131I-Omburtamab, in Recurrent Medulloblastoma and Ependymoma

INCLUSION CRITERIA: Stratum 1

   - Patients with histologically confirmed diagnosis of medulloblastoma that is recurrent,
   progressive, or refractory to standard therapy. All tumors must have histologic
   verification at either time of initial diagnosis or recurrence. Note: For this study,
   refractory disease is specifically defined as presence of persistent abnormality on
   conventional MRI that is further distinguished by histology (tissue sample) or
   advanced imaging, i.e., diffusion weighted sequences or MR spectroscopy.

   - Patients must have disease, defined as tumor measurable in two perpendicular diameters
   on MRI, OR diffuse leptomeningeal disease, OR clear MRI evidence of disease that may
   not be measurable in two perpendicular diameters. Patients may have tumor cells in CSF
   with or without radiographic evidence of disease at time of enrollment.

   - Patients must be < 22 years of age at time of enrollment.

   - Protocol treatment with radioimmunotherapy (131I-omburtamab) will require the presence
   of an appropriate intraventricular access device (e.g., programmable
   ventriculoperitoneal [VP] shunt or Ommaya reservoir). Patients are not required to
   have an existing programmable VP shunt or Ommaya at time of study enrollment but must
   be willing and able to undergo a surgical procedure to have one placed prior to
   Radioimmunotherapy. Note: Patients with an existing intraventricular VP shunt without
   a programmable component must be willing and able to undergo modification of the shunt
   before treatment with 131I-omburtamab.

   - Patients must have recurrent, progressive, or refractory medulloblastoma after prior
   craniospinal irradiation (CSI) therapy with or without prior chemotherapy, unless CSI
   is contraindicated or determined to be not in the best interest of patient due to
   underlying medical conditions or declined by patient/family. Patients must have
   experienced no more than two recurrences of medulloblastoma or have refractory
   disease. Note: Patients with contraindications to radiation therapy are still
   eligible.

   - Patients must have received their last dose of known myelosuppressive anticancer
   therapy at least 21 days prior to enrollment or at least 42 days if prior nitrosourea.

   - Biologic or investigational agent (anti-neoplastic) - Patient must have recovered from
   any acute toxicity potentially related to the agent and received their last dose of
   the investigational or biologic agent ≥ 7 days prior to study enrollment. 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.

   - Monoclonal antibody treatment and agents with known prolonged half-lives - Patient
   must have recovered from any acute toxicity potentially related to the agent and
   received last dose of the agent ≥ 21 days prior to study enrollment.

   - Radiation - Patients must have had their last fraction of:

      1. Craniospinal irradiation, whole brain radiation, total body irradiation, or
      radiation to >= 50% of pelvis or spine 24 weeks prior to study enrollment. Tumor
      designated as "measurable" for protocol purposes must not have received radiation
      within 12 weeks prior to study enrollment.

      2. Focal radiation to areas of symptomatic metastatic disease at least 14 days prior
      to study enrollment.

   - Stem Cell Transplant (SCT) - For autologous SCT >= 3 months must have elapsed prior to
   study enrollment.

   - Patients with neurological deficits should have deficits stable for a minimum of 1
   week prior to enrollment. A baseline detailed neurological exam should clearly
   document neurological status of the patient at time of study enrollment. Patients with
   seizure disorders may be enrolled if seizures are controlled and on non-enzyme
   inducing anticonvulsants. Patients must not be taking enzyme-inducing antiepileptic
   medicines within 1 week prior to study enrollment.

   - Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score
   (LPS for ≤ 16 years of age) assessed within 2 weeks prior to study enrollment must be
   ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who are up
   in a wheelchair, will be considered ambulatory for the purpose of assessing the
   performance score.

   - Organ Function - Patients must have:

      1. Peripheral absolute neutrophil count (ANC) ≥ 1 x 10^9/ L (must not have received
      G-CSF within 7 days prior to enrollment or pegfilgrastim within 14 days prior to
      enrollment)

      2. Platelet count ≥ 100 x 10^9/ L (unsupported, defined as no platelet transfusion
      within 7 days prior to study enrollment)

      3. Hemoglobin ≥ 8.0 g/dL (may receive packed red blood cell [PRBC] transfusions)

      4. Serum creatinine based on age/gender. Patients that do not meet the criteria in
      Table 1 but have a 24 hour Creatinine Clearance or GFR (radioisotope or
      iothalamate) ≥ 70 mL/min/1.73 m^2 are eligible.

