Therapeutic Targeting of Sex Differences in Pediatric Brain Tumor Glycolysis

Study Overview
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Brief Summary
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The investigators will develop the concept of a sex-specific therapeutic intervention for gliomas that is based upon dietary carbohydrate restriction. The investigators will integrate metabolomics tools and FDG-PET imaging to validate the ketogenic diet on a sex-specific basis.

Official Title
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Therapeutic Targeting of Sex Differences in Pediatric Brain Tumor Glycolysis

Conditions
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Pediatric Brain Tumor

Intervention / Treatment
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* Procedure: Ketogenic diet
* Drug: BCNU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of a recurrent primary brain tumor with no curative therapy available. Measurable disease using pediatric Response Assessment in Neuro-Oncology Criteria (RANO) criteria. Life expectancy > 12 weeks Prior treatment with radiation alone, chemotherapy alone or combined radiation and chemotherapy is allowed. Patient is < 21 years of age Normal bone marrow and organ function as defined below: Leukocytes ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcl Platelets ≥ 100,000/mcl Total bilirubin ≤ 1.5 x IULN AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Normal room air oxygenation must be documented. If room air oxygen saturation is less than 97%, a diffusion capacity of carbon monoxide (DLCO) of greater than 80%, must be demonstrated. Karnofsky or Lansky performance score of ≥ 60 Patients of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a female patient become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Patient does not have any of the following conditions as they are contraindicated for ketogenic diet: Primary and secondary carnitine deficiency Carnitine palmitoyltransferase I or II deficiency Carnitine translocase deficiency Mitochondrial β-oxidation defects Pyruvate carboxylase deficiency Glycogen storage diseases Ketolysis defects Ketogenesis defects Porphyria Prolonged QT syndrome Liver insufficiency Renal insufficiency Pancreatic insufficiency Pulmonary insufficiency Hyper insulinism Pregnant and/or breastfeeding. Female patients of childbearing potential must have a negative pregnancy test within 14 days of study entry.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketogenic Diet<br>Caregivers (and participating children) attend intro ketogenic diet class (4 - 30 min lectures) Clinic visit with neurologist, nurse, and dietitian prior to hospital admission and then once every 3 months Laboratory studies prior to hospital admission and then at each follow-up visit Hospital admission (3-5 day) to start the ketogenic diet Standard of care chemotherapy with BCNU for up to 2 years Ketogenic diet can continue for up to 2 years | Procedure: Ketogenic diet<br>* Children under 2 years will immediately start on a full calorie classical 3:1 ketogenic diet. The 3:1 ratio indicates that the diet contains 3 g of fat for every 1 g of protein + carbohydrate, which results in about 87% of calories coming from fat. Children 2 years or older will skip breakfast and lunch on the day of admission but start a full calorie 3:1 ketogenic diet at dinner.<br>Drug: BCNU<br>* -Standard of care<br>* Other names: BiCNU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of combining a ketogenic diet with chemotherapy in children with relapsed brain tumors as measured by the number of patients who can recruited with 3 years | The study will be defined as being feasible if all 15 patients can be recruited within 3 years Please note that feasibility of the study is dependent on both primary outcome measures | Through completion of enrollment of all participants (estimated to be 3 years) | 
| Feasibility of combining a ketogenic diet with chemotherapy in children with relapsed brain tumors as measured by if at least 80% of the patients comply with the intervention | -The study will be defined as being feasible if at least 80% of the patients comply with the intervention as defined as achieving 80% of the targeted level of ketosis as assessed from laboratory measures and 80% of the planned BCNU doses --Please note that feasibility of the study is dependent on both primary outcome measures | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of combining a ketogenic diet with chemotherapy in male children with relapsed brain tumors versus female children with relapsed brain tumors as measured by toxicity | All toxicities will be summarized by noting the count of participants who experience each toxicity The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting. | Up to 2 years | 
| Tumor response of male children with relapsed brain tumors to a ketogenic diet combined with chemotherapy versus female children with relapsed brain tumors as measured by progression-free survival (PFS) | PFS is defined as the duration of time from start of treatment to time of radiographic progression or death due to any cause, whichever occurs first. Progression will be defined by the Response Assessment in Neuro-Oncology (RANO) working group guideline. | Up to 10 years |