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

This is an interventional treatment trial for Childhood Cerebellar Anaplastic Astrocytoma Read More

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