Neoadjuvant SGLT2 Inhibition in High-Risk Localized Prostate Cancer

Study Overview
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Brief Summary
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This is a study of the tolerability and safety of neoadjuvant dapagliflozin for patients with high-risk or very high risk prostatic adenocarcinoma prior to radical prostatectomy. The primary hypothesis is that four weeks of daily dapagliflozin prior to surgery is well-tolerated and safe to use in this patient population.

Official Title
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Pilot Clinical Trial of Neoadjuvant SGLT2 Inhibition in High-Risk Localized Prostate Cancer

Conditions
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Prostate Cancer, Cancer of Prostate

Intervention / Treatment
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* Drug: Dapagliflozin
* Device: BIOSENSE Meter


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed localized prostatic adenocarcinoma. Patients with primarily neuroendocrine/small cell histology will be excluded. Patients with high risk or very high risk prostatic adenocarcinoma as defined by NCCN criteria. High risk is defined by NCCN as meeting at least one of the following criteria: T3a grade group 4 or 5 PSA > 20 Very high risk is defined by NCCN as meeting at least one of the following criteria: T3b-T4 primary Gleason pattern 5 2-3 high risk features **> 4 cores with grade group 4 or 5 Willing and able to undergo prostate MRI at baseline, with a measurable prostate lesion present. Planning to undergo radical prostatectomy as primary treatment for localized prostate cancer. At least 18 years of age. ECOG performance status ≤ 1 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 institutional upper limit of normal (IULN) AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN Estimated glomerular filtration rate eGFR ≥ 30 mL/min/1.73m^2 Agreement to adhere to Lifestyle Considerations throughout study duration Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Current or previous treatment with SGLT2i or thiazolidinedione. Currently receiving regularly scheduled systemic steroids in the form of prednisone or dexamethasone (more than 10 mg prednisone daily or equivalent). Topical steroid ointments or creams for occasional skin rash is allowed. 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. History of stroke or transient ischemic attack in the last 5 years. Patients with type 1 diabetes mellitus will be excluded or patients with insulin-requiring diabetes mellitus will be excluded. Only patients with well-controlled type 2 diabetes mellitus will be allowed. HbA1c > 10%, unless approved by endocrinologist. Currently receiving any other investigational agents. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to dapagliflozin. 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. 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. Any evidence of pelvic instrumentation (i.e. hip arthroplasty) that would obscure and/or limit prostate MRI evaluation at the discretion of the investigator, or any type of medical device that would be incompatible with MRI imaging.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Dapagliflozin<br>Dapagliflozin will be initiated once daily approximately 6 weeks prior to planned prostatectomy Dapagliflozin will be given at 10 mg by mouth once daily for 4 weeks (days 1-28) prior to prostatectomy. | Drug: Dapagliflozin<br>* -The 10 mg dose is reflective of current clinical practice for diabetes and heart failure<br>* Other names: Farxiga;Device: BIOSENSE Meter<br>* BIOSENSE meters are investigational devices utilized in this trial to evaluate utility for assessing breath ketones in a non-invasive manner To be used once daily, prior to breakfast<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of toxicities related to dapagliflozin as measured by CTCAE v 5.0 |  | From start of treatment through day 64 | 
| Number of patients enrolled in 24 months | -Feasibility will be met if 24 patients are enrolled in 24 months | Through 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent reduction in prostate tumor size as determined by pre-operative prostate MRI |  | At the time of pre-operative prostate MRI (estimated to be at week 6) | 
| Percentage of prostate tumor necrosis |  | At the time of radical prostatectomy (estimated to be at week 6) | 
| Change in plasma glucose |  | From day 1 to day 29 | 
| Change in ketones |  | From day 1 to day 29 | 
| Change in HbA1C |  | From baseline to day 29 |