A Randomized Phase II Study of Pembrolizumab With or Without Defactinib, a Focal Adhesion Kinase Inhibitor Following Chemotherapy as a Neoadjuvant and Adjuvant Treatment for Resectable Pancreatic Ductal Adenocarcinoma (PDAC)
Phase: PHASE2
Conditions: Resectable Pancreatic Ductal Adenocarcinoma (PDAC), Pancreatic Ductal Adenocarcinoma
Sponsor: Lei Zheng

Product: Pembrolizumab (MK-3475), Defactinib 
Protocol No: IRB00182490, J18140 
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COVER PAGE  
 
 
 
 
 
Official Study Title: A randomized phase II study of pembrolizumab with or 
without defactinib, a focal adhesion kinase inhibitor following chemotherapy 
as a neoadjuvant and adjuvant treatment for resectable pancreatic ductal 
adenocarcinoma (PDAC) 
 
 
NCT number: NCT03727880 
 
IRB Approval Date: 08.05.2024 
 
 
Unique Protocol ID: IRB00182490, J18140 (local University of Texas Health 
Science Center at San Antonio protocol ID: CTMS 25-0012) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Product: Pembrolizumab (MK-3475), Defactinib 
Protocol No: IRB00182490, J18140 
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A randomized phase II study of pembrolizumab with or without defactinib, a focal 
adhesion kinase inhibitor following chemotherapy as a neoadjuvant and adjuvant 
treatment for resectable pancreatic ductal adenocarcinoma (PDAC) 
 
Johns Hopkins Protocol #: 
IRB00182490, J18140 
 
Merck Protocol #: 
MK-3475-926 
 
Verastem Protocol #: 
VS-6063-009 
 
NCT #: 
NCT03727880 
 
Coordinating Center: 
Sidney Kimmel Comprehensive Cancer Center, 
 
Johns Hopkins University 
 
Principal Investigator 
Lei Zheng, M.D., Ph.D. 
and Protocol Chair (JHU): 
1650 Orleans Street, CRB I Room 351 
 
Baltimore, MD 21287 
 
410-502-6241 / 410-614-8216 
 
lzheng6@jhmi.edu 
 
Co-Lead Investigator:  
Richard Burkhart, M.D 
(JHU): 
rburkha6@jhmi.edu 
 
Principal Investigator:  
Arsen Osipov, M.D. 
(Cedars-Sinai) 
8700 Beverly Blvd., North Tower. Lower Level. 
AC1044   
 
Los Angeles CA 90048 
 
310‐423‐6066 / Fax: 424‐314‐8777     
 
Arsen.Osipov@cshs.org 
 
IND#: 
IND 140745 
 
IND Sponsor: 
Lei Zheng, M.D., Ph.D.  
 
 
 
 
 

Product: Pembrolizumab (MK-3475), Defactinib 
Protocol No: IRB00182490, J18140 
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Version:  
Version 1.0, 8/27/2018 
Version 1.1, 9/28/2018 
Version 1.2, 10/02/2018 
Version 1.3, 10/03/2018 
Version 1.4, 10/19/2018 
Version 1.5, 11/06/2018 
Version 2.0, 3/19/2019 
Version 3.0, 5/31/2019 
Version 4.0, 10/17/2019 
Version 5.0, 02/27/2020 
Version 6.0, 06/17/2020 
Version 7.0, 09/01/2020 
Version 8.0, 10/06/2020 
Version 9.0, 01/27/2021 
Version 10.0, 05/07/2021 
Version 11.0, 10/13/2021 
Version 12.0, 04/04/2022 
Version 13.0, 05/16/2023 
Version 14.0, 04/17/2024 
 
 

Product: Pembrolizumab (MK-3475), Defactinib 
Protocol No: IRB00182490, J18140 
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Table of Contents 
Table of Contents .......................................................................................................... 4 
1.0 
TRIAL SUMMARY ................................................................................................ 8 
2.0 
TRIAL DESIGN ..................................................................................................... 9 
2.1 
Trial Design .................................................................................................... 9 
2.1.1 
Part 1: Pre-study Consent, Screening, and Randomization....................... 11 
2.1.2 
Part 2: Neoadjuvant Chemotherapy .......................................................... 11 
2.1.3 
Part 3: Neoadjuvant Pembrolizumab and Defactinib ................................. 11 
2.1.4 
Part 4: Surgery .......................................................................................... 12 
2.1.5 
Part 5: Adjuvant Chemotherapy ................................................................. 12 
2.1.6 
Part 6: Adjuvant Immunotherapy Maintenance .......................................... 13 
2.1.7 
Part 7: Follow up ........................................................................................ 13 
2.2 
Trial Diagram: .............................................................................................. 13 
3.0 
OBJECTIVES & HYPOTHESES ......................................................................... 14 
3.1 
Primary Objectives & Hypotheses: ............................................................ 14 
3.2 
Secondary Objectives & Hypotheses: ....................................................... 14 
3.3 
Exploratory Objectives: .............................................................................. 15 
4.0 
BACKGROUND AND RATIONALE.................................................................... 16 
4.1 
Introduction ................................................................................................. 16 
4.2 
Rationale for Neoadjuvant Chemotherapy ................................................ 16 
4.3 
Rationale for PD-1 Blockade (Pembrolizumab [MK-3475]) ...................... 17 
4.4 
Rationale for FAK Inhibition (Defactinib) .................................................. 19 
4.5 
Combination Therapy, Study Rationale and Biologic Markers ............... 21 
5.0 
METHODOLOGY ................................................................................................ 24 
5.1 
Study Population ......................................................................................... 24 
5.1.1 
Participant Inclusion Criteria for Initial Enrollment (Pre-Neoadjuvant 
Chemotherapy) ......................................................................................... 25 
5.1.2 
Participant Exclusion Criteria for Initial Enrollment (Pre-Neoadjuvant 
Chemotherapy) ......................................................................................... 26 
5.1.3 
Participant Inclusion Criteria for Neoadjuvant Immunotherapy (Post-
Neoadjuvant Chemotherapy) .................................................................... 28 
5.1.4 
Participant Exclusion Criteria for Neoadjuvant Immunotherapy (Post-
Neoadjuvant Chemotherapy) .................................................................... 29 

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5.1.5 
Participant Inclusion Criteria for Adjuvant Immunotherapy (Post-Surgery) 30 
5.1.6 
Participant Exclusion Criteria for Adjuvant Immunotherapy (Post-Surgery)
 .................................................................................................................. 31 
5.1.7  
Lifestyle Restrictions .................................................................................. 31 
5.1.8 
Pregnancy ................................................................................................. 32 
5.1.9 
Use in Nursing Women .............................................................................. 32 
5.1.10 Staging information .................................................................................... 33 
5.1.11 Criteria for Resectability............................................................................. 33 
5.2 
Trial Treatments .......................................................................................... 34 
5.2.1 
Timing of Dose Administration ................................................................... 36 
5.2.2 
Dose Modifications .................................................................................... 37 
5.2.3 
Toxicity management for immune-related AEs associated with 
pembrolizumab .......................................................................................... 37 
5.2.4 
Toxicity management for AEs associated with defactinib .......................... 45 
5.2.5 
Dosing Delays ........................................................................................... 46 
5.3 
Trial Blinding and masking ........................................................................ 47 
5.4 
Randomization or Treatment Allocation ................................................... 48 
5.5 
Stratification ................................................................................................ 48 
5.6 
General Concomitant Medication and Supportive Care Guidelines ....... 48 
5.6.1 
Neoadjuvant Chemotherapy (Gemcitabine and Nab-Paclitaxel) ................ 48 
5.6.2 
Pembrolizumab .......................................................................................... 48 
5.6.3 
Defactinib ................................................................................................... 51 
5.6.4 
Concomitant Medications/Vaccinations (allowed & prohibited) .................. 52 
5.6.5 
Acceptable Concomitant Medications ........................................................ 52 
5.6.6 
Prohibited and Restricted Therapies ......................................................... 53 
5.7 
Unacceptable Toxicities ............................................................................. 54 
5.8 
Criteria for Removal from Study Treatment .............................................. 55 
5.9 
End of Treatment (EOT) Visit ..................................................................... 56 
5.10 
Duration of Follow Up ................................................................................. 57 
5.10.1  Safety Follow-up ........................................................................................ 57 
5.10.2  Survival Follow-up ..................................................................................... 57 
6.0 
TRIAL FLOW SHEET ......................................................................................... 57 
6.1  
Screening, Standard of Care Neoadjuvant Chemotherapy/Pre 
Immunotherapy Phase Study Calendar..................................................... 60 
6.2  
Neoadjuvant Immunotherapy Phase Study Calendar .............................. 62 

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6.3  
Surgery, Standard of Care Adjuvant Chemotherapy Phase Study 
Calendar ....................................................................................................... 65 
6.4  
Maintenance Immunotherapy Phase Study Calendar .............................. 67 
7.0 
TRIAL PROCEDURES ........................................................................................ 70 
7.1 
Administrative Procedures ......................................................................... 70 
7.1.1  
Informed Consent ...................................................................................... 70 
7.1.2  
Inclusion/Exclusion Criteria ........................................................................ 71 
7.1.3  
Registration Guidelines and Procedures ................................................... 71 
7.1.4  
Medical History .......................................................................................... 71 
7.1.5 
Prior and Concomitant Medications Review .............................................. 71 
7.1.6  
Disease Details and Treatments ................................................................ 72 
7.1.7  
Assignment of Screening Number ............................................................. 72 
7.1.8  
Assignment of Randomization Number ..................................................... 73 
7.1.9 
Trial Compliance (Medication/Diet/Activity/Other) ..................................... 73 
7.2 
Clinical Procedures/Assessments ............................................................. 73 
7.2.1 
Adverse Event (AE) Monitoring ................................................................. 73 
7.2.2 
Complete Physical Exam ........................................................................... 73 
7.2.3  
Focused Physical Exam ............................................................................ 74 
7.2.4 
Vital Signs and Pulse Oximetry ................................................................. 74 
7.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale .......... 74 
7.2.6 
Tumor Imaging and Assessment of Disease ............................................. 74 
7.3 
Laboratory Procedures/Assessments ....................................................... 75 
7.3.1 
Basic Laboratory Testing ........................................................................... 75 
7.3.2 
Tumor Tissue Collection and Correlative Studies ...................................... 77 
7.4 
Other Procedures ........................................................................................ 79 
7.4.1 
Withdrawal/Discontinuation ....................................................................... 79 
7.4.2  
Blinding/Unblinding .................................................................................... 79 
7.5  
Visit Requirements ...................................................................................... 79 
7.5.1 
Screening .................................................................................................. 79 
7.5.2. 
Treatment Period ....................................................................................... 80 
7.5.3 
Post-Treatment Follow-up Visits ................................................................ 80 
7.6 
Assessing and Recording Adverse Events .............................................. 81 
7.6.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the IND Sponsor, Merck, and Verastem .................................................... 82 

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7.6.2 
Reporting of Pregnancy and Lactation to the IND Sponsor, Merck, and 
Verastem ................................................................................................... 83 
7.6.3 
Immediate Reporting of Adverse Events to the IND Sponsor, Merck, and 
Verastem ................................................................................................... 84 
7.6.4 
Evaluating Adverse Events ........................................................................ 87 
7.6.5 
Special considerations for adverse events that occur during the surgery and 
postoperative course ................................................................................. 91 
7.6.6  
IND Sponsor Responsibility for Reporting Adverse Events ....................... 94 
8.0 
STATISTICAL METHODS .................................................................................. 95 
8.1 
Study Design and Sample Size .................................................................. 95 
8.2 
Interim Monitoring for Toxicity .................................................................. 96 
8.2.1  
Surgical Complications/Toxicity ................................................................. 97 
8.3 
Interim Analysis for Futility ........................................................................ 98 
8.4 
Data Analysis ............................................................................................... 98 
9.0 
LABELING, PACKAGING, STORAGE, AND SUPPLIES .................................. 98 
9.1 
Investigational Product............................................................................... 98 
9.2 
Packaging and Labeling Information ........................................................ 99 
9.3 
Clinical Supplies Disclosure ...................................................................... 99 
9.4 
Storage, Stability, and Handling Requirements ....................................... 99 
9.5 
Returns and Reconciliation ........................................................................ 99 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS ......................................... 100 
10.1 
Data Collection and Processing .............................................................. 100 
10.2 
Meetings ..................................................................................................... 101 
10.3 
Monitoring .................................................................................................. 101 
11.0 References ....................................................................................................... 103 
Appendix 1: Performance Status Criteria ............................................................... 108 
Appendix 2: Contraceptive Guidance and Pregnancy Testing ............................. 109 
Appendix 3: Substrates, Inhibitors, Inducers of CYP2C9, CYP3A4, OATP1B1 and 
 
OATPIB3 ........................................................................................................... 112 
Appendix 4: Adverse Event of Clinical Interest (ECI) Reporting Form ................. 115 
Appendix 5: SAE Reporting Form ............................................................................ 117 
END OF PROTOCOL ................................................................................................. 119 
 
 
 
 
 

Product: Pembrolizumab (MK-3475), Defactinib 
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1.0 
TRIAL SUMMARY 
 
Abbreviated Title 
A Randomized Phase II Study of Pembrolizumab With or Without 
Defactinib, 
a 
Focal 
Adhesion 
Kinase 
Inhibitor 
Following 
Chemotherapy as a Neoadjuvant and Adjuvant Treatment for 
Resectable Pancreatic Ductal Adenocarcinoma  
Trial Phase 
Phase II 
Clinical Indication 
High-Risk Resectable Pancreatic Ductal Adenocarcinoma  
Trial Type 
Interventional 
Type of control 
Historical Control 
Route of administration 
Intravenous (Pembrolizumab) and Oral (Defactinib) 
Trial Blinding 
Unblinded Open-label 
Treatment Groups  
Arm A:  
Two cycles of standard of care (SOC) neoadjuvant chemotherapy 
with gemcitabine and nab-paclitaxel. Followed by two cycles 
pembrolizumab (MK-3475) 200 mg IV every 3 weeks (Q3W) and 
focal adhesion kinase (FAK) inhibitor, defactinib, 400 mg twice daily 
(BID) throughout each immunotherapy (pembrolizumab) cycle, 
extending up until 2 days prior to surgery (last dose 48 hours prior 
to surgery). Followed by SOC surgery and adjuvant chemotherapy. 
Followed by eight cycles pembrolizumab (MK-3475) 200 mg IV 
every 3 weeks and defactinib, 400 mg twice daily (BID) throughout 
each immunotherapy (pembrolizumab) cycle. 
 
OR 
 
Arm B:  
Two cycles of standard of care (SOC) neoadjuvant chemotherapy 
with gemcitabine and nab-paclitaxel. Followed by two cycles 
pembrolizumab (MK-3475) 200 mg IV every 3 weeks (Q3W) only. 
Followed by SOC surgery and adjuvant chemotherapy.  Followed 
by eight cycles pembrolizumab (MK-3475) 200 mg IV every 3 
weeks alone. 
Number of trial participants 
36 subjects (18 per arm)  
Estimated enrollment period 
12-24 months 
Estimated duration of trial 
The trial will require approximately 36-48 months from the time the 
first subject signs the informed consent until the last subject’s last 
study-related phone call or visit. 
Duration of Participation 
Each subject will participate in the trial from the time the subject 
signs the Informed Consent Form (ICF) through the final protocol 
specified contact.  Eligible subjects will be randomized to either 
pembrolizumab and defactinib (Arm A) with SOC neoadjuvant 
chemotherapy, surgical resection and adjuvant chemotherapy or 
pembrolizumab only (Arm B) with SOC neoadjuvant chemotherapy, 
surgical resection and adjuvant chemotherapy. After enrollment, all 
subjects will receive two cycles (~2 months) of standard 
neoadjuvant chemotherapy with gemcitabine and nab-paclitaxel 
through local oncologist. Then subjects will undergo endoscopic 
ultrasound (EUS) with biopsy followed by on-study treatment with 
two cycles (~2 months) pembrolizumab and oral defactinib (Arm A) 
or two cycles of pembrolizumab alone (Arm B) until surgery. All 

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subjects will undergo surgical evaluation and in the absence of 
systemic disease, pancreatectomy. Following surgery, all subjects 
will receive standard of care adjuvant chemotherapy at discretion 
of treating oncologist (~6 months; surgery followed by SOC 
adjuvant therapy together). Surgical resection and adjuvant 
chemotherapy will not be a part of the study protocol, as they are 
SOC therapies for resectable PDAC. After completion of SOC 
adjuvant chemotherapy, subjects will be treated on-study with 
immunotherapy and FAK inhibition or immunotherapy alone. 
Subjects in Arm A will be placed on maintenance pembrolizumab 
and oral defactinib twice daily every 3 weeks and subjects in Arm B 
will receive maintenance pembrolizumab only every 3 weeks for a 
total of 24 weeks (~6 months). 
 
After the end of treatment, which is the final administration of any 
study drug, pembrolizumab or defactinib, each subject will be 
followed for 30 days for AE monitoring, culminating with a post 
treatment visit 30 days after final administration. Serious adverse 
events (SAEs) will be collected for 90 days after the end of 
treatment or for 30 days after the end of treatment if the subject 
initiates new anticancer therapy, whichever is earlier.  
 
All subjects will have post-treatment follow-up for disease status, 
adverse events and survival, until initiating a non-study cancer 
treatment, experiencing disease recurrence/progression, death, 
withdrawing consent, or becoming lost to follow-up per protocol. 
 
Estimated average length of 
treatment per patient 
16 months (including SOC chemotherapies and surgery) 
 
2.0 
TRIAL DESIGN 
 
2.1 
Trial Design 
 
This is a multi-center, two-arm, randomized, open-label, phase II clinical trial of a 
combination of neoadjuvant and adjuvant immunotherapy with pembrolizumab (MK-
3475) and defactinib, a focal adhesion kinase inhibitor (FAK), following neoadjuvant 
standard of care (SOC) chemotherapy in subjects with high-risk resectable pancreatic 
ductal adenocarcinoma (PDAC).  
 
This immunotherapy and FAK inhibitor trial will primarily evaluate if reprograming the 
tumor microenvironment by targeting FAK following chemotherapy can potentiate anti-
programmed death-1 (PD-1) antibody by modulating myeloid (tumor associated 
macrophages [TAM] & myeloid–derived suppressor cells [MDSC]) inflamed stroma and 
lead to an increase in CD8 T cell infiltration in PDAC. We will also assess for improvement 
of pathologic complete response. This trial will also assess for safety, disease free 
survival (DFS) and overall survival (OS) of immunotherapy and FAK inhibition 
combinatorial therapy and peritumoral immunologic implications through exploratory 
biologic endpoints. 
 

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Subjects who have newly diagnosed and surgically resectable PDAC, who will undergo 
a potentially curative resection and have an elevated CA 19-9 >200, are eligible to 
participate in this study.  Criteria for determining resectability will strictly follow consensus 
guidelines issued by the Americas Hepatopancreatobiliary Association (AHPBA)/Society 
for Surgery of the Alimentary Tract (SSAT)/Society of Surgical Oncology (SSO)/National 
Comprehensive Cancer Network (NCCN).  Eligible subjects will be randomized, stratified 
by age (≥65, <65), in a 1:1 fashion into either Arm A (pembrolizumab [MK-3475] 200 mg 
IV q3w following SOC neoadjuvant chemotherapy and eight cycles pembrolizumab 200 
mg IV every 3 following SOC surgical resection and adjuvant chemotherapy with the 
addition of FAK inhibitor, defactinib, 400 mg twice daily [BID] throughout each 
immunotherapy [pembrolizumab] cycle in both the neoadjuvant and adjuvant settings) or 
Arm B (pembrolizumab 200 mg IV q3w following SOC neoadjuvant chemotherapy and 
eight cycles pembrolizumab 200 mg IV every 3 following SOC surgical resection and SOC 
adjuvant chemotherapy, only). 36 subjects (18 per arm) will be enrolled and randomized 
in the study. The study will consist of seven parts.  
 
In part one, all subjects will undergo consent and pre-study screening procedures for 
eligibility in preparation for neoadjuvant therapy. An EUS-guided core biopsy for 
diagnostic, research purposes and organoid tissue culture will be obtained prior to the 
initiation of neoadjuvant chemotherapy, if a diagnostic biopsy has not been done prior to 
the enrollment.  In part two, all subjects will receive two cycles of standard chemotherapy 
in the neoadjuvant setting with gemcitabine and nab-paclitaxel. Of note, patients can be 
enrolled and randomized up to 1 week after initiating chemotherapy as long as all 
screening procedures and eligibility criteria have been completed prior to starting 
treatment. In the SOC chemotherapy phase subjects will be able to receive chemotherapy 
through a local oncologist. A second EUS-guided core biopsy for research purposes and 
organoid tumor tissue production, is required prior to the administration of neoadjuvant 
immunotherapy and FAK inhibition in part three of the study. In part three, subjects will 
receive two cycles of pembrolizumab 200mg q3weeks and twice daily oral defactinib 400 
mg for 3 weeks (Arm A) or pembrolizumab 200mg q3weeks alone (Arm B). Defactinib will 
be continued until 2 days before surgery (last dose 48 hours prior to surgery). In part four, 
all subjects will undergo surgical evaluation and in the absence of systemic disease, 
pancreatectomy. Standard surgical procedure will be determined by the operating 
surgeon. Pancreatectomy is considered standard of care for pancreatic cancer and 
therefore will not be a part of the study protocol. The surgery will be scheduled between 
day 10 to day 25 from the administration of cycle two of pembrolizumab. If the subject is 
found to have unresectable disease intraoperatively, core biopsies will be performed 
intraoperatively. Subjects who are found to have unresectable or metastatic disease 
intraoperatively will be excluded from continuing in the study. Following the surgery, 
subjects with R0 or R1 resection will continue to the next phase of the study. In part five, 
following surgery, all subjects will receive standard of care adjuvant chemotherapy at 
discretion of treating oncologist. Part four and five will not be a part of the study protocol, 
as pancreatectomy and adjuvant chemotherapy are standard therapies for resectable 
PDAC. In part six, subjects with no evidence of disease recurrence and who continue 
meet inclusion criteria after completion of SOC adjuvant chemotherapy will be treated on 
study with maintenance immunotherapy and FAK inhibition or immunotherapy alone. 

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Subjects will receive maintenance immunotherapy with pembrolizumab 200 mg q3weeks 
and defactinib 400 mg BID for 3 weeks (Arm A) or pembrolizumab 200 mg q3w (Arm B) 
alone, as one cycle for a total of 8 cycles/24 weeks. Part seven of the study will be the 
follow up phase. 
 
Adverse events (AE) will be monitored from the first administration of any study drug (ie 
pembrolizumab or defactinib) and graded in severity according to the guidelines outlined 
in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. Each subject will be followed for 30 days after last dose of any 
study drug administration for AE monitoring. Serious adverse events (SAEs) will be 
collected for 90 days after the end of treatment or 30 days after the end of treatment if 
the subject initiates new anticancer therapy, whichever is earlier.  
 
This study will be conducted in conformance with Good Clinical Practices (GCP). Specific 
procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of 
each procedure are provided in Section 7.0 – Trial Procedures.  
 
Details of each phase of the study are outlined below. 
 
2.1.1 
Part 1: Pre-study Consent, Screening, and Randomization 
 
The pre-surgical staging of disease will be performed by the Department of Surgery.  
Pretreatment biopsy is necessary for enrollment in this study.  If the subject is referred to 
the study without a diagnostic biopsy, a diagnostic core biopsy will be performed. If a 
diagnostic biopsy has already been done prior to enrollment, we will request the archived 
tissue in lieu of performing a core biopsy. If a subject is found to be eligible for this study 
based on pre-surgical staging and pre-study screening, they will be consented for this 
study and then randomized to either treatment Arm A or treatment Arm B.   
 
2.1.2 
Part 2: Neoadjuvant Chemotherapy  
 
Following clinical trial enrollment, subjects will begin neoadjuvant therapy with planned 
two, 28-day cycles of gemcitabine and nab-paclitaxel. Gemcitabine and nab-paclitaxel 
are standard therapies for pancreatic cancer. As a standard of care therapy, subjects will 
be allowed to receive this portion of therapy with local oncologist. Adverse events 
monitoring will begin after the completion of standard of care therapy and with the first 
administration of study drugs pembrolizumab +/- defactinib.   
 
2.1.3 
Part 3: Neoadjuvant Pembrolizumab and Defactinib 
 
A computed tomography (CT) scan will occur every 2 months or at the completion of cycle 
2 of neoadjuvant chemotherapy. At the completion of two cycles of gemcitabine and nab-
paclitaxel, subjects will undergo a second EUS-guided core biopsy for research purposes 
and organoid tissue procurement. 
 

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All subjects who have completed neoadjuvant chemotherapy will undergo re-screening in 
order to receive combination immunotherapy and FAK inhibition. Re-screening criteria 
can be found in Section 5.1.3 and in Section 5.1.4.  
 
Following second EUS-guided core biopsy and pre-immunotherapy imaging, subjects 
assigned to treatment Arm A will receive two cycles of pembrolizumab 200mg given every 
three weeks and oral defactinib 400 mg given twice daily every day up until 2 days 
preceding surgery (last dose 48 hours prior to surgery). Those subjects assigned to 
treatment Arm B will receive two cycles of pembrolizumab 200mg alone given every three 
weeks. The first dose of pembrolizumab will start within 1 week from second EUS guided 
biopsy. A second CT scan will occur at the end of the second cycle of pembrolizumab 
and prior to surgery. The surgery will be scheduled between 10 to 25 days following the 
start of the second cycle of pembrolizumab. If patient is unable to receive second cycle 
of neoadjuvant immunotherapy, patient’s surgery can occur after the end of the first cycle 
of immunotherapy and after surgical evaluation has occurred. Surgical evaluation will 
include assessments as noted in section 6.2.  
 
2.1.4 
Part 4: Surgery 
 
Subjects will undergo the pancreatectomy at the clinical trial site at which they are enrolled. 
The surgical procedure performed will result in either a R0, R1 or R2 resection as 
determined by final pathology.  Perioperative outcomes will be recorded including the 
operation performed, whether vascular resection and reconstruction was required, 
completeness of the resection (R0, R1 or R2), duration of the operation, blood loss, the 
length of stay, the need for re-admission within 30 days of surgery, and intraoperative 
and postoperative complications.  Pancreatectomy is the standard of care to which 
immunotherapy and FAK inhibition or immunotherapy alone will be added to. As standard 
of care therapy for PDAC, this part of the study will be conducted outside of the study 
protocol. Adverse events monitoring will still occur throughout the SOC surgery phase. If 
the subject is found to have unresectable disease, core biopsies will be performed 
intraoperatively. Resected specimens will be archived for research purposes. Tumor 
infiltrating immune cells will be isolated from resected tumor tissue.  
 
2.1.5 
Part 5: Adjuvant Chemotherapy  
 
Following surgery, all subjects with R0 or R1 SOC resection will receive standard of care 
adjuvant chemotherapy with gemcitabine plus capecitabine or another standard of care 
chemotherapy at the discretion of the primary treating oncologist. As standard of care 
therapy for PDAC, this part of the study will be outside of the study protocol. While the 
subject is receiving the SOC adjuvant chemotherapy, she/he will not receive any 
immunotherapy. Because chemotherapy can have significant toxicities we will not be 
monitoring chemotherapy or adjuvant SOC treatment related toxicities during adjuvant 
SOC therapy. However, we will monitor and report toxicities that are not attributable to 
surgery, post-operative course, chemotherapy, radiation therapy and disease 
progression 90 days from administration of neoadjuvant immunotherapy. 
 

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2.1.6 
Part 6: Adjuvant Immunotherapy Maintenance  
 
All subjects who complete at least one cycle of neoadjuvant immunotherapy, undergo 
SOC surgical resection, complete SOC adjuvant therapy and have no evidence of 
recurrence will undergo re-screening in order to receive 8 additional cycles of adjuvant 
combination immunotherapy and FAK inhibition (arm A) or immunotherapy alone (Arm 
B). Re-screening criteria for adjuvant immunotherapy can be found in Section 5.1.5 and 
Section 5.1.6. 
 
After completion of adjuvant SOC chemotherapy, subjects will resume the study protocol 
for continuation of immunotherapy and FAK inhibition or immunotherapy alone.  Subjects 
in Arm A will receive maintenance pembrolizumab 200mg every 3 weeks and defactinib 
400 mg twice daily every 3 weeks for a total of 24 weeks (8 cycles).  Subjects in Arm B 
will be placed maintenance 200mg pembrolizumab alone every 3 weeks for a total of 24 
weeks (8 cycles). 
 
2.1.7 
Part 7: Follow up 
 
After subjects have completed all planned therapy, they are considered off treatment 
beginning 90 days after the last immunotherapy or FAK inhibitor (pembrolizumab or 
defactinib). All subjects will undergo an EOT evaluation 30 days after last dose of study 
drug, pembrolizumab or defactinib. Once off treatment, all subjects will undergo standard 
of care evaluations through their primary oncologist, consisting of history and physical, 
CT of the chest/abdomen/pelvis (or MRI abdomen/pelvis and non-contrast CT chest if do 
not tolerate contrast) every three to six months or as indicated to evaluate for local 
recurrence and metastatic disease.  The study will collect the follow-up information 
including; disease status, adverse events and survival from primary oncologist and 
subjects. 
 
Throughout the study, an internal and external real-time monitoring plan will be put in 
place to ensure that toxicities are captured and evaluated in a timely, appropriate, and 
non-biased manner. Subjects will be monitored at regular intervals for a broad range of 
toxicities, including enhanced inflammatory related complications prior to surgery, 
delayed surgery related healing, and immune-related adverse events (irAEs). 
 
2.2 
Trial Diagram: 
The trial design is depicted in Figure 1 below: 

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3.0 
OBJECTIVES & HYPOTHESES 
 
3.1 
Primary Objectives & Hypotheses: 
 
1. Objective (1): To assess changes in CD8 T cell intratumoral infiltration with 
pembrolizumab and defactinib or pembrolizumab alone, following neoadjuvant 
chemotherapy utilizing established multiplex IHC.  
 
Hypothesis: Pembrolizumab and defactinib or pembrolizumab alone increases CD8 
T cell infiltration compared to chemotherapy alone. 
  
2. Objective (2):  To assess the pathologic complete response (pCR) rate of 
neoadjuvant pembrolizumab and focal adhesion kinase (FAK) inhibitor, defactinib or 
pembrolizumab alone following neoadjuvant chemotherapy. 
 
Hypothesis: Pembrolizumab and defactinib or pembrolizumab alone, improves pCR 
by 15%. 
 
 
3.2 
Secondary Objectives & Hypotheses: 
 
1. Objective (1): To assess overall survival (OS). 
 
Hypothesis (1): Pembrolizumab and defactinib or pembrolizumab alone, following 
standard of care neoadjuvant therapy, surgical resection and adjuvant therapy 
improves OS as compared to historical outcomes with standard of care therapy.  
 

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Hypothesis (2): Pembrolizumab and defactinib improves OS compared to 
pembrolizumab alone.  
 
2. Objective (2): To assess disease free survival (DFS). 
 
Hypothesis (1): Pembrolizumab and defactinib or pembrolizumab alone, following 
standard of care neoadjuvant therapy, surgical resection and adjuvant therapy 
improves DFS as compared to historical outcomes with standard of care therapy. 
 
Hypothesis (2): Pembrolizumab and defactinib improves DFS compared to 
pembrolizumab alone.  
 
3. Objective (3):  To assess safety: the proportion of subjects experiencing at least one 
grade 3/4 non-lymphopenia adverse events (AE). 
 
3.3 
Exploratory Objectives: 
 
1. Objective (1): To assess immunogenic cell death (calreticulin IHC and signaling 
pathways following neoadjuvant chemotherapy/pre-immunotherapy and surgical 
biopsy specimens through immunohistochemistry and nanostring PCR analysis. 
 
2. Objective (2): To assess CD68/CD8 ratio via multiplex IHC .  
 
3. Objective (3): To assess expression of programmed death-ligand (PD-L1) and 
programmed death (PD-1) via IHC.  
 
4. Objective (4): To assess immune signatures relevant to PD-L1/PD-1 activation and 
associated immunosuppressive pathways. 
 
5. Objective (5): To assess pre- vs. post-treatment (pre-immunotherapy biopsy 
specimens and post-immunotherapy resected tumor specimens) intratumoral and 
peripheral blood T cell receptor (TCR) clonality.  
 
6. Objective (6): To assess changes of TAM (tumor associated macrophages), myeloid–
derived suppressor cells (MDSC) and T-reg cells with pembrolizumab and defactinib 
or pembrolizumab alone, following neoadjuvant chemotherapy utilizing established 
multiplex IHC. 
 
7. Objective (7): To assess activity of pancreatic stellate cells via α-Smooth muscle actin 
(αSMA) and fibroblast activate protein (FAP) immunohistochemistry (IHC) with 
pembrolizumab and defactinib or pembrolizumab alone, following neoadjuvant 
chemotherapy. 
 
8. Objective (8): To assess near pathologic CR rate and grade 3 pathologic response 
rate. 

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See Section 7.3.2 for further information regarding analysis of exploratory objectives.  
 
4.0 
BACKGROUND AND RATIONALE 
 
4.1 
Introduction 
 
Pancreatic ductal adenocarcinoma (PDAC) is presently the third leading cause of cancer 
related death and is expected to surpass colorectal cancer to become second by 2030.1,2 
Despite advances in chemotherapy and radiotherapy over the last 10 years, the best 
clinical outcomes are appreciated in patients that undergo surgical resection. Yet among 
the 20% who are surgical candidates at the time of diagnosis, the rate of recurrence is 
nearly 80%. The median survival among this cohort is only 13-20 months.3 The addition 
of adjuvant radiation and/or chemotherapy has demonstrated limited improvement in 
survival of resectable PDAC to 25-28 months.4–6 Novel multidisciplinary and multimodal 
therapeutic approaches are needed for all stages of this aggressive disease.  
 
4.2 
Rationale for Neoadjuvant Chemotherapy 
 
Presently the only the curative option for PDAC is surgical resection. Most patients recur 
after surgery and therefore adjuvant strategies have been investigated in the last decade 
to improve clinical outcomes. Multiple contemporary studies, including ESPAC-4 have 
clearly established the benefit of adjuvant chemotherapy.5–9  However, the application of 
adjuvant therapy is not uniform across all resected patients. It is estimated that up to 50% 
of patients do not receive adjuvant therapy due to variety of post-operative 
circumstances.10  Additionally, post-operative recovery delays time to adjuvant therapy 
and allows growth of potential micrometastatic disease. As a result of the high degree of 
recurrence and the potential of occult disease at time of diagnosis, neoadjuvant therapy 
has been investigated as a treatment approach among all stages of PDAC. Neoadjuvant 
therapy can lead to tumor regression, eradication of micrometastatic disease and 
increase the probability of achieving an R0 (no residual tumor) resection. Numerous 
studies have shown that neoadjuvant therapy can lead to a pCR in PDAC.11 Pathologic 
complete response has significant clinical implications on local and distant recurrence, as 
well as overall survival.12,13 Despite these benefits, there is no clear consensus on the 
role of neoadjuvant therapy. The utility of neoadjuvant therapy has predominantly been 
supported in studies looking at patients with borderline resectable or locally advanced 
disease.14–16 Presently, multiple active clinical trials are evaluating neoadjuvant therapy 
for patients that are deemed resectable at time of diagnosis. Despite the paucity of data 
regarding the role of neoadjuvant therapy in upfront resectable PDAC, neoadjuvant 
therapy has been shown to confer a clinical benefit in patients with more aggressive or 
advanced disease.  
 
Typically, radiographic assessment is utilized in determining the degree of advanced 
disease, appropriate management and the role of neoadjuvant therapy and/or surgical 
resection. Yet in patients with radiographically resectable disease, other biological 

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markers are needed to assist surgeons and oncologists in identifying the subset of 
patients who are at high risk of recurrence and who may benefit from neoadjuvant 
therapy. One prognostic marker that has been suggested as a tool for selection of high 
risk disease individuals, is cancer antigen 19-9 or sialylated Lewis antigen (CA 19-9). 
Perioperative CA 19-9 levels have been found to correlate with clinical outcomes and long 
term survival.17 More importantly, a CA 19-9 >200u/ml has been associated with an 
increased risk of early recurrence after resection for PDAC as suggested by Tamburrino 
et al, World J Gastroenerol, 2014 and Shimizu et al, American Surgeon, 2018.18,19 Higher 
CA 19-9 levels are correlated with advanced disease and have implications on 
resectability. Despite advancements in radiographic imaging for staging, up to 15% of 
patients with radiographically resectable disease are noted to have unresectable disease 
at time of surgery because of occult metastasis or locally invasive malignancy. CA 19-9 
has been looked as a surrogate marker for resectability and disease stage, where 
significant elevations confer advanced and higher risk disease.20 In order to improve 
clinical outcomes in patients with resectable disease, it is critical to move beyond 
radiographic assessment, as this does not take into account the biological 
aggressiveness of PDAC.  The selection of patients who will benefit most from 
neoadjuvant therapy needs to take into account both patients who are resectable and 
those who have a substantially elevated CA 19-9.  
 
4.3 
Rationale for PD-1 Blockade (Pembrolizumab [MK-3475]) 
 
Immune surveillance is a critical aspect in the regulatory mechanism of cell growth and 
malignant transformation. The immune system has built in “checkpoints” to assist in 
differentiating “self” from “non-self” and more importantly in maintaining the homeostasis 
of inflammatory response.  Neoplastic conversion of cells allows for the capture of cellular 
mechanisms in order to manipulate these checkpoints. Malignant cells are then able to 
avoid immune detection and diminish an anti-tumor inflammatory response.  
 
Within the immune milieu, the adaptive T cell response, utilizing CD8+ and CD4+ T cells, 
plays a vital role in autoimmunity and acute inflammatory response. These same cells are 
involved in the adaptive immunity against tumor cells as tumor infiltrating lymphocytes 
(TILs).  Over the last decade there has been a growing body of evidence suggesting that 
TILs play an important role in facilitating the response of standard chemotherapy and 
improving clinical outcomes in various tumors like breast cancer, melanoma and 
esophageal cancer.21–23 Additionally, it has been suggested that many tumor antigens are 
“self” proteins and that the altered expression of these proteins increases tumor 
immunogenicity. However, self–tumor antigens may also induce the preferential 
propagation of CD4+ CD25+ FOXP3+ T-regulatory (T-reg) cells. T-reg cells function to 
maintain immune homeostasis and limit acute inflammation.24  
 
The degree of CD8+ T-cell infiltration and the ratio of CD8+ effector T-cells / FoxP3+ T-reg 
has been shown to correlate with improved clinical outcomes and prognosis in solid 
malignancies such as ovarian, colorectal, urothelial, hepatocellular carcinoma, malignant 
melanoma, renal cell cancer and pancreatic cancer.25–27 
 

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Although historically pancreatic adenocarcinoma has been thought of a minimally 
immunogenic tumor, recent comprehensive genomic analysis provides evidence 
suggesting that a subtype of pancreatic adenocarcinoma can be highly immunogenic. 
This is thought to occur through the upregulation of the immune environment with TILs 
and increased immune checkpoint molecule expression, like programmed cell death 1 
(PD-1) and programmed cell death ligand 1 (PD-L1).28  
 
PD-1 is expressed on activated T, B, NK and dendritic cells as well as monocytes and 
serves as an immune checkpoint.29 It has a vital role in the development and regulation 
of the adaptive immune system via T cells.  Under normal circumstances, PD-1 functions 
to inhibit effector T cells through downstream kinase inhibition, decreased signaling of T 
cell receptors (TCR), as well as decrease in INF-γ and IL-2 leading to immune 
suppression. This is done to modulate unwanted or excessive immune responses, 
including autoimmune reactions. However, this interaction between PD-1 and its ligands 
PD-L1 and PD-L2, is hijacked by tumors in order to suppress immune response. PD-L1 
is expressed at diminished levels on numerous non-hematopoietic tissues, such as the 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or environments with chronic inflammation.  PD-
L2 is involved in immune T-cell activation within lymphoid organs, whereas PD-L1 serves 
to control mechanism for unwarranted T-cell function in peripheral tissues.30 
 
Most normal healthy tissues express diminutive amounts of PD-L1. However a number 
of malignancies including ovarian, renal cell and hepatocellular carcinoma have been 
shown to express amplified levels of PD-L1 and consequently a diminished T cell 
response leading to poorer clinical outcomes and prognosis.26,27,31 Even in pancreatic 
cancer, PD-L1 expression has been shown to be inversely correlated with TILs, 
particularly CD8+ cells and associated with a significantly poorer prognosis as suggested 
by Nomi et al, Clinical Cancer Research, 2007.32 Since the discovery of PD-1 and its 
ligand in the early 90s, there has been increasing evidence to suggest that PD-L1 
expression and the PD-1/PD-L1 pathway is a critical mechanism by which tumors like 
PDAC can evade immune detection. As a result of its integral role in immune modulation, 
blockade of PD-1 has been appealing and rational target for therapeutic intervention.  
 
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal 
antibody of the IgG4/kappa isotype designed to directly block the interaction between PD-
1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab contains the S228P stabilizing 
mutation and has no antibody-dependent cell-mediated cytotoxicity (ADCC) or 
complement-dependent cytotoxicity (CDC) activity.  Pembrolizumab strongly enhances T 
lymphocyte immune responses in cultured blood cells from healthy human donors, cancer 
patients, and primates.  In T- cell activation assays using human donor blood cells, the 
EC50 was in the range of 0.1 to 0.3 nM. Pembrolizumab also modulates the level of 
interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and 
other cytokines.  The antibody potentiates existing immune responses only in the 
presence of antigen and does not nonspecifically activate T- cells. 

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Pembrolizumab is FDA-approved for unresectable or metastatic melanoma, metastatic 
non-small cell lung cancer, recurrent or metastatic head and neck squamous cell 
carcinoma and locally advanced or metastatic urothelial cancer at 200 mg flat dose every 
3 weeks.  
The observed correlation of clinical outcomes and prognosis with PD-L1 expression in 
multiple cancers suggests that the PD-1/PD-L1 pathway plays a critical role in tumor 
immune evasion and should be considered as an attractive and rational target for 
therapeutic intervention. However, the targeting of immune checkpoints alone are not 
ideal treatment strategies for pancreatic cancer, as other significant cellular and 
microenvironmental barriers remain.  
 
4.4 
Rationale for FAK Inhibition (Defactinib) 
 
PD-1 blockade in lung cancer, colorectal cancer and melanoma has led to significant 
improvements of clinical outcomes.33–35 However,  pancreatic cancer has remained 
relatively refractory to checkpoint inhibition in comparison to other tumor types.36 Immune 
modulation via upregulation of checkpoint molecules, like PD-1/PD-L1, is only one of 
many important barriers in an effective anti-tumor response. The tumor microenvironment 
(TME) serves as another critical barrier in pancreatic cancer treatment in general and 
immune checkpoint blockade. The reason that the TME in PDAC functions as critical 
barrier is twofold; 1) the pancreatic cancer is a significantly stroma rich tumor and 2) 
increased myeloid cell and immunosuppressive cell infiltration is noted within the TME. 
37,38  
 
In order maximize the effect of traditional chemotherapy or any potential immune 
modulation via PD-1 blockade in favor of an anti-tumor response, the aforementioned 
obstacles of the TME must be overcome. Recently, a non-receptor tyrosine kinase, focal 
adhesion kinase (FAK) has been found to play an integral role modifying stromal fibrosis 
and TME immune suppression.39  
 
In many malignancies, FAK is often upregulated with downstream signaling of integrins 
and growth factor receptors in order to maintain the neoplastic nature and survival of 
cancer cells. It does this by controlling a wide range of integral cellular functions from 
adhesion, migration, invasion, proliferation, and survival.40 FAK has also been implicated 
in production of increased pathologic fibrosis, cytokine release and inflammation. 41,42  
FAK signaling is critically involved in various aspects of the TME, particularly 
immunosuppression and stromal alterations.  Studies have shown that inhibition of FAK 
decreases the recruitment and migration of carcinoma associated fibroblasts (CAFs) and 
TAMs.43 The tumor stromal environment is rich in CAFs which are implicated in the 
growth, drug resistance, angiogenesis and metastasis of cancer.44 For example, in 
pancreatic cancer, the stromal and tumor microenvironment is characterized by increased 
collagen deposition with an elevated fibrotic response and infiltration of CAFs.45 
Additionally, CAFs have been shown to suppress CD8+ T cells and are associated with 
T cell dysfunction via mechanisms that involve immune checkpoints.46 In a study by 
Stokes et al.,  pancreatic tumors from animals treated with PF-562,271 (a small molecule 

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inhibitor of FAK) led to a significant decrease in the number α-SMA-staining (CAFs) cells 
and a significant decrease in tumor cell proliferation.43 Numerous preclinical studies have 
shown that FAK signaling is intimately involved in modulating MDSCs, TAMs, and T 
regulatory cells(T-Reg) within the TME.41,43,47,48  In squamous cell carcinoma preclinical 
mouse models, small molecule FAK inhibitor VS-4718 was revealed to reduce 
immunosuppressive MDSCs, TAMs and T-Reg cells. This consequently led to increased 
CD8+ T-cells within the tumor  environment and enhancement of CD8+ T cell mediated 
suppression of cancerous cells.41 
 
Similarly, VS-4718 was evaluated in combination with standard cytotoxic chemotherapy 
employed in the treatment of PDAC and with immunotherapy by Jiang et al, 
2016.49</sup> Jiang and colleagues have recently shown that by inhibiting the FAK 
pathway, pancreatic stellate cells can be modulated leading to a decrease in immune 
suppressive cells including MDSC, TAM, and Treg within the TME in PDAC of mouse 
models. They also noted that there was an increase in CD8+ T cells in FAK-depleted 
tumors and that inhibition of FAK decreased collagen deposition.39 Together, these 
changes within the TME of pancreatic cancer lead to modulation of the immune system 
in favor tumor eradication. Jiang et al, also evaluated the role of FAK inhibition as 
synergistic modality along with immunotherapy and traditional chemotherapy. They found 
that mice treated with gemcitabine, anti-PD1 therapy and FAK inhibition had 2.5 fold 
increase in median survival time compared to those treated with gemcitabine and anti-
PD1 therapy alone.  
 
An additional benefit of FAK inhibition is its ability to reduce cancer stem cells (CSCs). 
Within a tumor, CSCs are capable of self-renewal, are able to generate more cancer cells 
with heterogenous differentiation and are typically resistant to standard therapies, 
resulting in tumor resistance, recurrence and metastasis.5>,51 In preclinical malignant 
mesothelioma models, standard cytotoxic therapies such as pemetrexed, cisplatin, 
gemcitabine and vinorelbine have been shown to increase CSCs, but when FAK inhibition 
is added to the treatment backbone, CSCs are decreased.52 CSCs are influenced by 
critical factors within the TME from cytokines, small RNAs, TAMs and fibroblasts which 
impact its unique niche.38,53 These factors regulate the invasiveness, metastatic potential 
and differentiation of CSCs. 
 
Defactinib is an oral, well tolerated, inhibitor of FAK, which is currently being investigated 
for the treatment of advanced solid tumors, including malignant pleural mesothelioma, 
ovarian cancer, pancreatic cancer and non-small cell lung cancer. Defactinib was found 
to be a potent and selective ATP- competitive, reversible inhibitor of recombinant human 
FAK kinase in biochemical and cell-based assays. A comprehensive evaluation of 
selectivity against a large panel of other kinases in enzyme assays demonstrated that 
defactinib was highly selective for FAK strongly suggesting that its predominant 
pharmacologic activity is mediated by inhibition of FAK. Additionally, utilizing cancer stem 
cell assays, both in vitro and in vivo, defactinib was observed to eradicate cancer stem 
cells. In a recent phase I study by Gilliam et al, defactinib was evaluated in combination 
with pembrolizumab and gemcitabine in advanced pancreatic adenocarcinoma. The triple 
drug regimen was shown to be well tolerated with the 400 mg BID determined to be the 

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RP2D dose. In patients who were heavily pre-treated one had (13%) partial response and 
3 (38%) had stable disease. Additionally, paired biopsies showed an increase in 
proliferating CD8+ T cells and a reduction of T-reg cells and macrophages with 
treatment.5> 
 
Findings from preclinical and clinical studies have elucidated the broad role of FAK 
inhibition as an important modulator of the immunosuppressive components and cancer 
promoting aspects of the tumor microenvironment.  FAK inhibition is an appealing 
therapeutic target and adjunctive therapy that can potentially increase the effectiveness 
of traditional cytotoxic chemotherapy and immunotherapy, particularly for aggressive and 
refractory malignancies, like pancreatic adenocarcinoma.   
 
4.5 
Combination Therapy, Study Rationale and Biologic Markers 
 
Despite the curative intent of surgery and the addition of adjuvant therapy, clinical 
outcomes in PDAC remain poor. Immunotherapy, TME modulation and chemotherapy 
each in their own right may serve as viable therapeutic options. However, each has its 
limitations as evidenced by the unfortunate outcomes appreciated in pancreatic cancer 
relative to many other malignancies that utilize similar therapies.  
 
The aforementioned rationale for each therapeutic modality; its influence on other 
modalities and their interrelationship, suggests that sequential/combinatorial therapy in 
the neoadjuvant setting may provide a unique and novel avenue through which clinical 
outcomes can be improved.  
 
Our previous studies demonstrated granulocyte-macrophage colony-stimulating factor 
gene transfected tumor cell vaccine (GVAX) can reprogram the tumor microenvironment 
(TME) in PDAC by inducing lymphoid infiltration.5> Additionally, we found that 
intratumoral CD68/CD8 ratio is a  potential biomarker of myeloid-inflamed stroma that 
limits efficacy of immunotherapeutic responses despite induction of lymphoid infiltration 
(Figure 2).56 Presently, we are developing a multiplex CD68/CD8 IHC into a CLIA 
biomarker assay using the tumor biospecimens from a clinical trial testing the synergistic 
activity of Nivolumab and GVAX as neoadjuvant and adjuvant therapy for PDAC (clinical 
trial design similar to this study) and using the tumor biospecimens from a clinical trial 
testing the synergistic activity of pembrolizumab, GVAX, SBRT in treating locally 
advanced PDACs (an ongoing Merck MISP study). 
 

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Additionally our group also found that chemotherapy can reprogram the TME in PDAC. 
We found that lower level of CSF-1R TAM was associated with longer overall survival 
following neoadjuvant chemotherapy and surgical resection (Figure 3). 
 
 
 
Figure 3 “Single Cell Based Cytometry” of cell populations expressing different phenotypic and 
functional markers in the PDA TME. This demonstrates the feasibility of analyzing the % of different 
immune populations within the TME for patients treated either with our vaccine or standard chemotherapy. 
 
 
 
 
Figure 2 Left panel: Immune cell densities (cells/mm2) of three leukocyte hotspots in intratumoral regions 
were assessed by sequential multiplex IHC/image cytometry. A heat map according to color scale is shown 
with a dendrogram of unsupervised hierarchical clustering, depicting low and high myeloid-inflamed 
subgroups. Right panel: Kaplan-Meier analysis of neoadjuvant GVAX-treated PDAC cohort (N = 24) 
stratified by subgroups. Statistical significance was determined via log-rank test. (From Tsujikawa et al. Cell 
Reports 2017). 
 
 

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Note that lower level of CSF1R TAM was associated with longer overall survival (OS) following neoadjuvant 
chemotherapy and surgical resection (Tsujikawa and Zheng, et al., unpublished). 
 
Although the appropriate sequencing of chemotherapy and immunotherapy in diseases 
where both therapies are known to be active remains unclear, there is emerging evidence 
that chemotherapy can modulate the host immune system. This can be achieved through 
the expression of cancer neoantigens leading to changes in expression and induction of 
PD-L1. Interestingly, work from our group has shown PD-L1 induction on tumor epithelium 
following neoadjuvant chemotherapy (Figure 4), suggesting a role for combinatorial 
therapy with immunotherapy and traditional cytotoxic chemotherapy. Yet this combination 
can be further augmented by modulating the TME. 
 
 
 
Figure 
4: 
Multiplex 
immunofluorescence 
staining 
of 
PDACs 
following 
neoadjuvant 
gemcitabine/abraxane.  CD 8 Yellow; FOXP3 Red; CD68 Magenta; PD-1 Cyan; PD-L1 Green; Keratin 
Orange; DAPI.  Note that PD-L1 expression (in green) on tumor epithelium was induced following 
neoadjuvant chemotherapy. (Zheng Lab, unpublished) 
 
As noted previously, inhibiting the FAK pathway is known to modulate pancreatic stellate 
cells and decrease the immune suppressive cells including MDSCs, TAMs, and T-regs 
within the TME in PDAC of mouse models (Jiang et al. Nature Medicine 2016). Therefore, 
by regulating the TME, FAK inhibition may serve as a further enhancer of the anti-tumor 
response of immunotherapy and traditional chemotherapy. This anti-tumor response can 
be appreciated both histologically and clinically, by observing pathologic response and 
disease related recurrence/survival, respectively.  
 
Pathologic complete response, is clinically relevant prognostic indicator in many 
gastrointestinal malignancies, like rectal and esophageal cancer.5>,58  In pancreatic 
cancer, patients with complete pathologic outcomes have superior outcomes.59 
Chemotherapy alone in the neoadjuvant setting results in a pathologic complete response 
rate of approximately 0-3%.11  Chemotherapy followed by stereotactic body radiation 
potentially increases pCR to 13%.60,61 Therefore, the standing hypothesis is that by 
adding FAK inhibitor to anti-PD-1 antibody following neoadjuvant chemotherapy will also 
enhance the pCR rate, modulate pancreatic stellate cells and sensitize PDAC to anti-PD-
1 therapy.  Additionally, by improving the pCR rate through immunotherapy and FAK 

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inhibition, systemic antitumor activity may be increased leading to an improvement in 
clinical outcomes and the survival in patients with PDAC. 
 
This clinical trial will evaluate whether treatment that reprograms the tumor 
microenvironment by targeting FAK following chemotherapy can potentiate anti-PD-1 
antibody by modulating myeloid (TAM&MDSC)-inflamed stroma and promote effector T 
cell infiltration in the PDACs, leading to a high rate of pathologic complete response and 
potentially an improvement in clinical outcomes. 
 
5.0 
METHODOLOGY 
 
5.1 
Study Population 
 
Subjects with pretreatment biopsy-proven (or clinically suspected if the biopsy is not 
sufficient for diagnosis), surgically resectable (see Section 5.1.7 for resectability criteria) 
and subsequently pathologically proven AJCC stage I or stage II adenocarcinoma of the 
head, neck, uncinate, body or tail of the pancreas (see 5.1.6 for staging criteria) and who 
have no radiographic evidence of metastatic or unresectable pancreatic cancer prior to 
the starting of immunotherapy. Subjects must also be defined as high risk by a CA 19-
9 >200. 
 
Our targeted accrual goal is 36 evaluable subjects, who will be randomly assigned to two 
treatment arms.  Subjects are considered evaluable if they have a pretreatment biopsy 
demonstrating pancreatic ductal adenocarcinoma, an R0 or R1 resection of their tumors, 
their tumors are pathologically proven stage I/II adenocarcinoma of the pancreas and 
receive at least one dose of pembrolizumab/defactinib or pembrolizumab alone. These 
subjects are also considered evaluable for DFS and OS endpoints.  All subjects who 
receive any dose of study therapy (ie pembrolizumab or defactinib) therapy will be 
monitored and evaluated for safety endpoints. These 36 subjects will be randomized to 
the two treatment arms via the Research Electronic Data Capture (REDCap) application 
to the two treatment arms in a 1:1 ratio. To ensure comparability of the two study arms, 
randomization will be stratified up-front by age (≥65, <65).  The participants will be notified 
of their assigned arm after they have enrolled in the study. 
 
Eligible participants will receive a total of two cycles of SOC neoadjuvant chemotherapy 
with gemcitabine and nab-paclitaxel. Each arm will receive 2 cycles of pembrolizumab in 
the neoadjuvant setting and then will be placed on maintenance pembrolizumab for a total 
of 8 cycles for a total of 24 weeks in the adjuvant setting following SOC surgery and SOC 
adjuvant chemotherapy. One investigational arm will receive defactinib throughout the 
cycles of immunotherapy with pembrolizumab.  
 
▪ In Arm A, subjects will receive pembrolizumab 200mg IV every 3 weeks following 
neoadjuvant chemotherapy and every 3 weeks following adjuvant chemotherapy. 
Subjects in Arm A will also receive defactinib (FAK inhibitor) at 400 mg BID during 
immunotherapy cycles in both the neoadjuvant and adjuvant settings in addition to 
pembrolizumab. 

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▪ In Arm B, subjects will receive pembrolizumab 200mg IV alone every 3 weeks 
following neoadjuvant chemotherapy and every 3 weeks following adjuvant 
chemotherapy. 
 
5.1.1 
Participant Inclusion Criteria for Initial Enrollment (Pre-Neoadjuvant 
Chemotherapy) 
 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
1. Are at least 18 years of age on the day of signing informed consent.  
 
2. Has histologically confirmed diagnosis of pancreatic ductal adenocarcinoma will 
be enrolled in this study.  
 
3. Has resectable disease at the time of diagnosis (see Section 5.1.11, for criteria of 
resectability). 
 
4. Has received no systemic therapy for PDAC (prior symptomatic treatments such 
as pain medicines are acceptable). 
 
5. Has stage ≤ IIb disease at time of diagnosis and trial enrollment (see Section 
5.1.10, for disease staging). 
 
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
to 1. Evaluation of ECOG is to be performed within 14 days prior to the date of 
allocation/randomization.  (Appendix 1) 
7. Has CA 19-9 >200 in setting of a total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤
ULN for participants with total bilirubin levels >1.5 × ULN. If total bilirubin levels are 
>1.5 x ULN, CA 19-9 must be >695 for patient to be included in the study. This 
criteria only applies at the time of initial pre study enrollment evaluation.  
 
8. A male participant must agree to use a contraception as detailed in Appendix 2 of 
this protocol during the treatment period and for at least 120 days after the last 
dose of any study treatment and refrain from donating sperm during this period. 
 
9. A female participant is eligible to participate if she is not pregnant (in the case of a 
positive HCG test, a transvaginal ultrasound must be used to confirm lack of 
pregnancy, see Appendix 2), not breastfeeding, and at least one of the following 
conditions 
applies:  
 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 2  
OR  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 

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during the treatment period and for at least 120 days after the last dose of any 
study treatment. 
 
10. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
 
*If, after the participant has met the eligibility criteria, the participant is reevaluated for 
other indications either clinically or by laboratory tests, such re-evaluations will not be 
considered as the re-valuation of eligibility.  However, whether or not to proceed with the 
study treatment is at the discretion of principal investigator or the designee.  Decisions 
still can be made to take the participant off the study based on such re-evaluations.  If the 
eligibility criteria for treatment are not met, the research participant may be re-evaluated 
if the Principal Investigators anticipates that the research participant may later meet the 
eligibility criteria. There is no time limit.  
 
5.1.2 
Participant Exclusion Criteria for Initial Enrollment (Pre-Neoadjuvant 
Chemotherapy) 
 
Participants are excluded from the study if any of the following criteria apply: 
 
1. Receiving, or previously received, any chemotherapy, radiation therapy or 
investigational agent for pancreatic cancer. 
 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor 
(e.g., CTLA-4, OX-40, CD137). 
 
3. Has received prior therapy with FAK inhibitor.  
 
4. A WOCBP who has a positive urine pregnancy test within 72 hours prior to 
randomization and allocation (see Appendix 2).  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
 
5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study 
drug.  
 
6. Has a known additional malignancy whose natural history or treatment has the 
potential to interfere with the safety or efficacy assessment of this study’s 
investigational drugs. Note: Participants with basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, low grade prostate cancer or carcinoma in 
situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially 
curative therapy are not excluded. Note: If participant received major surgery, they 
must have recovered adequately from the toxicity and/or complications from the 
intervention prior to starting study treatment. 

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7. Has known active metastasis, CNS metastases and/or carcinomatous meningitis.  
  
8. Has active autoimmune disease that has required systemic treatment in the past 
2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
 
9. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. 
 
10. Has an active infection requiring systemic therapy. 
 
11. Has a known history of Human Immunodeficiency Virus (HIV).  
 
12. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA qualitative 
detection) infection. Note: no testing for Hepatitis B and Hepatitis C is required 
unless mandated by local health authority.  
 
13. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the subject’s 
participation for the full duration of the study, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.   
 
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days 
after the last dose of trial treatment. 
 
16. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to agents used in study: Pembrolizumab and Defactinib. 
 
17. Received growth factors including, but not limited to, granulocyte-colony 
stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug 
administration. Use of such agents while on receiving study treatments is also 
prohibited. Use of agents during SOC therapies, as long as they are >14 days from 
the administration of study therapies (pembrolizumab and defactinib) are allowed.  
 
18. Is taking a medication that is a strong inhibitor or inducer of CYP3A4, CYP2C9, 
OATP1B1 or OATPIB3 (Appendix 3). 
 

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19. Has history of any organ transplant, including corneal transplants. 
 
5.1.3 
Participant Inclusion Criteria for Neoadjuvant Immunotherapy (Post-
Neoadjuvant Chemotherapy) 
 
Participants are eligible to continue in the neoadjuvant immunotherapy portion of the 
study only if all of the following criteria apply: 
 
1. Have adequate organ function as defined in the following table (Table 1). 
Specimens must be collected within 3 days of dosing with investigational 
agent(s) 
Table 1:  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000/µL 
Platelets 
≥80,000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN 
(Except subjects with Gilbert syndrome, who 
may enroll as long as total bilirubin <3.0 
mg/dL) 
AST (SGOT) and ALT (SGPT) 
≤3.0 × ULN  
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell 
(pRBC) transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory 
value requirements should be adapted according to local regulations and guidelines for the 

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5.1.4 
Participant Exclusion Criteria for Neoadjuvant Immunotherapy (Post-
Neoadjuvant Chemotherapy) 
 
Participants are excluded from continuing in the study if any of the following criteria apply: 
 
1. Evidence of metastatic disease on pre-immunotherapy CT or MRI imaging.  
 
2. Unable to complete at least 1 cycle of neoadjuvant standard of care chemotherapy 
with gemcitabine and nab-paclitaxel (patient should have minimum of 3 doses over 
two cycles).  
 
3. Unable to meet inclusion criteria number 8 and 9 in Section 5.1.1.  
 
4. Received growth factors including, but not limited to, granulocyte-colony 
stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug 
administration. 
 
5. Is taking a medication that is a strong inhibitor or inducer of CYP3A4, CYP2C9, 
OATP1B1 or OATPIB3 (Appendix 3). 
 
6. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the 
first dose of study drug.  Administration of killed vaccines is allowed. Examples of 
live vaccines include, but are not limited to, the following:  measles, mumps, 
rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–
Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. 
 
7. Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to the first dose of study 
treatment. 
 
Note:  Participants who have entered the follow-up phase of an investigational 
study may participate as long as it has been 4 weeks after the last dose of the 
previous investigational agent. 
 
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study 
drug.  
 
administration of specific chemotherapies. 

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5.1.5 
Participant Inclusion Criteria for Adjuvant Immunotherapy (Post-
Surgery) 
 
Participants are eligible to continue in the adjuvant immunotherapy portion of the study 
only if all of the following criteria apply: 
 
1. Have adequate organ function as defined in the following table (Table 1). 
Specimens must be collected within 3 days of dosing with investigational 
agent(s) 
Table 2:  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000/µL 
Platelets 
≥80,000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN 
(Except subjects with Gilbert syndrome, who 
may enroll as long as total bilirubin <3.0 
mg/dL) 
AST (SGOT) and ALT (SGPT) 
≤3.0 × ULN  
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell 
(pRBC) transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory 
value requirements should be adapted according to local regulations and guidelines for the 
administration of specific chemotherapies. 

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5.1.6 
Participant Exclusion Criteria for Adjuvant Immunotherapy (Post-
Surgery) 
 
Participants are excluded from continuing in the study if any of the following criteria apply: 
 
1. 
More than 90 days have elapsed since surgery (in the absence of adjuvant 
chemotherapy). The subject will be considered off treatment.    
 
2. 
Subjects who were found to have unresectable or metastatic disease 
intraoperatively. 
 
3. 
Subjects who develop disease recurrence in the adjuvant setting. These subjects 
will be monitored for the safety endpoint but will not continue to receive further 
immunotherapy and FAK inhibition or immunotherapy alone. 
 
4. 
Are found to have an R2 resection following surgery. 
 
5. 
Unable to meet inclusion criteria number 8 and 9 in Section 5.1.1.  
 
6. 
Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients. 
 
7. 
Has severe hypersensitivity (≥Grade 3) to defactinib and/or any of its excipients. 
 
8. 
Received growth factors including, but not limited to, granulocyte-colony stimulating 
factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug 
administration. 
 
9. 
Is taking a medication that is a strong inhibitor or inducer of CYP3A4, CYP2C9, 
OATP1B1 or OATPIB3 (Appendix 3). 
 
10. 
Subjects who are unable to receive second cycle of neoadjuvant immunotherapy 
due to treatment related toxicity from pembrolizumab or defactinib. 
 
5.1.7  
Lifestyle Restrictions 
 
5.1.7.1 
Meals and Dietary Restrictions 
Participants/subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
 

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5.1.7.2 
Contraception 
The investigation agents, pembrolizumab and defactinib may have adverse effects on a 
fetus in utero.  Refer to Appendix 2 for approved methods of contraception and further 
information on WOCBP, pregnancy and nursing. 
 
Given the potential risk related to pharmacologically-mediated inhibition of the PD-1 
pathway, no reproductive or developmental toxicity studies were conducted with 
pembrolizumab. Defactinib has also not been studied in pregnant women and must not 
be given to subjects who are pregnant. Additionally, no teratology studies with defactinib 
have been conducted. Safety for women of childbearing capacity cannot be implied from 
the existing data. Furthermore, animal reproduction studies have not been conducted with 
defactinib. Therefore, potential effects of defactinib use during pregnancy are not known 
and the potential for developmental toxicity cannot be excluded.  
 
It is required for clinical studies that men and women of childbearing potential agree to 
use adequate contraception (double barrier birth control) for the duration of study therapy 
and for 3 months after the last dose of defactinib and pembrolizumab.  
 
For this study, male participants will be considered to be of non-reproductive potential if 
they have azoospermia (whether due to having had a vasectomy or due to an 
underlying medical condition).   
 
5.1.8 
Pregnancy 
 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab 
and or defactinib, the participant will be immediately discontinued from study treatment. 
The site will contact the participant at least monthly and document the participant’s status 
until the pregnancy has been completed or terminated.  Verastem will be notified of the 
participants’ pregnancy within 24 hours of investigator knowledge and Merck will be 
notified within 2 business days of investigator knowledge, and monthly updates will be 
relayed in a timely fashion. The outcome of the pregnancy will also be reported to Merck 
and Verastem within the same time frames listed above.  If the outcome of the pregnancy 
is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn) it will be reported to 
Merck and Verastem within the same time frames noted above.  The study Investigator 
will make every effort to obtain permission to follow the outcome of the pregnancy and 
report the condition of the fetus or newborn to Merck and Verastem.  If a male participant 
impregnates his female partner, the study personnel at the site must be informed 
immediately and the pregnancy must be reported to Merck and Verastem and followed 
as described in Section 7.6.2. 
 
5.1.9 
Use in Nursing Women 
 
It is unknown whether the investigational agents, pembrolizumab or defactinib are 
excreted in human milk.  Since many drugs are excreted in human milk, and because of 

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the potential for serious adverse reactions in the nursing infant, participants who are 
breast-feeding are not eligible for enrollment. 
 
5.1.10 
Staging information  
 
Staging criteria are from the “American Joint Committee on Cancer (AJCC) Staging 
Criteria for Pancreatic Cancer.” Subjects with stage <= IIb are eligible for this study. 
 
Stage Grouping 
▪ Stage Ia  T1 N0 M0 
▪ Stage Ib  T2 N0 M0 
▪ Stage IIa T3 N0 M0 
▪ Stage IIb T1-3 N1 M0 
▪ Stage III T4 Any N M0 
▪ Stage IV Any T Any N M 
 
Primary Tumor (T) 
▪ TX Primary tumor cannot be assessed 
▪ T0 No evidence of primary tumor 
▪ T1 Tumor limited to the pancreas 2 cm or less in greatest dimension 
▪ T2 Tumor limited to the pancreas more than 2 cm in greatest dimension 
▪ T3 Tumor extends beyond the pancreas but without involvement of the celiac axis 
or the superior mesenteric artery. 
▪ T4 Tumor involves the celiac axis or the superior mesenteric artery (unresectable 
primary tumor). 
 
Regional Lymph Nodes (N) 
▪ NX Regional lymph nodes cannot be assessed 
▪ N0 No regional lymph node metastasis 
▪ N1 Regional lymph node metastasis 
 
Distant Metastasis (M) 
▪ MX Presence of distant metastasis cannot be assessed 
▪ M0 No distant metastasis 
▪ M1 Distant metastasis 
 
5.1.11 
Criteria for Resectability  
 
Resectability is determined by the study team based on spiral CT with intravenous 
contrast enhancement or MRI if the subject is allergic to contrast, according to the 
AHPBA/SSO/NCCN criteria.  
 
Subjects with no arterial tumor contact (celiac axis, superior mesenteric artery or common 
hepatic artery) and no tumor contact with the superior mesenteric vein or portal vein or ≤ 
180 contact without vein contour irregularity who are deemed to be resectable will be 
eligible for the study.  

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Subjects who would be considered borderline resectable per the study team according to 
the AHPBA/SSO criteria and the NCCN criteria include subjects with severe unilateral 
SMV/portal impingement, tumor abutment on the SMA, GDA encasement up to the origin 
at the hepatic artery, or colon invasion are not eligible for this study. 
 
