Targeting Pancreatic Cancer With Sodium Glucose Transporter 2 (SGLT2) Inhibition

Study Overview
=================
Brief Summary
-----------------
This is a first-in-human, pilot study of the feasibility and safety of dapagliflozin (in addition to standard of care treatment) for the treatment of patients with metastatic pancreatic ductal adenocarcinoma. The primary hypothesis is that dapagliflozin is well-tolerated and safe to use in this patient population. The investigators also hypothesize that dapagliflozin will be efficacious as an adjunct to front-line chemotherapy assessed by decreased tumor markers mediated by its pleiotropic metabolic effects.

Official Title
-----------------
Targeting Pancreatic Cancer With Sodium Glucose Transporter 2 (SGLT2) Inhibition

Conditions
-----------------
Pancreas Cancer, Pancreatic Cancer, Cancer of the Pancreas

Intervention / Treatment
-----------------
* Drug: Dapagliflozin
* Device: BIOSENSE meters


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed metastatic or locally advanced pancreatic ductal adenocarcinoma, pancreatic adenosquamous carcinoma or squamous cell carcinoma Patients with treated/stable brain metastases, defined as patients who have received prior therapy for their brain metastases and whose CNS disease is radiographically stable at study entry, are eligible. Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. No prior systemic therapy for pancreatic ductal adenocarcinoma in the metastatic or locally advanced setting. Planning to receive treatment with nab-paclitaxel and gemcitabine. 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 IULN AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN Estimated glomerular filtration rate eGFR ≥ 30 mL/min/1.73m^2 Because chemotherapeutic agents such as nab-paclitaxel and gemcitabine are known to be teratogenic, women of childbearing potential and men 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 woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and at least one month after completion of the study 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: History of total pancreatectomy Current or previous treatment with SGLT2i or thiazolidinedione. Currently receiving regularly scheduled systemic steroids in the form of prednisone or dexamethasone. Note that dexamethasone that can be prescribed for nausea on the day of chemotherapy, but in subsequent days will be replaced by a nonsteroidal anti-emetic for patients in this trial. 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). 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, nab-paclitaxel, gemcitabine 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 is an oral drug which will be administered on an outpatient basis. Dosing will start at 5 mg daily and will increase to 10 mg daily after 2 weeks (after consulation with a study endrocrinologist) if the patient is tolerating the 5 mg dose. Dapagliflozin will be given for a total of 8 weeks (2 weeks at 5 mg and 6 weeks at 10 mg) Treatment with dapagliflozin will be initiated on Cycle 1 Day 1 of standard of care chemotherapy. Participants will use the BIOSENSE meter once daily | Drug: Dapagliflozin<br>* Dapagliflozin will be provided for this trial<br>* Other names: Farxiga;Device: BIOSENSE meters<br>* -Being used in this trial to evaluate utility for assessing breath ketones<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability as Measured by Number of Participants With Related Adverse Events | Adverse events will be graded with CTCAE v. 5.0. Related indicates adverse events possibly, probably, or definitely related to treatment. | From start of treatment through 30 days after treatment (estimated to be 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Plasma Glucose |  | Screening, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, and End of Treatment (estimated to be 2 months) | 
| Changes in Ketones | -Patients are to collect and test ketones weekly while on treatment. | Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, and Cycle 2 Day 22 | 
| Changes in HbA1c |  | Screening and Cycle 2 Day 15 | 
| Changes in CA19-9 |  | Cycle 1 Day 1, Cycle 2 Day 1, and End of Treatment, up to 8 weeks | 
| Changes in Total Fat Volume in Visceral Fat Area as Assessed by CT-based Body Composition |  | From pre-treatment and post-8 weeks of treatment | 
| Changes in Total Skeletal Muscle Volume in Visceral Fat Area as Assessed by CT-based Body Composition |  | From pre-treatment and post-8 weeks of treatment | 
| Changes in Total Muscle to Fat Ratio in Visceral Fat Area as Assessed by CT-based Body Composition |  | From pre-treatment and post-8 weeks of treatment | 
| Changes in CT-quantified Tumor Size |  | From pre-treatment and post-8 weeks of treatment | 
| Change in Tumor Necrosis |  | From pre-therapy to post-8 weeks of therapy |