Targeting Pediatric Brain Tumors With Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i)

Study Overview
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Brief Summary
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This is a longitudinal, dose-finding, open label safety and tolerability phase Ib treatment study. The study hypothesis is that dapagliflozin will be well-tolerated by brain tumor patients on chemotherapy as assessed by tolerability and side effect profiles.

Official Title
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Targeting Pediatric Brain Tumors With Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i)

Conditions
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Pediatric Brain Tumor

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Carmustine


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 between 6 and 21 years old (inclusive) 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 legal guardian/legally authorized representative, if applicable). Exclusion Criteria: Current or previous treatment with SGLT2i or thiazolidinedione. Current use of high dose dexamethasone (exceeding 4 mg/day). Seven days prior to start of dapagliflozin and carmustine, patients receiving dexamethasone must be on a stable or decreasing dose (≤ 0.1 mg/kg/day or maximum 4 mg/day). Note that it is preferred that patients not be on dexamethasone during the study. A history of other malignancy with the exceptions of malignancies for which all treatment was completed at least 2 years before registration with no evidence of disease and locally treated skin squamous or basal cell carcinoma. Type 1 diabetes or current insulin treatment. History of stroke or transient ischemic attack (in the last 5 years). HbA1c > 8.5%. The rationale is that this is the level that would require addition of insulin. However, insulin use is excluded in this study due to the increased risk of ketoacidosis. Currently receiving any other investigational agents. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to dapagliflozin, carmustine or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, peripheral arterial disease, ketoacidosis, severe kidney disease (estimated glomerular filtration rate eGFR < 30 mL/min/1.73m2), symptomatic hypotension, and chronic/frequent urinary tract infections or yeast infections. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.

Ages Eligible for Study
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Minimum Age: 6 Years
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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin + Standard of Care carmustine chemotherapy (Ages 6-10)<br>Dapagliflozin will be initiated by mouth once daily at the same time as standard of care carmustine chemotherapy. Dapagliflozin 5 mg by mouth once daily on days 1-84 (duration of study) All patients will stop taking dapagliflozin after 12 weeks of treatment, corresponding to 2 cycles of carmustine. Carmustine chemotherapy dose adjustments will be made per oncologist's judgement. | Drug: Dapagliflozin<br>* Commercially available<br>Drug: Carmustine<br>* Standard of care<br>|
| Experimental: Dapagliflozin + Standard of Care carmustine chemotherapy (Ages 11-21)<br>Dapagliflozin will be initiated by mouth once daily at the same time as standard of care carmustine chemotherapy. Dapagliflozin will be initiated at 5 mg by mouth once caily, days 1-4 (2 weeks) Dapagliflozin will be escalated to 10 mg by mouth once daily for the remaining 10 weeks Dose adjustment will need to be approved by endocrinologist Dr. Sprague/or another attending MD diabetologist at SLCH/WUSM on the HRPO-approved study team. This dose is reflective of current clinical practice for diabetes and heart failure. All patients will stop taking dapagliflozin after 12 weeks of treatment, corresponding to 2 cycles of carmustine. Carmustine chemotherapy dose adjustments will be made per oncologist's judgment. | Drug: Dapagliflozin<br>* Commercially available<br>Drug: Carmustine<br>* Standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and type of adverse events experienced by participants | -Adverse events will be graded by CTCAE (version 5.0). | From start of treatment through 30 days after last day of dapagliflozin treatment (estimated to be 4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood glucose |  | From baseline through end of treatment (estimated to be 3 months) | 
| Change in ketones |  | From baseline through end of treatment (estimated to be 3 months) | 
| Change in HbA1c |  | From baseline through end of treatment (estimated to be 3 months) | 
| Tumor response rate | Tumor response will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline. Tumor response rate = number of participants with complete or partial response. | From pre-therapy to post-12 weeks of therapy | 
| Feasibility of regimen | -Feasibility is defined as the successful enrollment of a total of 20 evaluable patients to the study within 3 years and the optimal dose of dapagliflozin is at least 5 mg. | Through completion of treatment for all enrolled patients (estimated to be 39 months) | 
| Changes in fructosamine |  | From baseline through end of treatment (estimated to be 3 months) | 
| Changes in c-peptide |  | From baseline through end of treatment (estimated to be 3 months) | 
| Changes in glucagon |  | From baseline through end of treatment (estimated to be 3 months) |