Clinical trial NCT01462695: Sunitinib Malate in Treating Younger Patients With Recurrent, Refractory, or Progressive Malignant Glioma or Ependymoma
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2011-10-31
Enrollment: 30
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Sustained Objective Response Rate
timeFrame: Up to 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Downey
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Long Beach
country: United States
facility: Miller Children's and Women's Hospital Long Beach
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Madera
country: United States
facility: Children's Hospital Central California
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Parnassus
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Lee Memorial Health System
state: Florida
city: Fort Myers
country: United States
facility: Golisano Children's Hospital of Southwest Florida
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic-Jacksonville
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Orlando
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Clinic - Orlando
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Clinic - Pensacola
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: Saint Joseph's Hospital/Children's Hospital-Tampa
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Savannah
country: United States
facility: Memorial University Medical Center
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Peoria
country: United States
facility: Saint Jude Midwest Affiliate
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Indianapolis
country: United States
facility: Saint Vincent Hospital and Health Services
state: Indiana
city: Des Moines
country: United States
facility: Blank Children's Hospital
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center-Fairview
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: Summit
country: United States
facility: Overlook Hospital
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Laura and Issac Perlmutter Cancer Center at NYU Langone
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Childrens Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Dayton Children's Hospital
state: Ohio
city: Toledo
country: United States
facility: The Toledo Hospital/Toledo Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Oncology Group
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Greenville
country: United States
facility: BI-LO Charities Children's Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Greenville Cancer Treatment Center
state: South Carolina
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Austin
country: United States
facility: Dell Children's Medical Center of Central Texas
state: Texas
city: Corpus Christi
country: United States
facility: Driscoll Children's Hospital
state: Texas
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Portsmouth
country: United States
facility: Naval Medical Center - Portsmouth
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Tacoma
country: United States
facility: Mary Bridge Children's Hospital and Health Center
state: Washington
city: Green Bay
country: United States
facility: Saint Vincent Hospital
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Children's Hospital-Brisbane
state: Queensland
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital at Hamilton Health Sciences
state: Ontario
city: Montreal
country: Canada
facility: The Montreal Children's Hospital of the MUHC
state: Quebec
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Quebec
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
Study officials:
affiliation: Children's Oncology Group
name: Cynthia Wetmore
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang E, DuBois SG, Wetmore C, Verschuur AC, Khosravan R. Population Pharmacokinetics of Sunitinib and its Active Metabolite SU012662 in Pediatric Patients with Gastrointestinal Stromal Tumors or Other Solid Tumors. Eur J Drug Metab Pharmacokinet. 2021 May;46(3):343-352. doi: 10.1007/s13318-021-00671-7. Epub 2021 Apr 14.
citation: Wang E, DuBois SG, Wetmore C, Khosravan R. Population pharmacokinetics-pharmacodynamics of sunitinib in pediatric patients with solid tumors. Cancer Chemother Pharmacol. 2020 Aug;86(2):181-192. doi: 10.1007/s00280-020-04106-z. Epub 2020 Jul 4.
citation: 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.