Intratumoral G207 with Radiation Therapy for the Treatment of Progressive or Recurrent High-Grade Gliomas

Inclusion Criteria

• Patients with a histologically confirmed diagnosis of high-grade glioma regardless of molecular characterization that is recurrent or progressive. All tumors must have histological verification at either the time of diagnosis or recurrence
• Patients are eligible following disease progression or recurrence after prior surgery and radiotherapy
• Supratentorial lesion must be ≥ 1.0 cm in longest dimension and surgically accessible as determined by contrast-enhanced MRI
• For patients with tumors > 4.0 cm without an adjacent cavity, the neurosurgeon must be 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 can be placed in each area of multifocal disease
• Tumor size will be determined using the maximal 2-dimensional cross-sectional tumor measurements, transverse x width, using either T1 images or T2/Fluid Attenuated Inversion Recovery (FLAIR) images for non-enhancing tumors
• Review of these MRI scans will be necessary to determine if the tumor location and size are such that the patient may undergo biopsy and catheter placement. The primary study team will be available as needed to review screening MRIs and support the local team with any clinical or eligibility-related questions
• Patient must be ≥ 3 at initial diagnosis but < 22 years of age at the time of enrollment on this study
• Patients must have received prior surgery and radiotherapy
• Patients must have recovered from the acute treatment-related toxicities of prior treatment (defined as ≤ grade 1 if not defined in eligibility criteria; excludes alopecia) prior to enrollment
• 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
• 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
• Monoclonal antibody treatment and agents with known prolonged half-lives: Patient must have received their last dose of the agent ≥ 21 days prior to study enrollment
• Immune effector cell (IEC) therapy (e.g., chimeric antigen receptor [CAR] T cells): For viral therapy or cellular therapy, patients must have received therapy ≥ 12 weeks prior to study enrollment
• Patients must have received their last fraction of standard radiation ≥ 12 weeks prior to enrollment. Patients must have received their last fraction of focal radiation to symptomatic metastatic sites or local palliative radiation ≥ 28 days prior to enrollment
• Patient must be: * ≥ 24 weeks since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease * ≥ 12 weeks since autologous stem cell transplant prior to enrollment
• Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment * A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study * Patients with seizure disorders may be enrolled if seizures are well-controlled
• Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 7 days 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
• Absolute neutrophil count > 1.0 x 10^9 cells/L
• Platelets > 100 x 10^9 cells/L (unsupported, defined as no platelet transfusion within 7 days)
• Hemoglobin ≥ 8 g/dL (may receive transfusions)
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT) ≤ 1.5 x ULN
• Alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) and aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) < 3 x institutional upper limit of normal (ULN)
• Albumin ≥ 3 g/dL
• Serum creatinine based on age/sex * Age 1 to < 2 years: Male 0.6; female 0.6 * Age 2 to < 6 years: Male 0.8; female 0.8 * Age 6 to < 10 years: Male 1; female 1 * Age 10 to < 13 years: Male 1.2; female 1.2 * Age 13 to < 16 years: Male 1.5; female 1.4 * Age ≥ 16 years: Male 1.7; female 1.4 ** Patients that do not meet the criteria but have a cystatin C, 24-hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m^2 are eligible
• Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 7 days prior to enrollment
• Patients must be off all colony-forming growth factor(s) for at least 1 week prior to enrollment (e.g., filgrastim, sargramostim, or erythropoietin). Two (2) weeks must have elapsed if the patient received a long-acting formulation
• The effects of G207 on the developing fetus are unknown. For this reason, 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 * Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately * Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of G207 administration
• 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

• 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 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
• 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 with primary tumor involving the cerebellum, brainstem or spinal cord, or that would require surgical access through a ventricle to deliver the prescribed protocol treatment
• Metastatic disease or diffuse, widespread, abnormal tumor pattern involving 3 or more lobes of the brain
• Tumor with evidence of clinically significant uncal herniation or midline shift, or evidence of ventricular obstruction from tumor or tonsillar herniation
• 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 undergo surgery and/or tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Known HIV seropositivity
• Diagnosis of encephalitis or central nervous system (CNS) infection < 12 weeks prior, or receiving ongoing treatment for encephalitis, CNS infection or multiple sclerosis
• Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible
• Patients who are receiving ≥ 2 mg of dexamethasone (or ≥ 10 mg of prednisone) daily * Patient requires an escalation in ongoing systemic corticosteroid therapy within 7 days prior to G207 inoculation * For this study, 'systemic corticosteroids' include oral, intravenous, or intramuscular formulations. A single, non-consecutive dose does not constitute exclusion. Physiologic corticosteroid replacement therapy (e.g., hydrocortisone for adrenal insufficiency), intermittent use of bronchodilators and topical steroids, is not considered immunosuppressive and does not constitute exclusion
• Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir)
• 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 the drug administration plan, other study procedures, and study restrictions