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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Childhood Cerebellar Anaplastic Astrocytoma; Childhood Cerebral Anaplastic Astrocytoma; Childhood 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	Other: Diagnostic Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Sunitinib Malate	Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	30 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase II Study of Sunitinib (NSC# 736511) in Recurrent, Refractory or Progressive High Grade Glioma and Ependymoma Tumors in Pediatric and Young Adult Patients
Study Start Date :	January 2012
Actual Primary Completion Date :	December 2013
Actual Study Completion Date :	March 2014

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Treatment (sunitinib); 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.	Other: Diagnostic Laboratory Biomarker Analysis; Correlative studies Other: Pharmacological Study; Correlative studies Drug: Sunitinib Malate; Given PO; Other Names: SU011248; SU11248; sunitinib; Sutent

Outcome Measures

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Primary Outcome Measures :

1. Sustained Objective Response Rate [ Time Frame: 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.

Eligibility Criteria

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Ages Eligible for Study:	1 Year to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

United States, Alabama
Children's Hospital of Alabama
Birmingham, Alabama, United States, 35233
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States, 35233
United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205
United States, California
Southern California Permanente Medical Group
Downey, California, United States, 90242
Miller Children's and Women's Hospital Long Beach
Long Beach, California, United States, 90806
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
Children's Hospital Central California
Madera, California, United States, 93636-8762
Children's Hospital of Orange County
Orange, California, United States, 92868
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States, 94304
Rady Children's Hospital - San Diego
San Diego, California, United States, 92123
UCSF Medical Center-Parnassus
San Francisco, California, United States, 94143
United States, Connecticut
Connecticut Children's Medical Center
Hartford, Connecticut, United States, 06106
United States, Delaware
Alfred I duPont Hospital for Children
Wilmington, Delaware, United States, 19803
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Florida
Lee Memorial Health System
Fort Myers, Florida, United States, 33901
Golisano Children's Hospital of Southwest Florida
Fort Myers, Florida, United States, 33908
Nemours Children's Clinic-Jacksonville
Jacksonville, Florida, United States, 32207
Florida Hospital Orlando
Orlando, Florida, United States, 32803
Nemours Children's Clinic - Orlando
Orlando, Florida, United States, 32806
Nemours Children's Clinic - Pensacola
Pensacola, Florida, United States, 32504
All Children's Hospital
Saint Petersburg, Florida, United States, 33701
Saint Joseph's Hospital/Children's Hospital-Tampa
Tampa, Florida, United States, 33607
United States, Georgia
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, United States, 30322
Memorial University Medical Center
Savannah, Georgia, United States, 31404
United States, Illinois
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States, 60611
University of Illinois
Chicago, Illinois, United States, 60612
Saint Jude Midwest Affiliate
Peoria, Illinois, United States, 61637
United States, Indiana
Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
Saint Vincent Hospital and Health Services
Indianapolis, Indiana, United States, 46260
United States, Iowa
Blank Children's Hospital
Des Moines, Iowa, United States, 50309
United States, Kentucky
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States, 40536
Kosair Children's Hospital
Louisville, Kentucky, United States, 40202
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Michigan
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Minnesota
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis, Minnesota, United States, 55404
University of Minnesota Medical Center-Fairview
Minneapolis, Minnesota, United States, 55455
United States, Mississippi
University of Mississippi Medical Center
Jackson, Mississippi, United States, 39216
United States, Missouri
The Childrens Mercy Hospital
Kansas City, Missouri, United States, 64108
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Mercy Hospital Saint Louis
Saint Louis, Missouri, United States, 63141
United States, New Hampshire
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
Morristown Medical Center
Morristown, New Jersey, United States, 07960
Overlook Hospital
Summit, New Jersey, United States, 07902
United States, New Mexico
University of New Mexico Cancer Center
Albuquerque, New Mexico, United States, 87106
United States, New York
Montefiore Medical Center - Moses Campus
Bronx, New York, United States, 10467-2490
