Cancer of the Pancreas, Pancreas Cancer, Pancreatic Cancer
Conditions
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.
Interventions
DRUGDapagliflozin
Dapagliflozin will be provided for this trial
DEVICEBIOSENSE meters
-Being used in this trial to evaluate utility for assessing breath ketones
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability as Measured by Number of Participants With Related Adverse Events | From start of treatment through 30 days after treatment (estimated to be 3 months) | * Adverse events will be graded with CTCAE v. 5.0. * Related indicates adverse events possibly, probably, or definitely related to treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Ketones | 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 | -Patients are to collect and test ketones weekly while on treatment. |
| 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 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 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 | — |
| 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 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | Dapagliflozin |
|---|---|
| Age, Continuous | 68 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 5 / 15 |
Outcome results
Primary
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.
Time frame: From start of treatment through 30 days after treatment (estimated to be 3 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Anemia | 15 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Atrial fibrillation | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Colitis | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Constipation | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Diarrhea | 6 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Dry mouth | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Nausea | 5 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Vomiting | 3 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Chills | 2 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Edema limbs | 2 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Fatigue | 6 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Fever | 2 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Sepsis | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Skin infection | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Alanine aminotransferase increased | 8 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Alkaline phosphatase increased | 5 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Aspartate aminotransferase increased | 6 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Lymphocyte count decreased | 7 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Neutrophil count decreased | 7 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Platelet count decreased | 12 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | White blood cell decreased | 10 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Anorexia | 5 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Hypoalbuminemia | 2 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Hyponatremia | 2 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Dysgeusia | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Headache | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Peripheral sensory neuropathy | 4 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Chronic kidney disease | 2 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Proteinuria | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Alopecia | 11 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Hyperhidrosis | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Pruritus | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Rash maculo-papular | 2 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Rash on arm | 1 Participants |
| Dapagliflozin | Tolerability as Measured by Number of Participants With Related Adverse Events | Hypotension | 1 Participants |
Secondary
Change in Tumor Necrosis
Time frame: From pre-therapy to post-8 weeks of therapy
Population: The CT scans were unable to determine the scope of tumor necrosis.
Secondary
Changes in CA19-9
Time frame: Cycle 1 Day 1, Cycle 2 Day 1, and End of Treatment, up to 8 weeks
Population: The three patients who did not complete treatment are not evaluable for this outcome measure. There are 3 additional patients not evaluable for this outcome measure because 2 patients did not have detectable levels of CA19-9 prior to treatment and 1 patient did not have the end of treatment CA19-9 drawn.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dapagliflozin | Changes in CA19-9 | Cycle 1 Day 1 | 1060 U/mL |
| Dapagliflozin | Changes in CA19-9 | Cycle 2 Day 1 | 315.6 U/mL |
| Dapagliflozin | Changes in CA19-9 | End of Treatment | 256.1 U/mL |
Secondary
Changes in CT-quantified Tumor Size
Time frame: From pre-treatment and post-8 weeks of treatment
Population: The three patients who did not complete treatment are not evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Changes in CT-quantified Tumor Size | Pre-treatment | 7.541666667 cm | Standard Deviation 4.825775177 |
| Dapagliflozin | Changes in CT-quantified Tumor Size | Post-8 weeks of treatment | 7.358333333 cm | Standard Deviation 5.946038916 |
Secondary
Changes in HbA1c
Time frame: Screening and Cycle 2 Day 15
Population: The three patients who did not complete treatment are not evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dapagliflozin | Changes in HbA1c | Screening | 5.95 percentage of glycosylated hemoglobin |
| Dapagliflozin | Changes in HbA1c | Cycle 2 Day 15 | 5.95 percentage of glycosylated hemoglobin |
Secondary
Changes in Ketones
-Patients are to collect and test ketones weekly while on treatment.
Time frame: 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
Population: The three patients who did not complete treatment are not included in this outcome measure and an additional patient is not included as they didn't collect any ketone readings. There are additional patients who missed ketone readings at additional time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dapagliflozin | Changes in Ketones | Cycle 1 Day 1 | 0.5 mg/dL |
| Dapagliflozin | Changes in Ketones | Cycle 1 Day 8 | 0 mg/dL |
| Dapagliflozin | Changes in Ketones | Cycle 1 Day 15 | 0 mg/dL |
| Dapagliflozin | Changes in Ketones | Cycle 1 Day 22 | 0 mg/dL |
| Dapagliflozin | Changes in Ketones | Cycle 2 Day 1 | 0 mg/dL |
| Dapagliflozin | Changes in Ketones | Cycle 2 Day 8 | 0 mg/dL |
| Dapagliflozin | Changes in Ketones | Cycle 2 Day 15 | 0 mg/dL |
| Dapagliflozin | Changes in Ketones | Cycle 2 Day 22 | 0 mg/dL |
Secondary
Changes in Plasma Glucose
Time frame: 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)
Population: The three patients who did not complete treatment are not evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dapagliflozin | Changes in Plasma Glucose | Screening | 110 mg/dL |
| Dapagliflozin | Changes in Plasma Glucose | Cycle 1 Day 1 | 106.5 mg/dL |
| Dapagliflozin | Changes in Plasma Glucose | Cycle 1 Day 15 | 108.5 mg/dL |
| Dapagliflozin | Changes in Plasma Glucose | Cycle 2 Day 1 | 100.5 mg/dL |
| Dapagliflozin | Changes in Plasma Glucose | Cycle 2 Day 15 | 102.5 mg/dL |
| Dapagliflozin | Changes in Plasma Glucose | End of Treatment | 98 mg/dL |
Secondary
Changes in Total Fat Volume in Visceral Fat Area as Assessed by CT-based Body Composition
Time frame: From pre-treatment and post-8 weeks of treatment
Population: The three patients who did not complete treatment are not evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Changes in Total Fat Volume in Visceral Fat Area as Assessed by CT-based Body Composition | Pre-treatment | 5009.845557 cm^3 | Standard Deviation 1894.271988 |
| Dapagliflozin | Changes in Total Fat Volume in Visceral Fat Area as Assessed by CT-based Body Composition | Post-8 weeks of treatment | 4334.134004 cm^3 | Standard Deviation 2127.102525 |
Secondary
Changes in Total Muscle to Fat Ratio in Visceral Fat Area as Assessed by CT-based Body Composition
Time frame: From pre-treatment and post-8 weeks of treatment
Population: The three patients who did not complete treatment are not evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Changes in Total Muscle to Fat Ratio in Visceral Fat Area as Assessed by CT-based Body Composition | Pre-treatment | 0.378776105 ratio | Standard Deviation 0.274872687 |
| Dapagliflozin | Changes in Total Muscle to Fat Ratio in Visceral Fat Area as Assessed by CT-based Body Composition | Post-8 weeks of treatment | 0.518539627 ratio | Standard Deviation 0.638171644 |
Secondary
Changes in Total Skeletal Muscle Volume in Visceral Fat Area as Assessed by CT-based Body Composition
Time frame: From pre-treatment and post-8 weeks of treatment
Population: The three patients who did not complete treatment are not evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Changes in Total Skeletal Muscle Volume in Visceral Fat Area as Assessed by CT-based Body Composition | Pre-treatment | 1494.813884 cm^3 | Standard Deviation 324.0522377 |
| Dapagliflozin | Changes in Total Skeletal Muscle Volume in Visceral Fat Area as Assessed by CT-based Body Composition | Post-8 weeks of treatment | 1360.211117 cm^3 | Standard Deviation 315.4997407 |