Summary

This phase I trial studies the side effects of SurVaxM in treating children and young adults with brain tumors that are newly diagnosed, have come back (relapsed), or have spread to other places in the body (metastatic). SurVaxM is designed to tell the body’s immune system to look for tumor cells that express a protein called survivin and destroy them. The survivin protein can be found on up to 95% of glioblastomas and other types of cancer but is not found in normal cells. If the body’s immune system knows to destroy cells that express survivin, it may help to control tumor growth and recurrence. This trial is studying a vaccine called SurVaxM combined with Montanide ISA 51 to see if it is safe and tolerated without severe side effects in children.

Objectives

PRIMARY OBJECTIVE:
I. To assess the toxicity profile of SVN53-67/M57-KLH peptide vaccine (SurVaxM) in emulsion with incomplete Freund's adjuvant (Montanide) plus sargramostim in children with relapsed or progressive medulloblastoma and high-grade glioma (HGG), ependymoma and non-recurrent diffuse intrinsic pontine glioma (DIPG) post-radiation therapy (RT).

SECONDARY OBJECTIVES:
I. To examine the ability of quantitative magnetic resonance (MR) diffusion weighted imaging/apparent diffusion coefficient (ADC) mapping to provide early assessment of tumor behavior and specifically distinguish pseudoprogression/tumor inflammation from tumor progression.
II. To explore the use of serial MR permeability (dynamic contrast-enhanced [DCE]) and MR perfusion (dynamic susceptibility contrast [DSC]) to determine if elevated relative cerebral blood volume (rCBV) and vascular permeability (ktrans) can distinguish pseudoprogression/tumor inflammation from tumor progression in tumors treated on this protocol.

EXPLORATORY OBJECTIVES:
I. To measure survivin-specific antibody and T cell responses to SurVaxM in emulsion with Montanide ISA 51 plus sargramostim in children with relapsed or progressive medulloblastoma, high grade glioma (HGG), ependymoma and non-recurrent DIPG post RT.
II. To describe the preliminary efficacy of the proposed regimen via radiographic response rates, progression free survival (PFS) and overall survival (OS) in the context of a pilot study.
III. To evaluate humoral immune responses and human leukocyte antigen (HLA) genotype in relationship to cellular measured immune responses in pediatric patients receiving SurVaxM vaccine.
IV. To assess tumor response using Response Assessment in Pediatric Neuro-Oncology (RAPNO) published criteria for medulloblastoma, HGG, DIPG in comparison to modified Macdonald response criteria.

OUTLINE:
Patients receive SurVaxM and Montanide ISA 51 mixture subcutaneously (SC) followed by sargramostim (or biosimilar) given as a separate SC injection every 2 weeks for 6 weeks. Starting week 9, patients receive SurVaxM and Montanide ISA 51 mixture SC followed by sargramostim (or biosimilar) given SC every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

Patients undergo magnetic resonance imaging (MRI) and blood sample collection throughout the study.

