A Pilot Study of SurVaxM in Children Progressive or Relapsed Medulloblastoma, High Grade Glioma, Ependymoma and Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Screening Inclusion Criteria:

• • DIAGNOSIS: Patients with a histologically confirmed diagnosis of a primary CNStumor that is progressive or recurrent defined as radiographic progression in anyknown residual tumor, or the appearance of one or more new lesions, leptomeningealdisease, or new cerebrospinal fluid (CSF) positivity for malignant cells, after mostrecent treatment modality. At the time of diagnosis or recurrence, all tumors musthave histologic verification 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)

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.

• TUMOR TISSUE- 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.

• Age: Patients must be ≥ 1 year of age and ≤ 21 years of age at the time ofscreening.

• Screening Consent: Participant is willing to sign a screening consent. The screeningconsent is to be obtained according to institutional guidelines. Assent, whenappropriate, will be obtained according to institutional guidelines.

• Potential Eligibility for Study Enrollment: Patients screened for this trial shouldbe expected to meet the criteria for treatment.

Enrollment Inclusion Criteria:

• DIAGNOSIS: Patients with a histologically confirmed diagnosis of a primary 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, NOS

• Anaplastic oligodendroglioma

• Anaplastic ependymoma (WHO Grade III)

• Ependymoma (WHO Grade II)

Patients with newly diagnosed DIPG: 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 a typical DIPG on MR imaging, defined as a tumor with a pontineepicenter and diffuse involvement of more than 2/3 of the pons, are eligible withouthistologic confirmation. o Note: Patients with typical DIPG who undergo a biopsy are eligible provided thetumor is a diffuse glioma WHO Grade II-IV with OR without H3 K27M mutation.

• Patients with pontine lesions that do not meet these MR imaging criteria will beeligible if there is histologic confirmation of diffuse glioma WHO Grade II-IV withH3 K27M mutation.

• DEMONSTRATION OF SURVIVIN EXPRESSION: For patients with relapsed or progressivemedulloblastoma, HGG, or ependymoma, demonstration of survivin expression asassessed after screening consent/assent of at least 1% on tumor tissue byimmunohistochemistry (ICH) is required and must have been performed in the centrallaboratory at Roswell Park Comprehensive Cancer Center (RPCCC) to confirmeligibility. For patients with DIPG, diagnostic biopsy for histologic confirmationis not required, and tumor expression of survivin is therefore not required foreligibility for these patients.

• DISEASE STATUS: Patients must have evaluable disease within the central nervoussystem to be eligible. Evaluable disease includes either measurable ORnon-measurable disease, defined as follows:

Measurable disease: bi-dimensionally measurable disease; at least one lesion that can be accurately measured in at least two dimensions (per protocol guidelines).

• Non-measurable disease:

• A lesion that does not meet the criteria for measurable disease as definedabove; or

• diffuse leptomeningeal disease, or

• no tumor visible on imaging but presence of malignant cells on cytologicexamination of CSF.

• AGE:

• Stratum 1 (progressive or recurrent) patients must be ≥10 years of age and ≤ 21years of age at the time of study screening.

• Stratum 2 (progressive or recurrent) patients must be ≥1 year of age and < 10years of age at the time of study screening.

• Stratum 3 (newly diagnosed DIPG) patients must be ≥1 year of age and ≤ 21 yearsof age at the time of study enrollment

• PRIOR THERAPY

• Patients with recurrent or progressive disease must have received priorchemotherapy, and/or radiotherapy.

• Patients must have recovered from the acute treatment related toxicities (defined as ≤ Grade 1 if not defined in eligibility criteria; excludesalopecia) prior to entering this study.

• Patients with newly diagnosed DIPG must have completed radiation therapy

• CHEMOTHERAPY - Patients must have received their last dose of known myelosuppressiveanticancer therapy at least 21 days prior to enrollment or at least 42 days ifnitrosourea. Patients must have received their last dose of non-myelosuppressivechemotherapy at least 7 days prior to enrollment.

• INVESTIGATIONAL/ BIOLOGIC AGENT:

• Biologic or investigational agent (anti-neoplastic): Patient must haverecovered from any acute toxicity potentially related to the agent and receivedtheir last dose of the investigational or biologic agent ≥ 7 days prior tostudy enrollment.

• For agents that have known adverse events occurring beyond 7 days afteradministration, this period must be extended beyond the time during whichadverse 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 theagent and received their last dose of the agent ≥ 28 days prior to studyenrollment.

• RADIATION:

• Recurrent or Progressive CNS tumor patients must have had their last fractionof:

• Craniospinal irradiation, whole brain radiation, total body irradiation orradiation to spine ≥ 6 weeks (42 days) prior to enrollment.

• Focal irradiation ≥ 14 days prior to enrollment.

• DIPG Patients: Patients with DIPG are eligible after completion of initialradiotherapy (with or without concurrent treatment) and in the absence ofprogressive disease on post-radiation imaging.

• Patients must have completed radiation therapy at least 14 days prior toenrollment but no longer than 56 days and cannot have received any othertumor-directed treatment except the following: Patient may have receivedtemozolomide or other non-investigational agents during irradiation at thetreating physician's discretion. If the patient has received such agentsconcurrently with radiation, then patient must have recovered from the acutetreatment related toxicities (defined as < Grade 1) prior to enrollment.

• CELLULAR THERAPY: Patient must be:

• ≥ 6 months since allogeneic stem cell transplant prior to enrollment with noevidence of active graft 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 toenrollment.

• CRANIAL SURGERY: Patients who have had recent cranial surgery (VP shunt, ETV, tumorresection) are eligible for inclusion, but the vaccine may not be administered priorto post-operative Day 14.

• NEUROLOGIC STATUS: Patients with neurological deficits should have deficits that arestable for a minimum of 1 week prior to enrollment. A baseline neurological examshould clearly document the neurological status of the patient at the time ofenrollment on the study.

• PERFORMANCE STATUS - Karnofsky Performance Scale (KPS for > 16 years of age) orLansky Performance Score (LPS for ≤ 16 years of age) assessed within 2 weeks priorto enrollment must be ≥ 60%. Patients who are unable to walk because of neurologicdeficits, but who are up in a wheelchair, will be considered ambulatory for thepurpose of assessing the performance score.

• ORGAN FUNCTION - Patients must have adequate organ and marrow function as definedbelow:

• Absolute neutrophil count ≥ 0.75 x 109 cells/L

• Platelets ≥ 100 x 109 cells/L (unsupported, defined as no platelet transfusionwithin 7 days prior to enrollment)

• Hemoglobin ≥ 8 g/dl (may receive transfusions)

• PT/INR, PTT ≤ 1.5 x ULN

• Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)

• ALT(SGPT) ≤ 3 x institutional upper limit of normal

• Albumin ≥ 2 g/dl

• Blood creatinine based on age/gender as noted below. Patients that do not meetthe criteria below but have a 24-hour Creatinine Clearance or GFR (radioisotopeor iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. Maximum Serum Creatinine forage/gender:

• Age 1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female)

• Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)

• Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)

• Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)

• Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)

• Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)

• INFECTIOUS DISEASES

• Human Immunodeficiency Virus (HIV) Infected Individuals: Patients who are knownto be Human immunodeficiency virus (HIV)-infected must be on effectiveanti-retroviral therapy with undetectable viral load for 6 months prior tostudy enrollment.

• Hepatitis B Chronically Infected Individuals: For patients with known evidenceof chronic hepatitis B virus (HBV) infection, the HBV viral load must beundetectable on suppressive therapy, if indicated.

• Hepatitis C (HCV) Infected Individuals: Patients with a known history ofhepatitis C virus (HCV) infection must have been treated and cured. Patientswith known HCV infection who are currently on treatment are eligible if theyhave an undetectable HCV viral load.

• CORTICOSTEROIDS: Patients who are receiving dexamethasone must be on a stable ordecreasing dose for at least 1 week prior to enrollment. A maximum dose of 0.1mg/kg/day (and maximum total daily dose 4 mg) of dexamethasone (or equivalent) ispermitted at study entry. Effort should be made to reduce to lowest toleratedsteroid 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.

• GROWTH FACTORS - Patients must be off all colony-forming growth factor(s) for atleast 14 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin).Two (2) weeks must have elapsed if the patient received a long-acting formulation.

• PREGNANCY - Pregnant women or nursing mothers are excluded from this study becauseSurVaxM is an agent with the potential for teratogenic effects. Female patients ofchildbearing potential must have a negative serum or urine pregnancy test. If theurine test is positive or cannot be confirmed as negative, a serum pregnancy testwill be required.

• PREGNANCY PREVENTION - Patients of childbearing or child fathering potential must bewilling to use a medically acceptable form of birth control, which includesabstinence, while being treated on this study.

