HSV G207 with a Single Radiation Dose in Children with Recurrent High-Grade Glioma

Treatment Inclusion Criteria:

Patients meeting the following inclusion criteria will be eligible for the study:

• Patients must have a histologically confirmed diagnosis of high-grade gliomaregardless of molecular characterization that is recurrent or progressive. Alltumors must have histologic verification at either the time of diagnosis orrecurrence.

• Patients are only eligible after their first progression following prior surgery andradiotherapy

• Supratentorial lesion must be ≥ 1.0 cm in longest dimension and surgicallyaccessible as determined by contrast-enhanced MRI

• For patients with tumors > 4.0 cm without an adjacent cavity, the neurosurgeon mustbe confident that the tumor can be debulked to ≤ 4.0 cm for eligibility.

• Multifocal disease on the ipsilateral side is eligible if at least one catheter canbe placed in all multifocal areas

• Tumor size will be determined using the maximal 2-dimensional cross-sectional tumormeasurements, transverse x width, using either T1 images or T2/FLAIR images fornon-enhancing tumors.

• Patient must be ≥ 3 at initial diagnosis but < 22 years of age at the time ofenrollment on this study.

• Prior therapy: Patients must have received prior surgery and radiotherapy andrecovered from the acute treatment related toxicities (defined as ≤ Grade 1 if notdefined in eligibility criteria; excludes alopecia) prior to enrollment.

• 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.

• Biologic or investigational agents (anti-neoplastic): patients must have receivedtheir last dose of the investigational or biologic agent ≥ 7 days prior to studyenrollment. For agents that have known adverse events occurring beyond 7 days afteradministration, this period must be extended beyond the time during which adverseevents are known to occur.

• Monoclonal antibodies and agents with known prolonged half-lives: Patient must havereceived their last dose of the agent ≥ 28 days prior to study enrollment.

• Immune Effector Cell (IEC) Therapy (e.g., CAR T cells): For viral therapy orcellular therapy, patients must have received therapy ≥ 3 months prior to studyenrollment.

• Radiation: Patients must have received their last fraction of standard radiation ≥ 3months prior to study entry.

• Stem Cell Transplant: 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.

• Patients with neurological deficits should have deficits that are stable for aminimum of 1 week prior to enrollment. A baseline detailed neurological exam shouldclearly document the neurological status of the patient at the time of enrollment onthe study.

• Patients with seizure disorders may be enrolled if seizures are well controlled.

• Karnofsky Performance Scale (KPS for children > 16 years of age) or LanskyPerformance Score (LPS for children ≤ 16 years or age) assessed within 7 days 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.

• Patients must have adequate organ and marrow function as defined below:

• Absolute neutrophil count > 1.0 x 109 cells/L

• Platelets > 100 x 109 cells/L (unsupported, defined as no platelet transfusionwithin 7 days)

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

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

• PT/INR, PTT ≤ 1.5 x ULN

• ALT(SGPT) and AST (SGOT) < 3 x institutional upper limit of normal (ULN)

• Albumin ≥ 3 g/dL

• Serum creatinine based on age/gender as noted in Table 2. Patients that do notmeet the criteria in Table 2 but have a Cystatin C, 24-hour CreatinineClearance or GFR (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 areeligible.

Age Maximum Serum Creatinine (mg/dL): 1 to < 2 years: Male 0.6, Female 0.6; 2 to < 6 years: Male 0.8, Female 0.8, 6 to < 10 years: Male 1, Female 1; 10 to < 13 years: Male 1.2, Female 1.2; 13 to < 16 years: Male 1.5 Female 1.4; ≥ 16 years: Male 1.7, Female 1.4

• Corticosteroids: Patients who are receiving dexamethasone must be on a stable ordecreasing dose for at least 1 week prior to enrollment.

• Growth Factors: Patients must be off all colony-forming growth factor(s) for atleast 1 week prior to enrollment (e.g., filgrastim, sargramostim, orerythropoietin). Two (2) weeks must have elapsed if the patient received along-acting formulation.

• 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.

Exclusion Criteria:

Pregnant women are excluded from this study. 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. Pregnant women are excluded from this study because G207 is an agent with the potential for teratogenic or abortifacient effects.

Lactating females are not eligible unless they have agreed not to breastfeed their infants. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with G207, breastfeeding should be discontinued if the mother is treated with G207.

Concurrent Illness

• Patients with any clinically significant unrelated systemic illness (seriousinfections or significant cardiac, pulmonary, hepatic or other organ dysfunction),that in the opinion of the investigator would compromise the patient's ability toundergo surgery and/or tolerate protocol therapy, put them at additional risk fortoxicity or would interfere with the study procedures or results.

• Known HIV seropositivity.

• 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.

• Patients with a secondary high-grade glioma are ineligible.

• Patient with primary tumor involving the cerebellum, brainstem or spinal cord orthat would require surgical access through a ventricle in order to deliver theprescribed protocol treatment.

• Metastatic disease or diffuse, widespread, abnormal tumor pattern involving 3 ormore lobes of the brain

• Tumor with evidence of clinically significant uncal herniation or midline shift, orevidence of ventricular obstruction from tumor or tonsillar herniation

• Diagnosis of encephalitis or CNS infection < 3 months prior, or receiving ongoingtreatment for encephalitis, CNS infection, or multiple sclerosis

Concomitant Medications

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

• Patients who are receiving ≥ 1.5 mg of dexamethasone (or ≥ 10 mg of prednisone)daily

• Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir,penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir)

• Patients may not be on immunosuppressive therapy, including corticosteroids (exceptfor patients receiving < 1.5 mg of dexamethasone or < 10 mg of prednisone daily) attime of enrollment. However, patients who require intermittent use ofbronchodilators or topical steroids will not be excluded from the study.

Inability to participate: 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.

Prior Cranial Spinal Irradiation: Patients who received cranial spinal irradiation (CSI) are ineligible.