Eligibility

1. SCREENING: Progressive or Recurrent Patients: Patients with a histologically confirmed diagnosis of a primary central nervous system (CNS) tumor that is progressive or recurrent defined as progression in any known residual tumor, or the appearance of one or more new lesions, or new cerebrospinal fluid (CSF) positivity for malignant cells, after having failed standard therapy. At the time of diagnosis or recurrence, all tumors must have histologic verification of one of the following: * Medulloblastoma * Glioblastoma multiforme (GBM) * Anaplastic astrocytoma * High-grade astrocytoma, not otherwise specified (NOS) * Anaplastic oligodendroglioma * Anaplastic ependymoma (World Health Organization [WHO] grade III) * Ependymoma (WHO grade II)
2. SCREENING: Diffuse Intrinsic Pontine Gliomas (DIPG) Patients: Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible without histologic confirmation and will proceed directly to enrollment without screening
3. SCREENING: Patients must provide tumor tissue (3 unstained slides or paraffin block) to determine their survivin expression status. Demonstration of survivin expression of at least 1% on tumor tissue by immunohistochemistry is required and must be performed in the central laboratory at Roswell Park Comprehensive Cancer Center (RPCCC) to confirm eligibility
4. SCREENING: Patients must be >= 1 year of age and =< 21 years of age at the time of screening
5. SCREENING: Participant is willing to sign a screening consent. The screening consent is to be obtained according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines
6. SCREENING: Patients screened for this trial should be expected to meet the criteria for treatment below
7. Histologic diagnosis (at initial diagnosis or recurrence) of one of the following: * Medulloblastoma * Glioblastoma multiforme (GBM) * Anaplastic astrocytoma * High-grade astrocytoma, NOS * Anaplastic oligodendroglioma * Anaplastic ependymoma (WHO Grade III) * Ependymoma (WHO Grade II)
8. Patients with diffuse intrinsic pontine gliomas (DIPGs) will be eligible 14 to 56 days post-completion of radiation therapy if they do not have any evidence of progression. Patients with diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible without histologic confirmation. Patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors have been biopsied and are proven to be a glioblastoma multiforme (GBM), or astrocytoma (grade II or grade III).
9. For patients with relapsed or progressive medulloblastoma, HGG, or ependymoma, demonstration of survivin expression as assessed after screening consent/assent of at least 1% on tumor tissue by immunohistochemistry (ICH) is required and must have been performed in the central laboratory at Roswell Park Comprehensive Cancer Center (RPCCC) to confirm eligibility. For patients with DIPG, diagnostic biopsy for histologic confirmation is not required, and tumor expression of survivin is therefore not required for eligibility for these patients
10. Patients must have either measurable or evaluable disease. Patients with recurrent or progressive medulloblastoma, GBM, anaplastic astrocytoma, high grade astrocytoma (NOS), anaplastic oligodendroglioma, anaplastic ependymoma (WHO grade III) or ependymoma (WHO grade II) with metastatic disease or leptomeningeal disease are eligible so long as there is clear MRI evidence of evaluable disease
11. Stratum 1 (progressive or recurrent) patients must be >= 10 years of age and =< 21 years of age at the time of study screening
12. Stratum 2 (progressive or recurrent) patients must be >= 1 year of age and < 10 years of age at the time of study screening
13. Stratum 3 (newly diagnosed DIPG) patients must be >= 1 year of age and =< 21 years of age at the time of study enrollment
14. Patients with recurrent or progressive disease must have received prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality
15. Patients with newly diagnosed DIPG must have completed radiation therapy
16. Patients must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria; excludes alopecia) prior to entering this study
17. 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 nitrosourea. Patients must have received their last dose of non-myelosuppressive chemotherapy at least 7 days prior to enrollment
18. Biologic or investigational agent (anti-neoplastic): Patient must have 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
19. Monoclonal antibody treatment and agents with known prolonged half-lives: Patient must have received their last dose of the agent >= 28 days prior to study enrollment.
20. Patients with recurrent or progressive CNS tumor must have had their last fraction of: * Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to spine >= 6 weeks (42 days) prior to enrollment. * Focal irradiation >= 14 days prior to enrollment
21. Patients with DIPG are eligible after completion of initial radiotherapy (with or without concurrent treatment) and in the absence of progressive disease. Patients must have completed radiation therapy at least 14 days prior to enrollment but no longer than 56 days and cannot have received any other tumor-directed treatment except the following: * Patient may have received temozolomide or other non-investigational agents during irradiation at the treating physician’s discretion. If the patient has received such agents concurrently with radiation, then patient must have recovered from the acute treatment related toxicities (defined as < grade 1) prior to enrollment
22. Patient must be: * >= 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease. * >= 3 months since autologous stem cell transplant prior to enrollment. * > 42 days since completion of any other type of adoptive cellular therapy prior to enrollment
23. Patients must be at least 14 days from recent cranial surgery (ventriculoperitoneal [VP] shunt, endoscopic third ventriculostomy [ETV], tumor resection) at the time of enrollment
24. Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study
25. 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 enrollment must be >= 60. 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
26. Absolute neutrophil count >= 0.75 x 10^9 cells/L
27. Platelets >= 100 x 10^9 cells/L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
28. Hemoglobin >= 8 g/dL (may receive transfusions)
29. Prothrombin time (PT)/institutional normalized ratio (INR), partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =< 1.5 x upper limit of normal (ULN)
30. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
31. Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x institutional upper limit of normal (ULN)
32. Albumin >= 2 g/dL
33. Blood creatinine based on age/gender. Patients that do not meet the criteria but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible. * Age 1 to < 2 years, maximum blood creatinine (mg/dL) male 0.6, female 0.6 * Age 2 to < 6 years, maximum blood creatinine (mg/dL) male 0.8, female 0.8 * Age 6 to < 10 years, maximum blood creatinine (mg/dL) male 1, female 1 * Age 10 to < 13 years, maximum blood creatinine (mg/dL) male 1.2, female 1.2 * Age 13 to < 16 years, maximum blood creatinine (mg/dL) male 1.5, female 1.4 * Age >= 16 years, maximum blood creatinine (mg/dL) male 1.7, female 1.4
34. Patients who are known to be Human immunodeficiency virus (HIV)-infected must be on effective anti-retroviral therapy with undetectable viral load for 6 months prior to study enrollment
35. For patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
36. 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
37. Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment. A maximum dose of 0.1 mg/kg/day (and maximum total daily dose 4 mg) of dexamethasone (or equivalent) is permitted at study entry. Effort should be made to reduce to lowest tolerated steroid dose. Patients must be willing to use brief courses (at least 72 hours) of steroids as directed for potential inflammatory side effects of the therapy if recommended by their treating physician
38. Patients must be off all colony-forming growth factor(s) for at least 14 days prior to enrollment (e.g., filgrastim, sargramostim, or erythropoietin). Two (2) weeks must have elapsed if the patient received a long-acting formulation
39. Pregnant women or nursing mothers are excluded from this study because SurVaxM is an agent with the potential for teratogenic effects. Female patients of childbearing potential must have a negative serum or urine pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
40. 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
41. The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines