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

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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer; Pancreas Cancer; Cancer of the Pancreas
• Intervention / Treatment: Drug: Dapagliflozin; Device: BIOSENSE meters

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Dapagliflozin; 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; Dapagliflozin will be provided for this trial; Other Names: Farxiga; Device: BIOSENSE meters; -Being used in this trial to evaluate utility for assessing breath ketones

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 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
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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH)

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 25, 2021
• Primary Completion (ACTUAL): December 24, 2021
• Study Completion (ACTUAL): January 19, 2022

Study Registration Dates

• First Submitted: September 1, 2020
• First Submitted That Met QC Criteria: September 8, 2020
• First Posted (ACTUAL): September 9, 2020

Study Record Updates

• Last Update Posted (ESTIMATE): February 14, 2023
• Last Update Submitted That Met QC Criteria: January 17, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 202011019; 1P50CA196510-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No