      5. Urine protein should be screened by dipstick analysis. If protein ≥ 2+ on
      dipstick, then Urine Protein Creatinine (UPC) ratio should be calculated. If UPC
      ratio > 0.5, 24-hour urine protein should be obtained, and the level should be <
      1000 mg/24 hours for patient enrollment.

      6. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

      7. ALT (SGPT) and AST (SGOT) < 5 x institutional upper limit of normal (ULN)

      8. INR/PT ≤ 1.5 x institutional upper limit of normal (ULN)

   - Hypertension must be well controlled (≤ 95th percentile) on stable doses of
   medication.

   - Patients must have recovered from any surgical procedure before enrolling on this
   study.

   - HIV Infected Individuals - Patients who are known to be Human immunodeficiency virus
   (HIV)-infected must be on effective anti-retroviral therapy with undetectable viral
   load within 6 months prior to study enrollment.

   - Hep B Chronically Infected Individuals - For patients with known evidence of chronic
   hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on
   suppressive therapy, if indicated.

   - Hep C (HCV) Infected Individuals - Patients with a known history of hepatitis C virus
   (HCV) infection must have been treated and cured. Patients with known HCV infection
   who are currently on treatment are eligible if they have an undetectable HCV viral
   load.

   - Corticosteroids - Patients who are receiving dexamethasone at a stable or decreasing
   dose for at least 7 days prior to study enrollment are eligible.

   - Growth Factors - Patients must be off all colony-forming growth factor(s) for at least
   1 week prior to enrollment (e.g., filgrastim, sargramostim, or erythropoietin) or at
   least 2 weeks for pegfilgrastim.

   - Patients of childbearing or child fathering potential must be willing to use a
   medically acceptable form of birth control, which includes abstinence, while being
   treated on this study and for at least 6 months after the completion of bevacizumab
   therapy.

   - The patient or parent/guardian can understand the consent and is willing to sign a
   written informed consent document according to institutional guidelines.

EXCLUSION CRITERIA: Stratum 1

   - Pregnant women are excluded from this study due to risks of fetal and teratogenic
   adverse events as seen in animal/human studies. Female patients of childbearing
   potential must have a negative serum or urine pregnancy test prior to enrollment. If
   the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
   will be required.

   - Patients must not have previously received the combination of bevacizumab, irinotecan,
   and temozolomide therapy.

   - Patients with a serious or non-healing wound, ulcer, or bone fracture are not eligible
   for this study.

   - Patients must not have a history of abdominal fistula, gastrointestinal perforation,
   or intraabdominal abscess within 6 months prior to study enrollment.

   - Patients must not have a known bleeding diathesis or coagulopathy.

   - Patients must not have had significant vascular disease (e.g., aortic aneurysm
   requiring surgical repair, deep venous or arterial thrombosis) within the last 6
   months prior to study enrollment.

   - Patients must not have a known thrombophilic condition (i.e., protein S, protein C or
   antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation,
   homocysteinemia or antiphospholipid antibody syndrome). Testing is not required in
   patients without thrombophilic history.

   - Patients must not have evidence of new CNS hemorrhage on baseline MRI obtained within
   14 days prior to study enrollment.

   - Patients with history of stroke, myocardial infarction, transient ischemic attack
   (TIA), severe or unstable angina, peripheral vascular disease, or grade II or greater
   congestive heart failure within the past 6 months are not eligible.

   - Patients must not have serious and inadequately controlled cardiac arrhythmia.

   - Patients with known hypersensitivity to Chinese hamster ovary cell products or other
   recombinant human antibodies are not eligible.

   - Patients must not be currently taking NSAIDS, clopidrogel, dipyridamole, or aspirin
   therapy > 81 mg/day.

   - Female patients who are breastfeeding are not eligible for this study unless they
   agree not to breastfeed.

   - Patients with any clinically significant unrelated systemic illness (serious
   infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction)
   that in the opinion of the investigator would compromise the patient's ability to
   tolerate protocol therapy, put them at additional risk for toxicity, or would
   interfere with the study procedures or results. Patients with a prior or concurrent
   malignancy whose natural history or treatment has the potential to interfere with the
   safety or efficacy assessment of the investigational regimen for this trial.

   - Patients who are receiving any other anti-cancer or investigational drug therapy are
   ineligible.

   - Patients currently receiving any of the following medications and cannot be
   discontinued 7 days prior to enrollment are ineligible:

      1. Known strong and moderate inducers or inhibitors of CYP3A4/5, including
      enzyme-inducing anti-convulsant drugs (EIACDs), grapefruit, echinacea, grapefruit
      hybrids, pummelos, starfruit, and Seville oranges

      2. Substrates of CYP3A4/5 with a narrow therapeutic index

      3. Herbal preparations/medications (except for vitamins) including, but not limited
      to: St. John's wort, Kava, ephedra (ma huang), gingko biloba,
      dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng.
      Patients should stop using all herbal medications and dietary supplements at
      least 7 days prior to enrollment.

   - Patients who in the opinion of the investigator are unwilling or unable to return for
   required follow-up visits or obtain follow-up studies required to assess toxicity to
   therapy or to adhere to drug administration plan, other study procedures, and study
   restrictions.

INCLUSION CRITERIA FOR SCREENING: Stratum 2

   - For patients with histological diagnosis of ependymoma, screening consent for B7H3
   must be obtained prior to enrollment on PBTC-058.

   - Patients must have evidence of tumor reactivity for B7H3 (CD276) to be eligible for
   treatment. Results from prior testing of tumor reactivity for B7H3 (CD276) using a
   CLIA-certified immunohistochemistry (IHC) assay may be used. For patients who do not
   have prior B7H3 testing results from a CLIA lab, samples must be sent to MSKCC.

   - Patients with a histologically confirmed diagnosis of ependymoma that is recurrent,
   progressive, or refractory to standard therapy. All tumors must have histologic
   verification at either the time of initial diagnosis or recurrence. Note: For this
   study, refractory disease is specifically defined as presence of persistent
   abnormality on conventional MRI that is further distinguished by histology (tissue
   sample) or advanced imaging, i.e., diffusion weighted sequences or MR spectroscopy.

   - Patients may have tumor cells in CSF with or without radiographic evidence of disease
   at time of screening.

   - Patients must be < 22 years of age at the time of screening.

   - Potential Eligibility for Study Enrollment - Patients screened for this trial should
   be expected to meet criteria for treatment as outlined in the protocol.

INCLUSION CRITERIA FOR ENROLLMENT: Stratum 2

   - Patients with histologically confirmed diagnosis of ependymoma that is recurrent,
   progressive, or refractory to standard therapy. All tumors must have histologic
   verification at either time of initial diagnosis or recurrence.

   - Patients must be positive for B7H3 reactivity by IHC performed in a CLIA-certified
   lab.

   - Patients may have tumor cells in CSF with or without radiographic evidence of disease
   at the time of enrollment. Patients are not required to have measurable or evaluable
   disease at time of study enrollment.

   - Patients must be < 22 years of age at the time of enrollment.

   - Intraventricular Access Device - Protocol treatment with radioimmunotherapy
   (131I-omburtamab) will require the presence of an appropriate intraventricular access
   device (e.g., programmable ventriculoperitoneal [VP] shunt or Ommaya reservoir).
   Patients are not required to have an existing programmable VP shunt or Ommaya at time
   of study enrollment but must be willing and able to undergo a surgical procedure to
   have one placed prior to Radioimmunotherapy. Note: Patients with an existing
   intraventricular VP shunt without a programmable component must be willing and able to
   undergo modification of the shunt before treatment with 131I-omburtamab.

   - Patients must have recurrent or refractory ependymoma after having received either
   focal or craniospinal irradiation (CSI) therapy, unless CSI is contraindicated or
   declined by the patient/family. There are no restrictions on the number of prior
   recurrences for this stratum. Note: Patients with contraindications to radiation
   therapy are still eligible.

   - Patients must have received their last dose of known myelosuppressive anticancer
   therapy at least 21 days prior to enrollment or at least 42 days if prior nitrosourea.

   - Biologic or investigational agent (anti-neoplastic) - Patients must have recovered
   from any acute toxicity potentially related to the agent and received their last dose
   of the investigational or biologic agent ≥ 7 days prior to study enrollment. 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.

   - Monoclonal antibody treatment and agents with known prolonged half-lives - Patients
   must have recovered from any acute toxicity potentially related to the agent and
   received their last dose of the agent ≥ 21 days prior to study enrollment.

   - Patients must have had their last fraction of:

      1. Craniospinal irradiation, whole brain radiation, total body irradiation or
      radiation to >= 50% of pelvis or spine 24 weeks prior to study enrollment. The
      tumor designated as "measurable" for protocol purposes must not have received
      radiation within 12 weeks prior to study enrollment.

      2. Focal radiation to areas of symptomatic metastatic disease 14 days prior to study
      enrollment.

   - Patients with neurological deficits should have deficits stable for a minimum of 1
   week prior to enrollment. A baseline detailed neurological exam should clearly
   document neurological status of the patient at time of study enrollment. Patients with
   seizure disorders may be enrolled if seizures are controlled and on non-enzyme
   inducing anticonvulsants. Patients must not be taking enzyme-inducing antiepileptic
   medicines within 1 week prior to study enrollment.

   - Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score
   (LPS for ≤ 16 years of age) assessed within 2 weeks prior to study enrollment must be
   ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who are up
   in a wheelchair, will be considered ambulatory for the purpose of assessing the
   performance score.

   - Organ Function

      1. Peripheral absolute neutrophil count (ANC) ≥ 1 x 10^9/ L (must not have received
      G-CSF within the 7 days prior to enrollment or pegfilgrastim within the 14 days
      prior to enrollment)

      2. Platelet count ≥ 100 x 10^9/ L (unsupported, defined as no platelet transfusion
      within 7 days prior to study enrollment)

      3. Hemoglobin ≥ 8.0 g/dL (may receive PRBC transfusions)

      4. Serum creatinine based on age/gender. Patients that do not meet the criteria but
      have a 24 hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70
      mL/min/1.73 m^2 are eligible.

      5. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age

      6. ALT (SGPT) and AST (SGOT) < 5 x institutional upper limit of normal (ULN) for age

   - HIV Infected Individuals - Patients who are known to be Human immunodeficiency virus
   (HIV)-infected must be on effective anti-retroviral therapy with undetectable viral
   load within 6 months prior to study enrollment.

   - Hep B Chronically Infected Individuals - For patients with known evidence of chronic
   hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on
   suppressive therapy, if indicated.

   - Hep C (HCV) Infected Individuals - Patients with a known history of hepatitis C virus
   (HCV) infection must have been treated and cured. Patients with known HCV infection
   who are currently on treatment are eligible if they have an undetectable HCV viral
   load.

   - Corticosteroids - Patients who are receiving dexamethasone at a stable or decreasing
   dose for at least 7 days prior to study enrollment are eligible.

   - Growth Factors - Patients must be off all colony- forming growth factor(s) for at
   least 1 week prior to enrollment (e.g., filgrastim, sargramostim or erythropoietin) or
   at least 2 weeks for pegfilgrastim.

   - Patients of childbearing or child fathering potential must be willing to use a
   medically acceptable form of birth control, which includes abstinence, while being
   treated on this study and for at least 40 days after the last dose of 131I-omburtamab.

   - The patient or parent/guardian can understand the consent and is willing to sign a
   written informed consent document according to institutional guidelines.

EXCLUSION CRITERIA FOR ENROLLMENT: Stratum 2

   - Pregnant women are excluded from this study due to risks of fetal and teratogenic
   adverse events as seen in animal/human studies. Female patients of childbearing
   potential must have a negative serum or urine pregnancy test prior to enrollment. If
   the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
   will be required.

   - Female patients who are breastfeeding are not eligible for this study unless they
   agree not to breastfeed.

   - Patients with any clinically significant unrelated systemic illness (serious
   infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) that
   in the opinion of the investigator would compromise the patient's ability to tolerate
   protocol therapy, put them at additional risk for toxicity or would interfere with the
   study procedures or results. Patients with a prior or concurrent malignancy whose
   natural history or treatment has the potential to interfere with the safety or
   efficacy assessment of the investigational regimen for this trial.

   - Patients who are receiving any other anti-cancer or investigational drug therapy are
   ineligible.

   - Patients who in the opinion of the investigator are unwilling or unable to return for
   required follow-up visits or obtain follow-up studies required to assess toxicity to
   therapy or to adhere to drug administration plan, other study procedures, and study
   restrictions.