial presentation or at the time of recurrence is required
Patients must have radiographically documented measurable disease in the brain, defined as at least one lesion that can be accurately measured in at least 2 planes
To document the degree of residual tumor, the following must be obtained:
- All patients must have a brain MRI with and without gadolinium and a spine magnetic resonance imaging (MRI), if clinically indicated,with and without gadolinium, performed within 2 weeks prior to study enrollment
- Patients with evidence of new central nervous system (CNS) hemorrhage of more than punctate size and/or more than 3 foci of punctate hemorrhage on baseline MRI obtained within 14 days prior to study enrollment are not eligible
Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2 (use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age)
- Neurological deficits in patients must have been relatively stable for a minimum of 1 week prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
Peripheral absolute neutrophil count (ANC) ≥ 1,000/μL
Platelet count ≥ 75,000/μL (transfusion independent, defined as not receiving platelet transfusions within the 7-day period prior to enrollment)
Hemoglobin ≥ 8.0 g/dL (may receive red blood cell [RBC] transfusions)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min OR serum creatinine based on age/gender as follows:
- 0.4 mg/dL (1 month to < 6 months of age)
- 0.5 mg/dL (6 months to < 1 year of age)
- 0.6 mg/dL (1 to < 2 years of age)
- 0.8 mg/dL (2 to < 6 years of age)
- 1.0 mg/dL (6 to < 10 years of age)
- 1.2 mg/dL (10 to < 13 years of age)
- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
- 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
Serum glutamic oxaloacetic transaminase (SGOT/AST) and serum glutamic pyruvic transaminase (SGPT/ALT) ≤ 2.5 times ULN
Shortening fraction of ≥ 27% by echocardiogram OR ejection fraction of ≥ 50% by radionuclide angiogram
Corrected QT interval < 450 msec (males) or < 470 msec (females)
Prothrombin time (PT) / international normalized ratio (INR) ≤ 1.5 times ULN
Partial thromboplastin time (PTT) ≤ 1.5 times ULN
Patients must not have a history of cardiac disease including, but not limited to:
- Uncontrolled hypertension within 12 months prior to enrollment; uncontrolled hypertension is defined as follows:
  - Patients aged ≤ 17 years: greater than 95th percentile systolic and diastolic blood pressure based on age and height which is not controlled by one anti-hypertensive medication
  - Patients aged > 17 years: systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg which is not controlled by one anti-hypertensive medication
- Ongoing cardiac dysrhythmias ≥ grade 2 or atrial fibrillation of any grade
- Unstable angina, symptomatic congestive heart failure, or myocardial infarction
Patients with a seizure disorder may be enrolled if on non-enzyme-inducing anticonvulsants and well controlled
- Commonly used non-enzyme-inducing anticonvulsants include: gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, valproic acid, and zonisamide
Patients must not have had a cerebrovascular accident or transient is chemic attack within 12 months prior to enrollment
Patients must not have had a pulmonary embolism or other significant thromboembolic event within 12 months prior to enrollment
Patients must not have had grade ≥ 3 hemorrhage within 4 weeks prior to enrollment
Patients must not have had any of the following diagnoses within 6 months prior to enrollment: peptic ulcer disease, inflammatory bowel disease, or diverticulitis
Patients with a diagnosis of abdomen fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to enrollment are not eligible
Patients who have an uncontrolled infection are not eligible
Patients with hypothyroidism that has not been well-controlled by medications for at least 2 weeks prior to study entry are not eligible
Patients who have a personal history of genetic and/or congenital cardiac abnormalities are not eligible
Patients who have a history of allergic reactions to compounds of similar chemical or biological composition to sunitinib are not eligible
Patients who have any other condition that could result in an inability to swallow capsules/sprinkles or absorb oral sunitinib administered through a gastric tube are not eligible
Patients with body surface area < 0.55 m^2 or > 2.18 m^2 are not eligible
Female patients who are pregnant are not eligible
Lactating females are not eligible unless they have agreed not to breastfeed their infants
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained within the past 4 weeks
Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
No concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), clopidogrel, warfarin, heparin, low molecular weight heparin, dipyridamole, or aspirin therapy > 81 mg/day
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy (RT) prior to entering this study
Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study (6 weeks if prior nitrosourea)
At least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody
At least 24 weeks must have elapsed if prior full-field RT
- ≥ 2 weeks must have elapsed if prior local palliative RT (small port) or limited-field RT
- ≥ 3 months must have elapsed since prior stem cell transplant (SCT) or rescue with total-body irradiation (TBI)
  - No evidence of active graft-vs-host disease
Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 7 days prior to enrollment
Patients must not have received potent cytochrome P450-3A4 (CY3A4) inhibitors and/or inducers within 7 days prior to study enrollment and potent inducers within 12 days prior to study enrollment and during study
At least 7 days must have elapsed since the completion of therapy with a hematopoietic growth factor
Patients who have previously received sunitinib or who have received other VEGF-, PDGFR-, or KIT-targeted therapy are not eligible
- Patients who received bevacizumab as part of their prior therapy may enroll on study
Patients must not have received more than 2 prior chemotherapy and/or RT regimens; for example, 1 initial treatment course of chemotherapy and/or RT (counts as 1 treatment course) and at relapse may have received 1 treatment course of chemotherapy and/or RT (counts as 1 treatment course)
Patients who received prior therapy with known risk for cardiovascular complications (e.g., anthracycline therapy or prior RT that included the heart and/or craniospinal radiation) are not eligible
Patients receiving ongoing treatment with therapeutic doses (i.e., therapeutic INR levels) of coumarin derivatives or oral anti-vitamin K agents are not eligible
Patients receiving antiretroviral therapy for human immunodeficiency virus (HIV) disease are not eligible
Patients who are started on protocol therapy on a phase II study prior to study enrollment are considered ineligible
No other concurrent chemotherapy, investigational agents, or immunomodulating agents
No concurrent RT

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (sunitinib)	Diagnostic Laboratory Biomarker Analysis	Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Treatment repeats every 42 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
Treatment (sunitinib)	Pharmacological Study	Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Treatment repeats every 42 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
Treatment (sunitinib)	Sunitinib Malate	Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Treatment repeats every 42 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Sustained Objective Response Rate	Up to 5 years	Sustained objective response was defined as a PR (Partial Response: ≥ 50% decrease in the sum of the products of the 2 perpendicular diameters of all target lesions (up to 5), taking as reference the initial baseline measurements) or CR (Complete Response: disappearance of all target lesions) lasting at least 8 weeks.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (96): Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Children's Hospital Central California
🇺🇸
Madera, California, United States
UT Southwestern/Simmons Cancer Center-Dallas
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Dallas, Texas, United States
Children's Hospital of Philadelphia
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Philadelphia, Pennsylvania, United States
Children's Healthcare of Atlanta - Egleston
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Atlanta, Georgia, United States
Royal Brisbane and Women's Hospital
🇦🇺
Herston, Queensland, Australia
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Rainbow Babies and Childrens Hospital
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Cleveland, Ohio, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Baylor College of Medicine
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Houston, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Nemours Children's Clinic-Jacksonville
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Jacksonville, Florida, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Greenville Cancer Treatment Center
🇺🇸
Greenville, South Carolina, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Saint Vincent Hospital and Health Services
🇺🇸
Indianapolis, Indiana, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Cincinnati Children's Hospital Medical Center
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Cincinnati, Ohio, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
Princess Margaret Hospital for Children
🇦🇺
Perth, Western Australia, Australia
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
University of Minnesota Medical Center-Fairview
🇺🇸
Minneapolis, Minnesota, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
Midwest Children's Cancer Center
🇺🇸
Milwaukee, Wisconsin, United States
Southern California Permanente Medical Group
🇺🇸
Downey, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸
Fort Myers, Florida, United States
Nemours Children's Clinic - Pensacola
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Pensacola, Florida, United States
All Children's Hospital
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Saint Petersburg, Florida, United States
Lurie Children's Hospital-Chicago
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Chicago, Illinois, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
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Saint Louis, Missouri, United States
Dartmouth Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Laura and Issac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
The Toledo Hospital/Toledo Children's Hospital
🇺🇸
Toledo, Ohio, United States
Penn State Hershey Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
Children's Oncology Group
🇺🇸
Philadelphia, Pennsylvania, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
St. Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸
San Antonio, Texas, United States
Naval Medical Center - Portsmouth
🇺🇸
Portsmouth, Virginia, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸
Tacoma, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Sydney Children's Hospital
🇦🇺
Randwick, New South Wales, Australia
Royal Children's Hospital-Brisbane
🇦🇺
Herston, Queensland, Australia
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
Centre Hospitalier Universitaire de Quebec
🇨🇦
Quebec, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Lee Memorial Health System
🇺🇸
Fort Myers, Florida, United States
Saint Vincent Hospital
🇺🇸
Green Bay, Wisconsin, United States
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Memorial University Medical Center
🇺🇸
Savannah, Georgia, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Florida Hospital Orlando
🇺🇸
Orlando, Florida, United States
Nemours Children's Clinic - Orlando
🇺🇸
Orlando, Florida, United States
Kosair Children's Hospital
🇺🇸
Louisville, Kentucky, United States
The Childrens Mercy Hospital
🇺🇸
Kansas City, Missouri, United States
Dell Children's Medical Center of Central Texas
🇺🇸
Austin, Texas, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
University of North Carolina at Chapel Hill
🇺🇸
Chapel Hill, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States