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A Phase II Study of Sunitinib (NSC# 736511, IND# 74019) in Recurrent, Refractory or Progressive High Grade Glioma and Ependymoma Tumors in Pediatric and Young Adult Patients

Phase 2
1 Year
21 Years
Open (Enrolling)
Childhood Cerebral Astrocytoma/Malignant Glioma, Childhood High-grade Cerebellar Astrocytoma, Childhood High-grade Cerebral Astrocytoma, Childhood Infratentorial Ependymoma, Childhood Mixed Glioma, Childhood Oligodendroglioma, Childhood Supratentorial Ependymoma, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Ependymoma, Recurrent Childhood Subependymal Giant Cell Astrocytoma

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Trial Information

A Phase II Study of Sunitinib (NSC# 736511, IND# 74019) in Recurrent, Refractory or Progressive High Grade Glioma and Ependymoma Tumors in Pediatric and Young Adult Patients


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.


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.

EXPLORATORY OBJECTIVES I. To describe the pharmacokinetic profile of pediatric and young
adult patients taking sunitinib malate.

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

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

IV. 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.

V. 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

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

VII. 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.

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 MRI,
if clinically indicated,with and without gadolinium, performed within 2 weeks
prior to study enrollment

- Patients with evidence of new 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

- 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
platelettransfusions within the 7-day period prior to enrollment)

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

- Creatinine clearance or radioisotope 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)

- SGOT (AST) and 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)

- PT/INR ≤ 1.5 times ULN

- 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: pepticulcer 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

- 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

- No concurrent use of 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

- 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

- 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., anthracyclinetherapy 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 derivativesor oral anti-vitamin K agents are not eligible

- Patients receiving antiretroviral therapy for 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

Type of Study:


Study Design:

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

Outcome Measure:

Sustained objective response rate, defined as a PR or CR lasting ≥ 8 weeks

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Cynthia Wetmore

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

February 2012

Completion Date:

Related Keywords:

  • Childhood Cerebral Astrocytoma/Malignant Glioma
  • Childhood High-grade Cerebellar Astrocytoma
  • Childhood High-grade Cerebral Astrocytoma
  • Childhood Infratentorial Ependymoma
  • Childhood Mixed Glioma
  • Childhood Oligodendroglioma
  • Childhood Supratentorial Ependymoma
  • Recurrent Childhood Cerebellar Astrocytoma
  • Recurrent Childhood Cerebral Astrocytoma
  • Recurrent Childhood Ependymoma
  • Recurrent Childhood Subependymal Giant Cell Astrocytoma
  • Astrocytoma
  • Ependymoma
  • Glioma
  • Oligodendroglioma



Baylor College of Medicine Houston, Texas  77030
Roswell Park Cancer Institute Buffalo, New York  14263
Mayo Clinic Rochester, Minnesota  55905
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
University of Mississippi Medical Center Jackson, Mississippi  39216-4505
Washington University School of Medicine Saint Louis, Missouri  63110
Medical City Dallas Hospital Dallas, Texas  75230
University of Texas Health Science Center at San Antonio San Antonio, Texas  78284-7811
Midwest Children's Cancer Center Milwaukee, Wisconsin  53226
Morristown Memorial Hospital Morristown, New Jersey  07962-1956
Dana-Farber Cancer Institute Boston, Massachusetts  02115
University of Arkansas for Medical Sciences Little Rock, Arkansas  72205
Hackensack University Medical Center Hackensack, New Jersey  07601
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Children's National Medical Center Washington, District of Columbia  20010-2970
All Children's Hospital St. Petersburg, Florida  33701
Saint Jude Midwest Affiliate Peoria, Illinois  61637
Carolinas Medical Center Charlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma  73104
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
Driscoll Children's Hospital Corpus Christi, Texas  78466
Southern California Permanente Medical Group Downey, California  90242
Children's Hospital Central California Madera, California  93638-8762
Kosair Children's Hospital Louisville, Kentucky  40202-3830
Children's Hospital Medical Center of Akron Akron, Ohio  44308
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
Overlook Hospital Summit, New Jersey  07902-0220
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Primary Children's Medical Center Salt Lake City, Utah  84113-1100
Naval Medical Center - Portsmouth Portsmouth, Virginia  23708-2197
Montefiore Medical Center Bronx, New York  10467-2490
Rady Children's Hospital - San Diego San Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis, Minnesota  55404
University of New Mexico Cancer Center Albuquerque, New Mexico  87131-5636
Nationwide Children's Hospital Columbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central Texas Austin, Texas  78723
Mary Bridge Children's Hospital and Health Center Tacoma, Washington  98415-0299
Lee Memorial Health System Fort Myers, Florida  33902
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Children's Hospital of Alabama Birmingham, Alabama  35233
Connecticut Children's Medical Center Hartford, Connecticut  06106
University of North Carolina Chapel Hill, North Carolina  27599
Nemours Children's Clinic - Pensacola Pensacola, Florida  32504
Wayne State University Detroit, Michigan  48202
BI-LO Charities Children's Cancer Center Greenville, South Carolina  29605
Dartmouth Hitchcock Medical Center Lebanon, New Hampshire  03756
University of Texas Southwestern Medical Center Dallas, Texas  
University of Kentucky Lexington, Kentucky  40536-0098
Oregon Health and Science University Portland, Oregon  97201
Virginia Commonwealth University Richmond, Virginia  
Florida Hospital Orlando, Florida  32803
Memorial Health University Medical Center Savannah, Georgia  31404
Seattle Children's Hospital Seattle, Washington  98105
Wake Forest University Health Sciences Winston-Salem, North Carolina  27157
Childrens Memorial Hospital Chicago, Illinois  60614
Saint Vincent Hospital and Health Services Indianapolis, Indiana  46260
Saint John's Mercy Medical Center Saint Louis, Missouri  63141
New York University Langone Medical Center New York, New York  10016
Columbia University Medical Center New York, New York  10032
State University of New York Upstate Medical University Syracuse, New York  13210
Saint Vincent Hospital Green Bay, Wisconsin  54301
University of Illinois Chicago, Illinois  60612
Cook Children's Medical Center Fort Worth, Texas  76104
The Children's Medical Center of Dayton Dayton, Ohio  45404
University of Minnesota Medical Center-Fairview Minneapolis, Minnesota  55455
Children's Oncology Group Arcadia, California  91006-3776
Riley Hospital for Children Indianapolis, Indiana  46202
Miller Children's Hospital Long Beach, California  90806
Childrens Hospital of Orange County Orange, California  92868-3874
Alfred I duPont Hospital for Children Wilmington, Delaware  19803
Nemours Children's Clinic - Jacksonville Jacksonville, Florida  32207-8426
Nemours Childrens Clinic - Orlando Orlando, Florida  32806
Saint Joseph Children's Hospital of Tampa Tampa, Florida  33607
Children's Healthcare of Atlanta - Egleston Atlanta, Georgia  30322
The Childrens Mercy Hospital Kansas City, Missouri  64108
Rainbow Babies and Childrens Hospital Cleveland, Ohio  44106
Penn State Hershey Children's Hospital Hershey, Pennsylvania  17033
Lucile Packard Children's Hospital Stanford University Palo Alto, California  94304
University of California San Francisco Medical Center-Parnassus San Francisco, California  94143
Raymond Blank Children's Hospital Des Moines, Iowa  50309
The Toledo Hospital/Toledo Children's Hospital Toledo, Ohio  43606
Greenville Cancer Treatment Center Greenville, South Carolina  29605
Sanford USD Medical Center - Sioux Falls Sioux Falls, South Dakota  57117-5134
Providence Sacred Heart Medical Center and Children's Hospital Spokane, Washington  99204