Non-Invasive Focused Ultrasound with Oral Etoposide for the Treatment of Children with Progressive/Recurrent Diffuse Midline Glioma

Inclusion Criteria

• Subjects must be ages 4 – 21 years.
• Subjects with 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.
• Peripheral absolute neutrophil count ≥ 1,500/uL.
• Platelet count ≥ 100,000/uL.
• Prothrombin time (PT) and activated partial thromboplastin time (APTT): within normal institutional limits.
• 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/1.73m^2 * Specific age and gender maximum creatinine as calculated below: ** 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 1.0; Female 1.0 *** 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 **** The threshold creatinine values derived from the Schwartz formula for estimating glomerular filtration rate (GFR).
• Total bilirubin below the institutional ULN for age.
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 × institutional ULN.
• 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 antiseizure medication for at least 1 week.
• Additional protections for children involved as research subjects, per Columbia University policy in accordance with Subpart D of both 45 Code of Federal Regulations (CFR) 46 and 21 CFR 50, are outlined as follows. No research involving children will be conducted without prior Institutional Review Board (IRB) approval. Adequate provisions will be made for soliciting the permission of the parents or guardian of each child involved in the research study. All requirements concerning informed consent apply to obtaining parental permission and the appropriate elements of consent must include a written informed consent document (i.e., a consent form that will apply to both adult participants in the study and parents of children).
• Adequate provisions will be made for soliciting the assent of all children involved in research when the children are capable of providing assent. Assent is required for all non-exempt research involving children aged 7 years or more unless the IRB determines that: (a) the capability of the child is so limited that he/she cannot be reasonably consulted (b) the research holds out the prospect of a direct benefit that is only available through participation in the research (i.e., research that offers a therapeutic benefit); or (c) all of the following factors are present and the IRB has specifically waived the requirement to obtain assent: the research involves no more than minimal risk; the waiver will not adversely affect the rights and welfare of the subjects; the research could not practically be carried out without the waiver; and, if appropriate, the subjects will be provided with additional pertinent information.
• Children will be given developmentally appropriate information about the research study in language that is understandable to them, given their age, maturity and previous experience. The provision of information will be a judgment made by the investigator. Any child who turns 18 during the course of the study must provide informed consent before his/her participation in the study continues.

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 postmenarchal. 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 electrocardiogram (EKG) with a corrected QT (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 MRI non compatible 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.
• 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 central nervous system (CNS) toxicity is reasonably suspected.