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Laura and Issac Perlmutter Cancer Center at NYU Langone
New York, New York, United States, 10016
Columbia University Medical Center
New York, New York, United States, 10032
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
State University of New York Upstate Medical University
Syracuse, New York, United States, 13210
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Carolinas Medical Center/Levine Cancer Institute
Charlotte, North Carolina, United States, 28203
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Children's Hospital Medical Center of Akron
Akron, Ohio, United States, 44308
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Rainbow Babies and Childrens Hospital
Cleveland, Ohio, United States, 44106
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
Dayton Children's Hospital
Dayton, Ohio, United States, 45404
The Toledo Hospital/Toledo Children's Hospital
Toledo, Ohio, United States, 43606
United States, Oklahoma
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States, 73104
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Penn State Hershey Children's Hospital
Hershey, Pennsylvania, United States, 17033
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Children's Oncology Group
Philadelphia, Pennsylvania, United States, 19104
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, South Carolina
BI-LO Charities Children's Cancer Center
Greenville, South Carolina, United States, 29605
Greenville Cancer Treatment Center
Greenville, South Carolina, United States, 29605
United States, South Dakota
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, United States, 57117-5134
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Dell Children's Medical Center of Central Texas
Austin, Texas, United States, 78723
Driscoll Children's Hospital
Corpus Christi, Texas, United States, 78411
Medical City Dallas Hospital
Dallas, Texas, United States, 75230
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, United States, 75390
Cook Children's Medical Center
Fort Worth, Texas, United States, 76104
Baylor College of Medicine
Houston, Texas, United States, 77030
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States, 78229
United States, Utah
Primary Children's Hospital
Salt Lake City, Utah, United States, 84113
United States, Virginia
Naval Medical Center - Portsmouth
Portsmouth, Virginia, United States, 23708-2197
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, United States, 23298
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Providence Sacred Heart Medical Center and Children's Hospital
Spokane, Washington, United States, 99204
Mary Bridge Children's Hospital and Health Center
Tacoma, Washington, United States, 98405
United States, Wisconsin
Saint Vincent Hospital
Green Bay, Wisconsin, United States, 54301
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Midwest Children's Cancer Center
Milwaukee, Wisconsin, United States, 53226
Australia, New South Wales
Sydney Children's Hospital
Randwick, New South Wales, Australia, 2031
The Children's Hospital at Westmead
Westmead, New South Wales, Australia, 2145
Australia, Queensland
Royal Brisbane and Women's Hospital
Herston, Queensland, Australia, 4029
Royal Children's Hospital-Brisbane
Herston, Queensland, Australia, 4029
Australia, Western Australia
Princess Margaret Hospital for Children
Perth, Western Australia, Australia, 6008
Canada, Nova Scotia
IWK Health Centre
Halifax, Nova Scotia, Canada, B3K 6R8
Canada, Ontario
McMaster Children's Hospital at Hamilton Health Sciences
Hamilton, Ontario, Canada, L8N 3Z5
Canada, Quebec
The Montreal Children's Hospital of the MUHC
Montreal, Quebec, Canada, H3H 1P3
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, Canada, H3T 1C5
Canada
Centre Hospitalier Universitaire de Quebec
Quebec, Canada, G1V 4G2

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Cynthia Wetmore	Children's Oncology Group

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wetmore C, Daryani VM, Billups CA, Boyett JM, Leary S, Tanos R, Goldsmith KC, Stewart CF, Blaney SM, Gajjar A. Phase II evaluation of sunitinib in the treatment of recurrent or refractory high-grade glioma or ependymoma in children: a children's Oncology Group Study ACNS1021. Cancer Med. 2016 Jul;5(7):1416-24. doi: 10.1002/cam4.713. Epub 2016 Apr 25.

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT01462695 History of Changes
Other Study ID Numbers:	NCI-2011-03536; NCI-2011-03536 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000712861; COG-ACNS1021; ACNS1021 ( Other Identifier: Children's Oncology Group ); ACNS1021 ( Other Identifier: CTEP ); U10CA098543 ( U.S. NIH Grant/Contract )
First Posted:	October 31, 2011
Results First Posted:	March 23, 2015
Last Update Posted:	August 27, 2015
Last Verified:	June 2015

Additional relevant MeSH terms:

Glioma; Astrocytoma; Ependymoma; Oligodendroglioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms	Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Sunitinib; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors