Targeting Pancreatic Cancer With Sodium Glucose Transporter 2 (SGLT2) Inhibition
Phase: PHASE1
Conditions: Pancreas Cancer, Pancreatic Cancer, Cancer of the Pancreas
Sponsor: Washington University School of Medicine

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Targeting pancreatic cancer with sodium glucose transporter 2 (SGLT2) inhibition 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 202011019 
Version Date: 07 April 2022 
 
Principal Investigator: 
Kian-Huat Lim, M.D. 
Phone: (314) 362-6157 
E-mail: kian-huat.lim@wustl.edu  
 
Sub-Investigators 
 
 
 
Modality 
Linda R. Peterson, M.D. 
 
 
Cardiology 
Joseph E. Ippolito, M.D., Ph.D. 
 
Radiology 
Janet McGill, M.D. 
 
 
 
Endocrinology 
William Hawkins, M.D. 
 
 
HPB Surgery 
Elena Deych, M.S. 
 
 
 
Biostatistics 
 
 
Study Drug:  
 
dapagliflozin 
Study Device: 
 
N/A 
 
IND#: 
153028 EXEMPT 
IND Sponsor: 
Linda Peterson, M.D. 
NCT#: 
NCT04542291 
Funded by: 
NIH Pancreas SPORE grant 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 

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Targeting pancreatic cancer with sodium glucose transporter 2 (SGLT2) inhibition 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
06 Oct 2020 
Amendment #1 Version 
 
 
 
 
 
 
29 July 2021 
Amendment #2 Version 
 
 
 
 
 
 
07 April 2022 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 

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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................. 6 
Synopsis ...................................................................................................................................... 6 
SCHEMA ........................................................................................................................................ 8 
SCHEDULE OF ACTIVITIES....................................................................................................... 9 
1.0 
INTRODUCTION ............................................................................................................. 10 
1.1 
Study Rationale .............................................................................................................. 10 
1.2 
Background .................................................................................................................... 10 
1.3 
Study Design .................................................................................................................. 13 
1.4 
Risk/Benefit Assessment ................................................................................................ 14 
2.0 
OBJECTIVES AND ENDPOINTS ................................................................................... 16 
3.0 
STUDY POPULATION .................................................................................................... 16 
3.1 
Inclusion Criteria ............................................................................................................ 16 
3.2 
Exclusion Criteria ........................................................................................................... 17 
3.3 
Retrospective Cohort ...................................................................................................... 18 
3.4 
Inclusion of Women and Minorities............................................................................... 18 
3.5 
Lifestyle Considerations ................................................................................................. 18 
4.0 
REGISTRATION PROCEDURES ................................................................................... 18 
4.1 
Confirmation of Patient Eligibility ................................................................................. 19 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 19 
4.3 
Assignment of UPN ....................................................................................................... 19 
4.4 
Screen Failures ............................................................................................................... 19 
5.0 
TREATMENT PLAN ........................................................................................................ 19 
5.1 
Study Intervention Description ...................................................................................... 19 
5.2 
Study Intervention Administration ................................................................................. 20 
5.3 
BIOSENSE Meters ......................................................................................................... 20 
5.4 
Definitions of Evaluability ............................................................................................. 21 
5.5 
Concomitant Therapy and Supportive Care Guidelines ................................................. 21 
5.6 
Women of Childbearing Potential .................................................................................. 21 
5.7 
Duration of Therapy ....................................................................................................... 22 
5.8 
Duration of Follow-up .................................................................................................... 22 
5.9 
Lost to Follow-Up .......................................................................................................... 22 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 23 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 23 
7.1 
Sponsor-Investigator Reporting Requirements .............................................................. 24 
7.2 
Exceptions to Expedited Reporting ................................................................................ 25 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 26 
8.1 
Dapagliflozin (Farxiga) .................................................................................................. 26 
9.0 
DATA SUBMISSION SCHEDULE ................................................................................. 27 
9.1 
Adverse Event Collection in the Case Report Forms ..................................................... 28 
10.0 MEASUREMENT OF EFFECT........................................................................................ 28 
10.1 Antitumor Effect – Solid Tumors................................................................................... 28 
10.2 Disease Parameters ......................................................................................................... 28 
10.3 Methods for Evaluation of Measurable Disease ............................................................ 29 
10.4 Response Criteria ........................................................................................................... 32 
11.0 DATA AND SAFETY MONITORING ............................................................................ 34 

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12.0 Retrospective Review of Matched Controls ...................................................................... 35 
13.0 STATISTICAL CONSIDERATIONS............................................................................... 35 
13.1 Safety Analyses .............................................................................................................. 36 
14.0 REFERENCES .................................................................................................................. 37 
APPENDIX A: Device IDE Exemption ....................................................................................... 41 
APPENDIX B: BIOSENSE Information ...................................................................................... 42 
APPENDIX C. Handout for patients for prevention of yeast infections ...................................... 47 
APPENDIX D: ECOG Performance Status Scale ........................................................................ 48 
APPENDIX E. Dietary guidance .................................................................................................. 49 
APPENDIX F: PATIENT’S MEDICATION DIARY ................................................................. 50 
APPENDIX G: Definitions for Adverse Event Reporting ........................................................... 52 
APPENDIX H: Reporting Timelines ............................................................................................ 54 
 
 

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PROTOCOL SUMMARY 
 
Synopsis 
 
Title: 
Targeting pancreatic cancer with sodium glucose transporter 2 
(SGLT2) inhibition 
Study Description: 
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.  Our primary hypothesis is that dapagliflozin is 
well-tolerated and safe to use in this patient population.  We 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. 
Objectives: 
Primary Objective: To assess tolerability and determine the optimal 
dosage of dapagliflozin added to standard of care front-line 
chemotherapy for metastatic pancreatic ductal adenocarcinoma. 
 
Secondary Objective: To explore the effects of dapagliflozin on 
metabolic and tumor response in patients with metastatic pancreatic 
ductal adenocarcinoma. 
Endpoints: 
Primary Endpoint: Toxicity by CTCAE v 5.0. 
 
Secondary Endpoints: Changes in clinical laboratory metabolic 
parameters (plasma glucose, ketones, HbA1c), CT-based body 
composition (visceral fat), and tumor markers (plasma CA19-9) and 
CT-quantified tumor size and tumor necrosis from pre-therapy to 
post-8 weeks of therapy. 
Study Population: 
Up to eighteen patients with metastatic pancreatic ductal 
adenocarcinoma undergoing treatment with nab-paclitaxel and 
gemcitabine in the frontline setting will be enrolled in this study.  
Additionally, retrospective data will be accessed for up to 16 
matched controls who have received nab-paclitaxel and gemcitabine 
SOC chemotherapy. 
Phase: 
Ib 
Description of Sites / 
Facilities Enrolling: 
This study will be open to enrollment at the Siteman Cancer Center 
at Washington University School of Medicine. 
Description 
of 
Study 
Intervention: 
Dapaglifozin is an oral medication taken once daily. 
Study Duration: 
6.5 mo/subject; total time for enrollment and follow-up of all patients 
~ 13 mo. 
Participant Duration: 
The intervention is an 8-week course of treatment. 
 
