FUS Etoposide for DMG - A Feasibility Study

Inclusion Criteria: Ages 4 - 21 years Radiological diagnosis of Diffuse Midline Glioma with tumor involving the pons (intrinsic, pontine based infiltrative lesion; hypointense on T1 weighted images (T1WIs) and hyperintense in T2 sequences, with mass effect on the adjacent structures and occupying at least 50% of the pons), thalami, and/or histological confirmation of H3K27M mutation of pontine or thalamic glioma. Subjects must have evidence of clinical and/or radiographic progression of disease. Lansky performance status score of at least 60 for subjects 16 years of age or younger. Karnofsky performance status of at least 60 for subjects greater than 16 years of age Organ Function: Adequate hematologic function defined as: Peripheral absolute neutrophil count ≥ 1,500/µL Platelet count ≥ 100,000/µL Partial thromboplastin time (PTT) and activated partial thromboplastin time (APTT): within normal institutional limits Adequate renal function defined as: Potassium and magnesium levels within institutional limits Serum creatinine below the institutional upper limit of normal (ULN) for age and gender, or creatinine clearance: ≥ 60 mL/min/1.73m2 Adequate hepatic function defined as: Total bilirubin below the institutional ULN for age Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN Prior Therapy: Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. Cytotoxic chemotherapy or anti-cancer agents known to be myelosuppressive: at least 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy. Anti-cancer agents not known to be myelosuppressive: at least 7 days must have elapsed from last dose of agent. Antibodies: at least 21 days must have elapsed from infusion of last dose of antibody. Interleukins, interferons, and cytokines: at least 21 days must have elapsed since the completion of interleukins, interferon, or cytokines. Stem cell infusions: at least 42 days must have elapsed after completion of an autologous stem cell infusion, and at least 84 days must have elapsed after completion of an allogeneic stem cell infusion. Cellular therapy: at least 42 days must have elapsed since the completion of any type of cellular therapy Radiotherapy (XRT): at least 1 month must have elapsed after local XRT. Subjects must be on a stable or decreasing dose of steroids, as well as stable dose of anti-seizure medication for at least 1 week. Subject able to give consent Exclusion Criteria: Subjects that have previously received etoposide therapy Subjects unable to tolerate study procedures and/or anesthesia based on the opinion of the principal investigator Uncontrolled seizure disorder Pregnancy or Breast-Feeding: pregnant or breast-feeding women will not be entered on this study, since there is yet no available information regarding human fetal or teratogenic toxicities; a pregnancy test must be obtained in girls who are post-menarchal. Males with female partners of reproductive potential or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control- including a medically accepted barrier method of contraception (e.g., a male or female condom) for the entire period in which they are receiving protocol therapy and for at least 1 month following their last study treatment requirement. Abstinence is an acceptable method of birth control. Women of childbearing potential will be provided a routine quantitative beta-human chorionic gonadotropin (B-hCG) test during the pre-study phase, prior to enrollment and each cycle. Concomitant medications: subjects who are currently receiving another investigational drug or other anti-cancer agents are not eligible. Screening EKG with a QTc > 450 msec. Subjects with evidence of active systemic infection Subjects with a documented allergy to compounds of similar chemical or biologic composition to etoposide or gadolinium compounds Subjects with implanted metallic or electrical devices Subjects with uncontrollable hypertension Subjects with a documented bleeding disorder Subjects with history of structural cardiac anomalies or arrhythmias Subjects with history of unprovoked stroke or signs of stroke in the area of FUS target Subjects with SARS-CoV-2 infection requiring hospitalization in the past month and requires anticoagulation as per the Columbia University Irving Medical Center (CUIMC) institutional "Anticoagulation for COVID-19 Positive Pediatric Inpatients" guidelines (See Appendix B) Subjects with coagulopathy or under anticoagulant therapy. Subjects with signs of impending herniation or an acute or previous intratumoral hemorrhage Subjects with spinal cord diffuse midline glioma Subjects receiving a drug where CNS toxicity is reasonably suspected