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

Recurrent Childhood Ependymoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01462695
• Other study ID #: NCI-2011-03536
• Secondary ID: NCI-2011-03536CD
• Status: Completed
• Phase: Phase 2
• First received: October 27, 2011
• Last updated: August 18, 2015
• Start date: January 2012
• Est. completion date: March 2014

Study information

• Verified date: June 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: March 2014
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 21 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Astrocytoma
• Childhood Cerebellar Anaplastic Astrocytoma
• Childhood Cerebral Anaplastic Astrocytoma
• Childhood Cerebral Astrocytoma
• Childhood Infratentorial Ependymoma
• Childhood Mixed Glioma
• Childhood Oligodendroglioma
• Childhood Supratentorial Ependymoma
• Ependymoma
• Glioma
• Oligodendroglioma
• Recurrent Childhood Cerebellar Astrocytoma
• Recurrent Childhood Cerebral Astrocytoma
• Recurrent Childhood Ependymoma
• Recurrent Childhood Subependymal Giant Cell Astrocytoma

Intervention

Other:
• Diagnostic Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Drug:
• Sunitinib Malate
Given PO

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sustained Objective Response Rate	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.	Up to 5 years	No