 
 
 
 
 
 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 
Days of 
treatment 
Dapagliflozin 
(QD) 
Gemcitabine       
(D1, 8, 15, q28 
days) 
Nab-paclitaxel       
(D1, 8, 15, q28 
days) 
Patients with 
metastatic 
PDAC, 
frontline setting 
C1D1-
C1D14 
5mg 
1000 mg/m2 
125 mg/m2 
C1D15-
C2D28 
10 mg 
  
 
Treatment Plan 
• Dapagliflozin will be initiated PO QD at the same time as nab-
paclitaxel and gemcitabine SOC chemo 
• Dapagliflozin will be initiated at 5 mg PO QD, D1-D14 (2 weeks) 
• Dapagliflozin will be escalated to 10 mg PO QD for 6 weeks. Dose 
adjustment will need to be approved by endocrinologist Dr. McGill/or 
another attending MD diabetologist at WUSM on the HRPO-
approved study team. This dose is reflective of current clinical 
practice for diabetes and heart failure. 
• Dapagliflozin toxicity will be assessed by criteria detailed below. 
• All patients will stop taking dapagliflozin after 8 weeks of treatment. 
• Nab-paclitaxel and gemcitabine chemotherapy dose adjustment will 
be made per oncologist’s judgement. 
Eligible Patients 
Metastatic pancreatic ductal adenocarcinoma undergoing treatment 
with nab-paclitaxel and gemcitabine in the frontline setting 

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SCHEDULE OF ACTIVITIES 
 
There is a +/- 2-day window for all assessments with the exception of C1D15, which has a -2 day 
window. 
 
 
Screening1 
C1D1 
C1D15 
C2D1 
C2D15 
C2D28 
EOT8 
F/U2 
Informed consent 
X 
 
 
 
 
 
 
 
H&P, ECOG PS, VS 
X 
X 
X 
X 
X 
 
X 
X 
Meet w/Dr. McGill / 
endocrinologist9 
X 
X 
X11 
X12 
X12 
 
X12 
 
Weight 
X 
Weekly 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
 
X 
 
Fasting CMP4 
X 
X 
X 
X 
X 
 
X 
 
HbA1c 
X 
 
 
 
X 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
 
X 
 
Beta-hydroxybutyrate ketone5 
 
X 
 
 
X 
 
 
 
Fasting serum c-peptide5 
 
X 
 
 
X 
 
 
 
Fasting serum glucagon5 
 
X 
 
 
X 
 
 
 
Fasting serum pancreatic 
polypeptide5 
 
X 
 
 
X 
 
 
 
Serum CA19-9 
X 
X 
 
X 
 
 
X 
 
Home quantitative fingerstick 
glucose 
As clinically indicated 
 
Home BIOSENSE ketone 
breath monitoring13 
 
Daily 
 
Urine ketone dipstick 
 
Weekly 
 
CT/MRI scan 
X7 
 
 
 
 
 
X6 
 
Dapagliflozin10 
 
PO QD C1D1 through C2D28 
 
 
SOC chemotherapy 
 
Per SOC 
 
 
AE assessment 
 
Continuous14 
1. within 14 days prior to C1D1 
2. biweekly for the first month after completion of study treatment and Q4W for 3 months thereafter; the first month 
of f/u can be in person or by phone with local records sent to the study team, while the remainder will be chart-based 
3. women of childbearing potential only 
4. visits for CMP to be in morning (fasting after midnight, sips of water allowed); screening CMP may be non-fasting 
5. research study (results not necessary for conduct of this study) 
6. may be up to 7 days before C3D1 
7. can be within 28 days before C1D1 
8. end of treatment will likely align with C3D1 of SOC chemotherapy; patients may continue SOC chemotherapy at 
the discretion of their physician after discontinuation of study treatment with dapagliflozin 
9. may occur in person or by phone 
10. cycles are 28 days but dispensing will occur every 2 weeks 
11. assessment by endocrinologist is required on C1D15 (-2 day window) prior to the patient taking the C1D15 dose 
of dapagliflozin 
12. endocrinologist evaluations after C1D15 are as clinically indicated. Endocrinology evaluations at Screening, 
C1D1, and C1D15 are mandatory. 
13. BIOSENSE monitoring to occur once daily prior to breakfast (preferably). See section 5.3 for more information. 
14. Patients will be contacted weekly, either in person or by phone, while patient is taking dapagliflozin. After 
completion of dapagliflozin, patient contacted biweekly until 30 days after the last dose. 
 

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1.0 INTRODUCTION 
 
1.1 
Study Rationale 
 
Dapagliflozin, a sodium glucose transporter 2 inhibitor (SGLT2i), is FDA-approved and 
has been used in numerous worldwide clinical trials. Much data exists regarding 
pharmacokinetic profiles of the drug as well as safety and dosing profiles in diabetic 
patients and those with heart failure.2, 3 However, to our knowledge, this drug has not been 
studied in the pancreatic ductal adenocarcinoma (PDAC) patient population. PDAC 
patients may be deconditioned with decreased oral intake and altered nutritional profiles. 
Moreover, the prevalence of diabetes and impaired glucose tolerance in pancreatic cancer 
cases may be as high as 80%, and reports have linked molecular mediators from PDAC 
tumors to the development of insulin resistance in these patients.4 Insulin deficiency is 
common due to local mass effects and pancreatic resection.4 Therefore, studies need to be 
performed to evaluate the safety and tolerability of SGLT2i in PDAC patients who are 
receiving chemotherapy. This study will evaluate the effect of dapagliflozin dosing on 
tolerability, safety and side effects in PDAC patients. As part of an innovative component 
to this proposal, we will utilize quantitative ketone breathalyzers to monitor side effects 
remotely and with real-time result transmission to the study team that will be used 
alongside conventional measurement methods for ketones. 
 
1.2 
Background 
 
1.2.1 Pancreatic Ductal Adenocarcinoma 
 
Pancreatic ductal adenocarcinoma (PDAC) is invariably lethal. Not including 
COVID-19, cancer is the second leading cause of death in the United States.5 
Pancreatic cancer has the 7th highest incidence with an estimated 57,600 diagnoses 
this year. However, pancreatic cancer has the 4th highest mortality of all cancers.5 
PDAC is a histologic subtype of pancreatic cancer that accounts for more than 90% 
of all pancreatic cancers6 and is an invariably lethal cancer with a 5 year mortality 
of 91%.5 Unfortunately, mortality due to pancreatic cancer has been relatively 
unchanged despite advances in cancer treatments.5 Because of the lethal 
progression of this disease and the inability to achieve significant increases in 
survival, new avenues need to be explored that delve into mechanisms that underlie 
disease progression, but even more importantly, mechanisms that are targeted by 
currently FDA-approved drugs that can be rapidly repurposed for pancreatic cancer. 
Metabolism is one avenue that meets all of these criteria.  
 
1.2.2 Enhanced Glycolysis in PDAC 
 
Glucose metabolism is a rational target for PDAC treatment. Several lines of 
evidence have demonstrated the prognostic potential of glucose utilization in 
pancreatic cancer. FDG-PET has been demonstrated as a highly sensitive modality 
for pancreatic cancer detection with a pooled sensitivity of 90%.7, 8 Enhanced 
glycolysis is one of the most, if not the most, critical metabolic alteration in 

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pancreatic cancer that is driven by the KRAS mutation. Enhanced glycolysis has 
also been recognized as an important metabolic alteration in PDAC metastasis that 
involves the epithelial–mesenchymal transition, angiogenesis, and subsequent 
seeding of cancer cells in distant organs.9, 10 One mechanism for this phenomenon 
involves the uptake of glucose and its conversion to lactate to recycle NAD and 
generate 2 ATP for the rapid energy generation required for cell viability (Warburg 
Effect).11 However, tumor growth also requires anabolic metabolism, or the ability 
to synthesize building blocks such as DNA, RNA, proteins, and lipids. The pentose 
phosphate pathway (PPP) uses glucose carbons to synthesize nucleotides, aromatic 
amino acids and generate the reducing equivalent NADPH, pathways that other 
cancer nutrients, such as glutamine, cannot supply.12 This has clinical implications, 
as the presence of diabetes and increased serum glucose increases the risk of 
PDAC.13 To further underscore the significance of this finding, we obtained 
metabolic data from a cohort of over 200 early stage PDAC patients from Siteman. 
We identified that patients with a random serum glucose over 112 mg/dL at 
diagnosis had a significantly shorter median OS (15 months) than patients under 
that glucose level (29 months; p=0.004; Figure 1). Collectively, these data suggest 
that reducing PDAC tumor access to glucose may have therapeutic benefit.  
 
1.2.3 SGLT2i in PDAC Glucose Metabolism 
 
Sodium Glucose Transport Protein 2 
(SGLT2) 
inhibitors 
impact 
both 
systemic 
and 
PDAC 
glucose 
metabolism. 
Metformin, 
an 
anti-
diabetic drug, has been evaluated in 
patients 
with 
PDAC. 
Although 
metformin was initially found to 
increase survival in diabetic PDAC 
patients, recent data suggest that there 
is no correlation between metformin 
and PDAC patient survival.9 Of note, 
metformin is believed to target 
mitochondrial 
oxidative 
phosphorylation with indirect effects 
on glucose uptake and metabolism. 
Although this works in non-cancerous 
cells with intact mitochondria and 
central carbon metabolism, metformin 
may not necessarily work with the same efficacy in PDAC tumor cells with 
dysfunctional mitochondria that may help explain the clinical results. Therefore, 
drugs that interfere directly with tumor glucose uptake or metabolism may have 
more efficacious results. 
 
In our search for novel metabolic therapeutics for pancreatic cancer, we have 
uncovered exciting new data showing mechanistic plausibility and preliminary 
Figure 1. Higher random serum 
glucose at diagnosis is associated 
with shorter median OS (15 months 
vs 29 months) in Siteman PDAC 
patients. Threshold identified with an 
optimized cutoff finding algorithm. 

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effectiveness of SGLT2 inhibitors (SGLT2i) for the treatment of PDAC. SGLT2i 
are a class of glucose-lowering drugs that inhibit renal glucose reabsorption and 
reduce serum glucose and increase urinary glucose as a result. They are not only 
FDA-approved for glycemic control in type 2 diabetes mellitus (T2DM), but they 
are currently showing significant potential in preventing heart failure 
decompensation and lowering cardiovascular risk in patients with T2DM.14  
 
SGLT2i has three key benefits for PDAC therapy. First and foremost, expression 
of the glucose transporter SGLT2 is distinct from conventional glucose transporter 
(GLUT) expression in PDAC. SGLT2 immunohistochemistry successfully 
localizes SGLT2 expression to neoplastic duct cells, not the surrounding stroma or 
inflammatory cells1 (Figure 2A). Second, functional expression of SGLT2 in 
clinical PDAC specimens has been demonstrated with the SGLT2-specific positron 
emission tomography (PET) tracer, [18F] Me-4DG.1 Thus, SGLT2 transporter 
quantification in tumors can be measured non-invasively and be used to predict 
response to therapy, as already has been done in humans with brain tumors.15 
Third, SGLT2i modulates systemic metabolism and therefore, tumor access to 
glucose is reduced, which leads to increased tumor cell death (Figure 2B). Lastly, 
SGLT2i has pleiotropic metabolic effects that decreases serum glucose, increases 
mild ketonemia, and reduces visceral obesity,14, 16-22 all of which improve can 
survival in patients with cancer, particularly PDAC (Figure 3).23-27 
 
1.2.4 SGLT2i in the Treatment of Other Diseases 
 
SGLT2i therapy has been shown to be generally safe and effective for type 2 
diabetes and for heart failure. Tens of thousands of patients have been studied in 
randomized, placebo-controlled trials including the DECLARE study28 and EMPA-
REG study.29 In the EMPA-REG trial of 7,020 subjects with type 2 diabetes, 
patients receiving empagliflozin had a lower rate of all-cause death or a composite 
of 
major 
cardiovascular 
events. In the recent 
DECLARE 
study 
(N=17,160), 
not 
only was there was a 
lower 
rate 
of 
cardiovascular death 
or hospitalization for 
heart failure with 
dapagliflozin, 
but 
there was also a low 
incidence of adverse 
events 
(AEs) 
or 
serious adverse events (SAEs). In fact, there were fewer SAEs in the dapagliflozin 
group than in the placebo group (p<0.001). There were fewer major hypoglycemic 
events (p=0.02), acute kidney injury events (p=0.002), and fewer bladder cancers 
Figure 2. SGLT2 is a therapeutic target in PDAC. A. Tumor cell-
specific expression of SGLT2 in PDAC. B. SGLT2i dapagliflozin 
treatment of a PDAC xenograft results in increasd tumor necrosis 
(red margin). Data from ref.1 

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(p=0.02). The risk of death from any cause was 7% less in the dapagliflozin group, 
but it did not reach statistical significance. “The rates of amputation, fracture, 
volume depletion, hypersensitivity, and urinary tract infections were balanced 
between the groups.”28 However, there were more genital infections in the 
dapagliflozin-treated groups (<0.001). Note that subjects in our trial will be 
monitored carefully for infections and will be given instructions on infection 
prevention. Diabetic ketoacidosis (DKA), though rare, was also higher in the 
SGLT2i treated group (0.3%) than in the placebo group (0.1%). Greater than 80% 
of these with DKA were patients with insulin-requiring diabetes.28 For this reason, 
PDAC patients in this trial will not have insulin-requiring diabetes. 
 