• INFORMED CONSENT - The patient or parent/guardian is able to understand the consentand is willing to sign a written informed consent document according toinstitutional guidelines. Assent, when appropriate, will be obtained according toinstitutional guidelines.

Exclusion Criteria:

• • BREAST FEEDING WOMEN - Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with SurVaxMbreastfeeding should be discontinued if the mother is treated with SurVaxM. Femalepatients who are breastfeeding are not eligible for this study unless they agree notto breastfeed.

Excluded Diagnoses:

• Patients with spinal cord primary tumors

• Patients with relapsed or progressive DIPG

• Patients with metastatic disseminated DIPG are not eligible. MRI of spine must beperformed if disseminated disease is suspected by the treating physician.

• Patients with midline high grade gliomas including those with H3 K27M-altereddiffuse midline glioma (DMG) centered outside of the pons

• Patients with Grade II myxopapillary ependymoma

• Patients with WHO Grade I or II gliomas are not eligible unless tumor is defined asDIPG as per above.

• Patients with bone-only metastatic lesions that do not have otherwise evaluable CNSdisease.

Bulky Disease

Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as any of the following:

• Tumor with evidence of clinically significant tonsillar herniation

• Tumor with evidence of clinically significant uncal herniation causing midbraincompression or midline shift greater than 5 mm

• Tumor with a diameter >4cm in one dimension on T2/FLAIR

• Tumor that in the opinion of the site investigator, shows significantly rapidprogression of mass effect in either the brain or spinal cord such that the primingphase of vaccination (i.e., 6 weeks) cannot be completed before clinicaldeterioration is likely to occur.

Treating physicians should contact the Study Chair to request a rapid central imaging review to confirm fulfilment of these eligibility criteria, if they have concerns. If clinically appropriate, surgical debulking of large tumors should be considered before study entry.

Concurrent Illness:

• Active, uncontrolled infection requiring treatment (including HIV infection)

• Patients with active autoimmune disease or documented history of autoimmunedisease/syndrome that requires ongoing systemic steroids or systemicimmunosuppressive agents, with the exception of:

• Patients with vitiligo or resolved asthma/atopy

• Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome

• History of or ongoing pneumonitis or significant interstitial lung disease

• Patients with any clinically significant unrelated systemic illness (significantcardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of theinvestigator would compromise the patient's ability to tolerate protocol therapy,put them at additional risk for toxicity or would interfere with the studyprocedures or results.

• Patients with a prior or concurrent malignancy whose natural history or treatmenthas the potential to interfere with the safety or efficacy assessment of theinvestigational regimen for this trial.

• Any medical condition that, in the opinion of the Principal Investigator, wouldcompromise the patient's ability to participate in the study.

• CONCOMITANT MEDICATIONS:

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

• Patients who are receiving any cannabidiol (CBD) or medical marijuana treatment areineligible.

• Patients who have received the last vaccination of a live vaccine ≤ 30 days prior toenrollment are ineligible. Examples of live vaccines include, but are not limitedto, the following: measles, mumps, rubella, varicella, yellow fever, rabies, BCG,and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generallykilled virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,Flu-Mist®) are live attenuated vaccines and must meet timeline for live vaccine.

• Patients who have received an inactivated virus, peptide, or mRNA vaccine within 14days of the start of protocol therapy are ineligible.

• Patients may not be on immunosuppressive therapy, including corticosteroids (exceptas defined in the corticosteroids inclusion criteria) at time of enrollment.However, patients who require intermittent use of bronchodilators, local steroidinjections, or topical steroids will not be excluded from the study.

• Patients may not be receiving concomitant chemotherapy, immunotherapy, radiotherapy,radiosurgery, interferon, allergy desensitization injections, growth factors,interleukins, or any investigational therapeutic medication at the time ofenrollment.

• INABILITY TO PARTICIPATE: Patients who in the opinion of the investigator areunwilling or unable to return for required follow-up visits or obtain follow-upstudies required to assess toxicity of therapy or to adhere to drugadministration plan, other study procedures, and study restrictions.

• ALLERGY: Known allergy or hypersensitivity to Keyhole Limpet Hemocyanin (KLH),granulocyte colony-macrophage stimulating factor (sargramostim) or MRI contrastagent.

• BLEEDING DISORDER: Patients with a known coagulopathy or bleeding diathesis orrequires the use of systemic, anticoagulant medication are not eligible.