The 
promise 
of 
SGLT2i-mediated 
metabolic modulation of cancer has yet to 
be extensively addressed in the literature 
and will be the focus of this proposal. As 
of now, only one clinical trial exists 
(NCT04073680) that tests the efficacy of 
SGLT2i in conjunction with PI-3K 
inhibitors in advanced solid tumors. The 
ability to simultaneously decrease serum 
glucose and inhibit tumor glucose uptake 
is a very appealing property of SGLT2i 
and not present in the vast majority of 
diabetic medications. Here, we will 
combine the SGLT2i dapagliflozin with 
conventional chemotherapy to assess 
tolerability and metabolic effects in 
PDAC patients. This feasibility study 
will set the stage for larger, more comprehensive trials in pancreatic cancer that will 
integrate metabolism, imaging, and therapeutics. In summary, identification of 
metabolic features that influence patient outcomes and are targetable with current 
clinical imaging and therapeutic workflows is highly innovative and represents a 
significant unmet need for patients with PDAC. 
 
1.3 
Study Design 
 
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 PDAC patients 
on chemotherapy as assessed by tolerability and side effect profiles.  The dose escalation 
scheme will consist of 5 mg of dapagliflozin once per day for 2 weeks, followed by 
escalation to 10 mg once per day for 6 weeks if the 5 mg dose is tolerated. 
 
Figure 3. Increased visceral 
obesity measured by CT in 
Siteman PDAC patients has 
poorer outcomes. Visceral fat % 
threshold 
identified 
with 
an 
optimized cutoff finding algorithm.  

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1.4 
Risk/Benefit Assessment 
 
1.4.1 Known Potential Risks 
 
The most common side effects of dapagliflozin include: (i) vaginal yeast infections 
and yeast infections of the penis, (2) stuffy or runny nose and sore throat, (3) 
changes in urination, including urgent need to urinate more often, in larger amounts, 
or at night.  
 
Less likely risks include intravascular volume depletion which may manifest as 
symptomatic hypotension or acute transient changes in creatinine. Patients with 
impaired renal function (eGFR < 60 mL/min/1.73m2), elderly patients, or patients 
on loop diuretics may be at increased risk for volume depletion.  To mitigate against 
this, subjects will be educated and given handouts regarding the importance of 
staying hydrated and holding dapagliflozin therapy if they are not taking p.o. well. 
Other less likely risks are urinary tract infections, hypoglycemia (when 
coadministered with insulin and insulin secretagogues; to mitigate against this, 
subjects will be meet with an endocrinologist and be educated regarding this 
possibility. Patients with diabetes will be required to monitor their glucose 
throughout the study using home glucometers), genital mycotic infections (see 
Appendix C). 
 
Rare risks include acute kidney injury requiring hospitalization and dialysis, 
ketoacidosis in diabetes mellitus (to mitigate against this, subjects will be educated 
and tested at screening. Subjects will be followed by an endocrinologist and will 
have home monitoring systems for ketosis. Conventional urine ketone monitoring 
using dipsticks will be provided to patients and will be measured weekly (see 
testing schedule). This will be supplemented with QD ketone breath monitoring as 
an investigational tool (see Appendices A and B) that will allow for frequent 
monitoring of abnormally high levels of ketones that will be reported to the clinical 
research assistant and investigators.  
 
Note: In the DECLARE-TIMI 58 trial28, “key safety results” are provided in Table 
2 and in Table S3 in the Supplementary Material28,. Fewer patients in the 
dapagliflozin group than in the placebo group discontinued the assigned regimen 
during the course of the trial, and fewer patients in the dapagliflozin group reported 
a serious adverse event or had major hypoglycemia (see the Supplementary 
Material28,), acute kidney injury, or bladder cancer. The rates of amputation, 
fracture, volume depletion, and hypersensitivity were balanced between the groups. 
Diabetic ketoacidosis was more common in the dapagliflozin group than in the 
placebo group (0.3% vs. 0.1%; hazard ratio, 2.18; 95% CI, 1.10 to 4.30; P=0.02). 
More than 80% of patients with diabetic ketoacidosis were using insulin at baseline. 
Genital infections that led to discontinuation of the trial regimen or were considered 
to be serious adverse events were more common in the dapagliflozin group than in 
the placebo group (0.9% vs. 0.1%; hazard ratio, 8.36; 95% CI, 4.19 to 16.68; 
P<0.001), both in men and in women, although genital infections reported as 

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serious adverse events were rare (two events in each group). Six cases of Fournier’s 
gangrene were re- ported, one in the dapagliflozin group and five in the placebo 
group.”  
 
In addition, “In a pool of 12 placebo-controlled studies, the most common adverse 
reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively 
were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis 
(6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).” 
(https://www.farxiga-hcp.com/dosing.html)                   
 
1.4.2 Known Potential Benefits 
 
• An FDA-approved indication for patients with heart failure (NYHA class II-
IV) with reduced ejection fraction, to reduce the risk of CV death and 
hospitalization for heart failure 
• An FDA-approved indication in patients with type 2 diabetes with evident 
cardiovascular disease (CVD) or CVD risk factors to reduce the risk of 
hospitalization for heart failure. 
• An FDA-approved indication to improve glycemic control in patients with type 
2 diabetes. 
• Decrease in weight (DECLARE-TIMI 58 study) 
• Decrease in systolic and diastolic blood pressure 
• Significantly less likely (HR 0.53; CI 0.43-0.66) to have a 40% decrease in 
eGFR, ESRD, or renal death. (DECLARE-TIMI 58 study). 
 
Additionally, known benefits of dapagliflozin in animal models include: 
• Mild ketonemia (which can have anti-tumor effects) 
• Increased PDAC tumor necrosis 
• Decreased growth of PDAC cells 
• Impairment of PDAC cells to take up glucose 
 
1.4.3. Assessment of Potential Risks and Benefits  
 
PDAC is a lethal disease. The overall 5-year survival rate is only 9%, and the 
survival rate for those with distant metastases is a dismal 3%. Clearly, there is an 
urgent need for new treatments that will extend survival in patients with this 
disease. Dapagliflozin is a generally safe, well-tolerated medication that is FDA-
approved for both diabetes and heart failure with reduced ejection fraction. 
Dapagliflozin and other SGLT2i’s are taken by tens of thousands of patients in the 
US and around the globe. The risk of severe adverse events (SAEs) and adverse 
events (AEs) is relatively low, especially when compared with placebo in trials. 
This low rate of potential SAEs and AEs can be made even lower by education of 
the subjects and following them closely in our clinical trial by our trial team (see 
mitigating steps outlined above). This low rate of potential SAEs and AEs is 
outweighed by the possibility of discovering and bringing to the clinic a new, oral, 

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once-a-day, well-tolerated, effective medication in the fight against this lethal 
disease – PDAC.   
 
 
2.0 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for 
Endpoints 
Primary 
To assess tolerability and 
determine the optimal dosage 
of dapagliflozin added to 
standard of care front-line 
chemotherapy for metastatic 
pancreatic ductal 
adenocarcinoma. 
Toxicity by CTCAE v 5.0.   
This is a phase Ib clinical 
trial and as such, safety and 
tolerability are a primary 
objective. 
Secondary 
To explore the effects of 
dapagliflozin on metabolic and 
tumor response in patients with 
metastatic pancreatic ductal 
adenocarcinoma. 
Changes in clinical laboratory 
metabolic parameters (plasma 
glucose, ketones, HbA1c), CT-
based body composition 
(visceral fat), and tumor markers 
(plasma CA19-9) and CT-
quantified tumor size and tumor 
necrosis from pre-therapy to 
post-8 weeks of therapy. 
The proposed beneficial 
effects of dapagliflozin are 
thought to be due to its 
metabolic effects on the 
tumor. Thus, several 
biomarkers of metabolism 
are included as secondary 
endpoints in addition to 
measures of efficacy such 
as tumor size changes 
and/or necrosis. 
 
 
3.0 
STUDY POPULATION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed metastatic or locally advanced pancreatic 
ductal adenocarcinoma, pancreatic adenosquamous carcinoma or squamous cell 
carcinoma 
 
2. 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. 
 
3. 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. 
 

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4. No prior systemic therapy for pancreatic ductal adenocarcinoma in the metastatic or 
locally advanced setting. 
 
5. Planning to receive treatment with nab-paclitaxel and gemcitabine. 
 
6. At least 18 years of age. 
 
7. ECOG performance status ≤ 1 (see Appendix D) 
 
8. Normal bone marrow and organ function as defined below: 
a. Leukocytes ≥ 3,000/mcL 
b. Absolute neutrophil count ≥ 1,500/mcL 
c. Platelets ≥ 100,000/mcL 
d. Total bilirubin ≤ 1.5 x IULN 
e. AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN 
f. Estimated glomerular filtration rate eGFR ≥ 30 mL/min/1.73m2 
 
9. 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 
 
10. Agreement to adhere to Lifestyle Considerations throughout study duration (see 
Section 3.4). 
 
11. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. History of total pancreatectomy. 
 
2. Current or previous treatment with SGLT2i or thiazolidinedione. 
  
3. 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. 
 
4. 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 

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and locally treated skin squamous or basal cell carcinoma. 
 
5. History of stroke or transient ischemic attack (in the last 5 years). 
 
6. HbA1c > 10%, unless approved by endocrinologist. 
 
7. Currently receiving any other investigational agents. 
 
8. 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. 
 
9. 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. 
  
10. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry. 
 
11. 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. 
 
3.3 
Retrospective Cohort 
 
Retrospective data will be accessed from EPIC for up to 16 matched control patients  
            receiving nab-paclitaxel and gemcitabine SOC chemotherapy.  These subjects will be  
            enrolled under a waiver of consent. 
 
3.4 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
3.5 
Lifestyle Considerations 
 
Patients must stay hydrated and eat a “normal” amount of carbs.  Refer to Appendix E on 
Dietary Guidance for details, and section 5.4.1.  
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 

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The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (if applicable).   
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Study Intervention Description 
 
Dapagliflozin is a commercially available medication indicated as an adjunct to diet and 
exercise to improve glycemic control in adults with type 2 diabetes mellitus, to reduce the 
risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and 
established cardiovascular disease or multiple cardiovascular risk factors, and to reduce the 
risk of cardiovascular death and hospitalization for heart failure in adults with NYHA class 

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II-IV heart failure with reduced ejection fraction.  By inhibiting sodium glucose 
cotransporter 2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal 
threshold for glucose, thereby increasing urinary glucose excretion.  It is available as a 
tablet for oral administration. 
 
In this study, dapagliflozin will be co-administered with standard of care IV chemotherapy 
(nab-paclitaxel and gemcitabine) for the treatment of metastatic pancreatic ductal 
adenocarcinoma.  The chemotherapy is not being given as part of this study; it is being 
given as part of patients’ routine care and dosing is not dictated by this protocol.  Routine 
doses of gemcitabine and nab-paclitaxel are 1000 mg/m2 and 125 mg/m2, respectively, and 
can be modified for the patient at the oncologist’s discretion.  
 
5.2 
Study Intervention Administration 
 
Dapagliflozin is an oral drug which will be administered on an outpatient basis.  Dosing 
will start at 5 mg QD and will increase to 10 mg QD after 2 weeks (after consultation with 
a study endocrinologist) 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). Following 8 weeks, 
all patients will come off of the study, regardless of treatment response.  Dapagliflozin will 
be continued regardless of holds or modifications to standard of care chemotherapy.  
 
Patients should take dapagliflozin at approximately the same time every day, with or 
without food.  If a patient misses a dose (has not taken it within 6 hours of the regular time), 
s/he should be instructed not to take or make up that dose and to resume dosing with the 
next scheduled dose.  Patients will be instructed to bring all unused tablets and their 
medication diary (Appendix F) to each study visit for assessment of compliance.   
 
Treatment with dapagliflozin will be initiated on Cycle 1 Day 1 of standard of care 
chemotherapy.  
 
During treatment and for 30 days after the last dose of dapagliflozin, AEs will be monitored 
weekly, either during regular office visits or phone calls, while patient is taking 
dapagliflozin, and after completion of therapy, follow-up will be biweekly for first month. 
Severe AEs that require immediate medical attention (i.e., DKA, hypoglycemia) will be 
reviewed promptly by an oncologist and endocrinologist.  . This will be reinforced with 
regularly scheduled visits with the endocrinologist at screening, C1D1, C1D15, and then 
as clinically indicated that will be targeted to coincide the same day as the oncologist visit. 
 
5.3 
BIOSENSE Meters 
 
BIOSENSE meters are investigational devices utilized in this trial to evaluate utility for 
assessing breath ketones in a non-invasive manner and therefore are being used under an 
IDE exemption (Appendix A). The BIOSENSE meters are provided by Readout Health. 
They are to be used once daily, preferably prior to breakfast, and Appendix B includes 
use instructions to be provided to the patient. Patients should be instructed to enter the 
BIOSENSE results on the diary in Appendix F.  

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5.4 
Definitions of Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment prior to 
completion of 8 weeks of treatment and have not had any disease assessment. 
 
Patients who miss more than 4 doses of dapagliflozin in any one week will be considered 
not evaluable for treatment response and will need to be replaced. 
 
5.5 
Concomitant Therapy and Supportive Care Guidelines 
 
See Appendix. If patients think that they have any side effect or just are feeling worse 
during the trial, they are to let the study team know. 
 
There are very few drug interactions with dapagliflozin. They are detailed in the package 
insert. The main ones are mefenamic acid (an NSAID), rifampin, and valsartan.  
 
5.5.1 Alcohol (Ethanol) ↔ dapagliflozin 
 
Participants will be instructed to talk to the study doctor before using ethanol 
together with dapagliflozin. Alcohol may affect blood glucose levels in patients 
with diabetes. Both hypoglycemia (low blood sugar) and hyperglycemia (high 
blood sugar) may occur. Participants will be advised to avoid using alcohol if their 
diabetes is not well controlled or if they have high triglycerides, neuropathy (nerve 
damage), or pancreatitis.  
 
5.6 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 14 days prior to the first dose of dapagliflozin.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 1 month following the last dose of dapagliflozin.  
 
If a patient is suspected to be pregnant, dapagliflozin should be immediately discontinued, 
as will be the chemotherapy. Because   In addition, a positive urine test must be confirmed 
by a serum pregnancy test.  If it is confirmed that the patient is not pregnant, the patient 
may resume dosing. 
 

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If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 1 month after the last dose of dapagliflozin, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for 8 
weeks or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar for patient follow-up. 
 
5.8 
Duration of Follow-up 
 
Following the end of study treatment, participants will be followed in person or by phone 
on a biweekly basis for the first month.  Following that, chart-based follow-up Q4W will 
be obtained for an additional 3 months.  Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event. 
 
5.9 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled 
visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 2 weeks and counsel the participant on the importance of maintaining 

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the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Dose modifications for nab-paclitaxel and gemcitabine will follow standard of care guidelines and 
will be made at the discretion of the treating oncologist.  Dosing with dapagliflozin will continue 
even if there are interruptions or modifications to nab-paclitaxel and/or gemcitabine. 
 
If estimated glomerular filtration ate (eGFR) falls below 30 mL/min/1.73 m2 and/or the patient is 
diagnosed with end-stage renal disease or require dialysis, dapagliflozin must be discontinued. 
 
Patients with signs and symptoms consistent with severe metabolic acidosis should be assessed for 
ketoacidosis regardless of presenting blood glucose levels (laboratory studies with plasma glucose 
of 250 mg/dL or greater and associated severe clinical symptoms such as increased urination, 
increased thirst and unintentional weight loss; neurologic changes such as confusion or 
drowsiness; metabolic acidosis with serum bicarbonate 15-18 mEq/L with elevated anion gap as 
well as elevated ketones. Of note, ketones may already be elevated as a result of dapagliflozin 
administration; thus, any of the above associated signs or symptoms suggestive of possible DKA 
in the setting of elevated ketones should be discussed with a study investigator immediately.  If 
ketoacidosis is suspected, dapagliflozin should be discontinued, the patient should be evaluated, 
and prompt treatment should be instituted. 
 
Because reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene) have been identified 
in patients receiving dapagliflozin, patients presenting with pain or tenderness, erythema, or 
swelling in the genital or perineal area, along with fever or malaise, should be assessed and 
discontinue dapagliflozin immediately. 
 
Other holds and modifications to dapagliflozin may be made at the discretion of the investigator. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix G for definitions and Appendix H for a grid of reporting 
timelines. 
 

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AEs that require immediate medical attention (i.e., DKA, hypoglycemia) will be reviewed 
promptly an oncologist and endocrinologist.  All AEs (i.e. chemotherapy-related AEs and 
dapagliflozin-related AEs) will be recorded from time of initiation of treatment, through the 8-
week treatment period, and for 30 days after discontinuation of dapagliflozin. This will allow the 
study team to determine if dapagliflozin impacts the frequency and/or severity of the 
chemotherapy-related AEs. All adverse events must be recorded on the toxicity tracking case 
report form (CRF) with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF. 
 
Refer to the data submission schedule in Section 10.0 for instructions on the collection of AEs in 
the EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.   
 
7.1 
Sponsor-Investigator Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Sponsor Investigator (or designee) is required to notify the QASMC of any 
unanticipated problems involving risks to participants or others occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by 
HRPO.  (Unanticipated problems reported to HRPO and withdrawn during the 
review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
7.1.3 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Sponsor-Investigator to report to the FDA as follows: 
 

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• Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix G for definitions) no later than 7 calendar days after 
initial receipt of the information.   
• Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix G) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix G) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
• Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
• Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
7.2 
Exceptions to Expedited Reporting 
 

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Events that do not require expedited reporting as described in Section 7.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Dapagliflozin (Farxiga) 
 
8.1.1 Dapagliflozin Description 
 
Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-
[(4ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, 
hydrate (1:1:1). The empirical formula is C21H25ClO6•C3H8O2•H2O and the 
molecular weight is 502.98. The structural formula is: 
 
 
 
8.1.2 Clinical Pharmacology 
 
Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, 
is responsible for the majority of the reabsorption of filtered glucose from the 
tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, 
dapagliflozin reduces reabsorption of filtered glucose and lowers the renal 
threshold for glucose, and thereby increases urinary glucose excretion. 
Dapagliflozin also reduces sodium reabsorption and increases the delivery of 
sodium to the distal tubule. This may influence several physiological functions 
including, but not restricted to, lowering both pre-and afterload of the heart and 
downregulation of sympathetic activity. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
Following oral administration of dapagliflozin, the maximum plasma concentration 
(Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC 
values increase dose proportionally with increase in dapagliflozin dose in the 
therapeutic dose range. The absolute oral bioavailability of dapagliflozin following 

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the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a 
high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by 
approximately 1 hour, but does not alter AUC as compared with the fasted state. 
These changes are not considered to be clinically meaningful and dapagliflozin can 
be administered with or without food. 
 
The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-
mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is 
extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which 
is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 
50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in 
human plasma. 
 
Dapagliflozin and related metabolites are primarily eliminated via the renal 
pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total 
radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of 
the dose is excreted as parent drug. In feces, approximately 15% of the dose is 
excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin 
is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg. 
 
8.1.4 Supplier 
 
Dapagliflozin will be provided for this trial. 
 
8.1.5 Dosage Form and Preparation 
 
Dapagliflozin is available as film-coated tablets at a dose of 5 mg and 10 mg. 
 
8.1.6 Storage and Stability 
 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C 
(59°F and 86°F). 
 
8.1.7 Administration 
 
Dapagliflozin should be taken by mouth once daily at the assigned dose. 
 
 
9.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 

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Medical History Form 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Biweekly for the first month after completion of study 
treatment, Month 1, 2, 3, and 4 post-EOT 
Tumor Measurement Form 
Baseline and 8 weeks after start of treatment 
Progression Form 
Time of disease progression 
Death Form 
Time of death 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
9.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form (Appendix I).  Baseline AEs should 
be captured on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
10.0 
MEASUREMENT OF EFFECT 
 
10.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients will be re-evaluated for response with standard of 
care computed tomography (CT/MRI) imaging, 8 weeks after the initiation of study 
treatment. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) 30.  Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECIST criteria. 
 
10.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 

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thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
10.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 

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evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 

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Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 31-33.  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer 31. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  

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Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
10.4 
Response Criteria 
 
10.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
10.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 

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10.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 

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*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
10.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 
11.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data.  A DSMB will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  DSMB members must be employed by Washington University, 
Barnes-Jewish Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members are 
subject to the Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the 
trial principal investigator and/or appropriate university officials, in accordance with institution 
policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMB must also 
be disclosed.  
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician, will be reviewed by the DSMB, and will be submitted to the QASM Committee.  The 
DSMB must meet at least every six months beginning six months after study activation at 
Washington University, no more than one month prior to the due date of the DSM report to 
QASMC.  This report will include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 

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• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 
 
Further DSMB responsibilities are described in the DSMB charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (please refer to 
Section 7.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMB. This is located on the 
QASMC website at https://siteman.wustl.edu/research/clinical-research-resources/protocol-
office-prmcqasmc/.   
 
12.0 
Retrospective Review of Matched Controls 
Retrospective data will be accessed from EPIC for up to 16 matched controls who have received 
nab-paclitaxel and gemcitabine SOC chemotherapy.  This data will be obtained under a waiver 
of consent.  All data will be deidentfied within the manuscript. Data from 2016 to present will be 
accessed. Only the necessary data will be pulled from EPIC and will contain lab values, 
demographics (date of birth, sex, race, ethnicity), imaging, tumor stage, metastatic sites, prior 
treatment and best results, with an emphasis on the matched treatment times for the study. 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
The study will be defined as being feasible if up to 18 patients can be recruited within the next 
academic year and at least 80% of patients comply with the intervention as defined as achieving 
80% of the targeted level of therapeutic action assessed from laboratory measures and 80% of the 
planned chemotherapy doses. Data analyses will be descriptive in nature. All data will be analyzed 
as observed without imputation. Variables will be summarized by descriptive statistics including 
mean, median, standard deviation, inter-quartile range, overall and by patient characteristics of 
interest (e.g., male and female patients). Hematological and non-hematological toxicities will be 
summarized by counts and percentages, overall and by patient characteristics. Effect of SGLT2i 

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as assessed by urine glucose, serum and breath ketones, visceral fat, tumor enhancement/necrosis 
(in various format: continuous, dichotomized by median, tertiles, quartiles) or other parameters on 
overall and progression free survival (PFS) will be analyzed by Kaplan-Meier product limit 
method and log rank test or Cox regression model as appropriate. 
 
13.1 
Safety Analyses 
 
Safety endpoints will be analyzed using summary statistics as described above acquired 
during treatment. AEs will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA). Each AE will be counted once only for a given participant.  The 
severity, frequency, and relationship of AEs to SGLT2i therapy will be presented by 
System Organ Class (SOC). AE’s will be reported with the following information: start 
date, stop date, severity, relationship, expectedness, outcome, and duration. Adverse events 
leading to premature discontinuation from the study intervention and serious treatment-
emergent AEs will be presented either in a table and are provided in the Data Safety 
Monitoring Plan. 
 
 

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Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, 
Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Wilding G, 
et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent 
prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Journal 

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of clinical oncology : official journal of the American Society of Clinical Oncology. 
1999;17(11):3461-7. Epub 1999/11/05. doi: 10.1200/JCO.1999.17.11.3461 [doi]. PubMed 
PMID: 10550143. 
33. 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, 
Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small 
EJ, Beer TM, Wilding G, Martin A, Hussain M, Prostate Cancer Clinical Trials Working G. 
Design and end points of clinical trials for patients with progressive prostate cancer and castrate 
levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2008;26(7):1148-59. Epub 2008/03/04. doi: 10.1200/JCO.2007.12.4487 [doi]26/7/1148 [pii]. 
PubMed PMID: 18309951; PMCID: PMC4010133. 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: Device IDE Exemption  
 
 
2940 Locust St. 
St. Louis, MO 63103 
 
 
July 28, 2020 
 
Washington University in St. Louis Institutional Review Board 
(IRB) RE: Device IDE exemption 
Dear Sir or Ma’am: 
 
Referring to the FDA Guidance document, In Vitro Diagnostic (IVD) Device Studies-Frequently Asked 
Questions, issued June 25, 2010, Readout, Inc. has determined that the BIOSENSETM breath acetone device used 
in Targeting pancreatic cancer with sodium glucose transporter 2 (SGLT2) inhibition qualifies for an 
exemption from the IDE submission requirements. 
  
 
Criteria 
Yes 
No 
The in vitro diagnostic device complies with the labeling requirements in 21 CFR Part 809.10(c) 
and the testing: 
X 
-     Is noninvasive 
X 
-     Does not require an invasive sampling procedure that presents significant risk 
X 
-     Does not by design or intention introduce energy into a subject; and 
X 
-     Will not be used as a diagnostic procedure without confirmation by another medically 
established diagnostic product or procedure 
X 
 
 
The study design of Targeting pancreatic cancer with sodium glucose transporter 2 (SGLT2) inhibition does 
not place the patient at any additional risk with the use of the BIOSENSETM device. The primary tool for ketone 
monitoring in this study is a urinary acetoacetate test (measured weekly). The BIOSENSETM breath ketone device 
is noninvasive and will be used for research purposes only. Data from the BIOSENSETM device will not impact 
patient care decisions in any way. 
 
Readout believes the strategies for use of the device during the study does not present a potential for serious risk 
to the health, safety, or welfare of a subject. 
 
The device is not intended as an implant nor is it to be used in supporting or sustaining human life. The 
BIOSENSETM device is not of substantial importance in diagnosing, curing, mitigating or treating disease. 
The device is non-invasive and not being used to determine treatment. Based on the information provided, 
the BIOSENSETM device does not present a potential for serious risk to the health, safety or welfare of the 
subject. 
  
 
 
Contact: 
 
Trey Suntrup Head of Product Readout Health 
trey@readouthealth.com 
 
 

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APPENDIX B: BIOSENSE Information 
 
 

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APPENDIX C. Handout for patients for prevention of yeast infections 
 
If you think you may have an infection, call your oncology clinic team. 
 
Prevention of yeast infections in Women (from Mayo clinics) 
https://www.mayoclinic.org/diseases-conditions/yeast-infection/symptoms-causes/syc-
20378999) 
 
To reduce your risk of vaginal yeast infections, wear underwear that has a cotton crotch and 
doesn't fit too tightly. 
 
It might also help to avoid: 
•   Tight-fitting pantyhose 
• 
Douching, which removes some of the normal bacteria in the vagina that protect 
you from infection 
•   Scented feminine products, including bubble bath, pads and tampons 
•   Hot tubs and very hot baths 
•   Unnecessary antibiotic use, such as for colds or other viral infections 
•   Staying in wet clothes, such as swimsuits and workout attire, for long periods of time 
 
Prevention of yeast infections in Men (from Medical News Today) 
https://www.medicalnewstoday.com/articles/184715#prevention  
 
To prevent infections, the head of the penis and the foreskin should be kept clean and dry. 
Daily washing, with particular attention to cleaning the penis, is essential. 
 
Here are some hygiene tips: 
•   The foreskin should be pulled back so that the glans is exposed. 
• 
The area should be washed thoroughly and gently with warm water. Soap may irritate, 
so it should be avoided. 
• 
An aqueous cream or some other neutral nonsoap cleanser may be used, but it should 
be completely rinsed off. 
•   Before replacing the foreskin, the glans should be completely dry. 
• 
Men who tend to develop balanitis after sex should wash their penis after 
engaging in sexual activity. 
 
Avoiding irritants 
 
If symptoms appear to be linked to substances present in condoms or lubricants, there are 
condoms available for sensitive skin. 
 
It is best to use non-biological washing powder for underwear and to make sure all the detergent 
is rinsed out. People who work with chemicals or have traces of potential irritants on their hands 
should wash them before using the bathroom. 
 
 

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APPENDIX D: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 

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APPENDIX E. Dietary guidance 
 
•  You will need to stay hydrated while on the study drug, dapagliflozin. 
o If you cannot stay hydrated for any reason, please call your oncology clinic team. 
 
•  You will need to take in a ‘normal’ amount of carbohydrates when you are taking an 
SGLT2 inhibitor, such as dapagliflozin, in order to avoid the rare possibility of excessive 
‘ketone’ levels in the blood. 
o If you cannot eat adequate carbohydrates (e.g. bread, crackers, sweets, milk, 
fruit) for any reason, please call your oncology clinic team. 
•  Alcohol may affect blood sugars while taking dapagliflozin. Please contact your 
oncology clinic team with questions. 
 
To help guide you on an adequate amount of carbohydrates/day (~250g/day) please see the 
attached information sheets. Please call your oncology clinic team with any questions. 
 
250 grams of carbohydrate/day is actually about 17 carb servings (255 g) with each 
carbohydrate serving equaling approximately 15 grams 
 
A serving of 15 gm is: 
A small piece of fruit or a cup of berries or melon 
1 slice bread 
4-6 crackers 
1/2 cup cooked cereal, potatoes, corn or peas 
3/4 cup dry unsweetened cereal 
1 cup soup 
1 cup of milk 
1 oz potato chips or 3 cups popcorn 
6 oz flavored Greek yogurt 
1/2 cup Ice cream 
2 small cookies 
 
30 gm carb equals: 
Large Apple, pear or banana 
1 cup of Chili with beans 
 
45 gm carb equals: 
1 cup rice or pasta 
 
60 gm carb equals: 
1 large baked potato 
 
 
 
 

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APPENDIX F: PATIENT’S MEDICATION DIARY 
 
Today’s Date:    
 
 
 
 
Agent:  dapagliflozin 
Cycle:    
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID#:   
 
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each 28 day cycle.  
a. Cycle 1 instructions: Take _____mg ( ___capsules) of dapagliflozin at approximately the same time 
each day, with or without food for days 1 through 14.Your dose may change starting day 15. Your 
dose starting at day 15 will be _____mg (___capsules) of dapagliflozin at approximately the same 
time each day, with or without food. 
b. Cycle 2 instructions: Take _____mg ( ___capsules) of dapagliflozin at approximately the same time 
each day, with or without food 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forgot to take your dapagliflozin dose within 6 hours of your regular time, then do not take a dose that 
day.  Restart taking it the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record 
the time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill 
count can be done. 
Day 
Date 
What time was 
dose taken? 
# of tablets 
taken 
BIOSENSE 
value 
Comments 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 

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24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX G: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 

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APPENDIX H: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Serious AND unexpected suspected 
adverse reaction 
 
 
Report no later than 15 calendar days after it is 
determined that the information qualifies for 
reporting 
Unexpected fatal or life-threatening 
suspected adverse reaction 
 
 
Report no later than 7 calendar days after 
initial receipt of the information 
Unanticipated problem involving risk 
to participants or others 
Report within 10 working days.  If the event 
results in the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day. 
Report via email after 
IRB acknowledgment 
 
Major deviation 
Report within 10 working days.  If the event 
results in the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day. 
 
 
A series of minor deviations that are 
being reported as a continuing 
noncompliance 
Report within 10 working days.   
 
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
Clinically important increase in the 
rate of a serious suspected adverse 
reaction of that list in the protocol or 
IB 
 
 
Report no later than 15 calendar days after it is 
determined that the information qualifies for 
reporting 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or others 
OR noncompliance, report within 10 working 
days.  If the event results in the death of a 
participant enrolled at WU/BJH/SLCH, report 
within 1 working day.  Otherwise, report at the 
time of continuing review. 
 
 
Breach of confidentiality 
Within 10 working days. 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
 
 

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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
If withdrawing the participant does not 
represent a safety issue and the patient will be 
withdrawn, report at continuing review. 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be reported in the 
toxicity table in the DSM report which is 
typically due every 6 months. 
The most current toxicity table from the 
DSM report is provided to the FDA 
with the IND’s annual report. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review.