5.2 
Trial Treatments  
 
Treatments will be administered on an outpatient basis.  Dosing delays are described in 
Section 5.2.3, 5.2.4, and 5.2.5. All subjects will receive two cycles of SOC neoadjuvant 
chemotherapy with gemcitabine and nab-paclitaxel during the SOC chemotherapy phase 
of the protocol.  This will be followed by two cycles of pembrolizumab for all study subjects 
and with the addition of defactinib for those in treatment Arm A only. Surgery will be 
scheduled between 10 to 25 days following the start of the second cycle of 
immunotherapy. All subjects who undergo SOC surgical resection will receive SOC 
adjuvant chemotherapy and maintenance immunotherapy unless 1) more than 90 days 
have elapsed since surgery (in the absence of adjuvant chemotherapy), or 2) there was 
unresectable or metastatic disease intraoperatively, or 3) there has been recurrence of 
disease. Following surgery, all subjects will receive standard of care chemotherapy 
through local oncologist. This will be followed by on study maintenance pembrolizumab 
with the addition of defactinib in treatment Arm A only, whereas subjects in treatment Arm 
B will receive pembrolizumab only. 
 
The treatments to be used in this trial is outlined below in 
Table 3. 
 
Table 3:  Trial Treatments 
 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion, 
over 30 
minutes* 
Day 1 of each 3-
week (21 day) cycle 
Experimental 
Defactinib (Arm 
A Only) 
400 mg** 
BID 
PO 
administration 
Each day of 3-week 
(21 day) cycle*** 
Experimental 
*Infusion times are approximate and may be adjusted based on subject tolerability (-10/+25 
minutes). 
**Defactinib comes as 200 mg tablet so patients will take 2 tablets for 400 mg 
***Defactinib will be continued beyond the end of cycle two of pembrolizumab until 2 days 
preceding surgery (last dose of defactinib is 48 hours prior to surgery). 
 
Treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated/assigned. 
 
Neoadjuvant Chemotherapy (Gemcitabine and Nab-Paclitaxel) 
 

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Gemcitabine and nab-paclitaxel is a standard treatment for PDAC. Patients will receive 
two cycles of neoadjuvant gemcitabine and nab-paclitaxel prior to immunotherapy and 
FAK inhibition.  General recommendations for treatment with gemcitabine and nab-
paclitaxel are provided here (see Von Hoff et al.6>) Subjects who are unable to receive 
gemcitabine and nab-paclitaxel or are intolerant to it may be switched to another standard 
chemotherapy regimen (ie, FOLFIRINOX 63) for pancreatic cancer for the remaining 
portion of the standard neoadjuvant chemotherapy portion of the study. Subjects are 
considered to have completed the standard neoadjuvant chemotherapy portion of the 
study when they have completed at minimum three doses of gemcitabine and nab-
paclitaxel. If tolerated patient should attempt to complete two 28-day cycles of 
gemcitabine and nab-paclitaxel, or at least two months of standard chemotherapy. This 
therapy can be given through local treating oncologist for a total of two cycles. Additionally 
dose and cycle modifications are allowed for gemcitabine and nab-paclitaxel at the 
discretion of the treating oncologist.  
 
Pembrolizumab (KEYTRUDA®, MK-3475)  
 
Pembrolizumab will be administered IV over 30 minutes at 200mg every 3 weeks (Q3W) 
in the neoadjuvant and adjuvant setting. The choice of the 200 mg Q3W as an appropriate 
dose for the switch to fixed dosing is based on simulations performed using the population 
PK model of pembrolizumab showing that the fixed dose of 200 mg Q3W will provide 
exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose 
Q3W, 2) will maintain individual subjects exposures in the exposure range established in 
melanoma as associated with maximal efficacy response and 3) will maintain individual 
subjects exposure in the exposure range established in melanoma that are well tolerated 
and safe.6> This is also FDA approved dose for other tumor types.  
 
The Pharmacy Manual contains specific instructions for pembrolizumab administration. 
Antiemetic medications should not be routinely administered prior to dosing of 
pembrolizumab. See Section 5.2.2 for subsequent premedication recommendations 
following a pembrolizumab-related infusion reaction. Subjects should be observed for a 
minimum of 30 minutes after administration of pembrolizumab. 
 
Defactinib (Arm A Only) 
 
Defactinib is an orally available, potent ATP-competitive, FAK inhibitor with a 
recommended phase II dose (RP2D) of 400 mg twice daily. The choice of 400 mg dose 
is based on preclinical studies, a first-in-human experience phase 1 study in subjects with 
advanced solid tumors and a subsequent Asian phase 1 dose-escalation study conducted 
to determine the MTD and overall safety.65,66 Additionally, there is an ongoing phase 1/1b 
study of the combination of pembrolizumab, defactinib, and gemcitabine chemotherapy 
that has also escalated to 400 mg twice daily (NCT02758587). Across multiple studies 
PK analyses has shown that the 400 mg BID is a tolerable dose, with mild treatment 
related adverse events and confers adequate plasma concentrations for FAK activity 
suppression. Based on both preclinical and clinical data the recommended Phase 2 dose 
schedule is 400 mg BID for current clinical formulation of defactinib.65,66 

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The tablets should be taken twice daily approximately 10-12 hours apart (2 tablets twice 
a day) immediately (within 30 minutes) after a meal. Tablets should be swallowed whole 
with a full glass of water. It is acceptable to take Defactinib within 2 hours of a missed 
dose. In the event of emesis occurring after study drug ingestion, the participant should 
simply adhere to the dosing schedule and resume dosing at the next scheduled time with 
the prescribed dosage. Patient diary for defactinib can be found in Appendix 4. 
 
Adjuvant Chemotherapy  
 
Subjects may receive any standard of care adjuvant therapy for resected pancreatic 
cancer through local oncologist. The study team advocates for gemcitabine and 
capecitabine as a standard treatment for PDAC to be utilized, however any standard 
treatment can be given at the discretion of treating oncologist. Additionally, treatments 
may be modified based on local treatment standards and guidelines as appropriate. 
General recommendations for treatment with gemcitabine and capecitabine are provided 
here (Neoptolemos et al.6) Subjects who are unable to receive gemcitabine and 
capecitabine or are intolerant to it may be switched to another standard chemotherapy 
regimen at the discretion of the subject’s treating oncologist for the remaining portion of 
the standard adjuvant chemotherapy portion of the study. Options for alternate therapy 
include FOLFIRINOX or other standard treatment options listed in the NCCN guidelines. 
This therapy will be given off protocol/study per treating oncologist. 
 
5.2.1 
Timing of Dose Administration 
 
Pembrolizumab should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 6.0).  Trial treatment may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons. 
 
Defactinib should be administered twice daily, beginning on Day 1 of each cycle, and 
should continue daily until the end of the cycle. During the final immunotherapy cycle prior 
to surgery, defactinib should continue until 2 days prior to surgery (last dose to be given 
48 hours prior to surgery).  
 
All trial treatments will be administered on an outpatient basis. 
 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -
5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
 

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5.2.2 
Dose Modifications  
In part two and part five of the study, dose or cycle modifications for standard of care 
chemotherapy (including gemcitabine, nab-paclitaxel, capecitabine or standard 
chemotherapy) will be allowed at the discretion of treating medical oncologist or study 
team.  
 
Dose modifications, which include dose reductions or dose increases of pembrolizumab 
and defactinib, will not be permitted in individual subjects in any part of the study. 
 
From part two of the study onwards, where study treatments are administered, 
pembrolizumab and defactinib related adverse effects will be closely monitored. Adverse 
events and toxicities, across all grades will be monitored and recorded for both defactinib 
and pembrolizumab.  The first two subjects in each arm will be enrolled and treated in a 
staggered fashion in order to closely monitor for adverse events. For the first two 
staggered subjects in each arm, the subjects will be followed until the time of surgery or 
for two weeks, whichever occurs first following neoadjuvant immunotherapy/FAK 
inhibition, before the next subject will be treated with neoadjuvant immunotherapy and 
FAK inhibition. Subjects will be closely monitored for the number of grade 3 or higher 
toxicities through the first two cycles of immunotherapy in part three of the study. No dose 
reductions will be allowed, however if grade 3/4 adverse events attributable to 
pembrolizumab/defactinib or pembrolizumab or Grade 3 infusion-related reaction or 
cytokine release syndrome that lasts ≥ 12 hours occurs, the toxicity monitoring and 
stopping rule as outlined in Section 8.2 will be assessed. Dose delays will be permitted.        
 
In part six of the study, no dose reductions will be allowed for either defactinib or 
pembrolizumab. Dose delays will be permitted. The toxicity monitoring and stopping rule 
as outlined in Section 8.2 will be invoked should subjects develop grade 3/4 adverse 
events attributable to pembrolizumab/defactinib or pembrolizumab or Grade 3 infusion-
related reaction or cytokine release syndrome that lasts ≥ 12 hours occurs in this phase 
of the study. 
 
5.2.3 
Toxicity management for immune-related AEs associated with 
pembrolizumab 
 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than on body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical 
to reduce complications.  Based on existing clinical study data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests 
such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. 
Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and 

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administer corticosteroids. Dose delays and toxicity management guidelines for irAEs 
associated with pembrolizumab are provided in Table 3. 

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Table 3: Dose delays and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab  
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive 
treatment should begin if the irAEs are not controlled by corticosteroids. 
 
2.  Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 
12 weeks of the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid 
taper. 
 
Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• Add prophylactic antibiotics for 
opportunistic infections 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
Grade 3 or 4, or 
recurrent Grade 
2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (ie, peritoneal signs and 
ileus). 

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Grade 4 or 
recurrent Grade 
3 
Permanently 
discontinue 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy 
to rule out colitis.  
• 
Participants with diarrhea/colitis should 
be advised to drink liberal quantities of 
clear fluids.  If sufficient oral fluid intake 
is not feasible, fluid and electrolytes 
should be substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2a 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone 
or equivalent) followed by taper 
• 
Monitor with liver function tests 
(consider weekly or more frequently until 
liver enzyme value returned to baseline 
or is stable 
Grade 3b or 4c  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 
diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure 
Withholdd 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia 
or other signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinued  
Hyperthyroidis
m  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinued 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 

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Nephritis and 
Renal 
dysfunction 
(Grading 
according to 
increased 
creatinine or 
acute kidney 
injury) 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the type 
of evente 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 

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AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x 
baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
  
 
Toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours 
of completion of infusion. Toxicity management guidelines on pembrolizumab associated infusion reaction are provided in 
Table 4.  
 
Table 4:  Pembrolizumab Infusion Reaction Treatment Guidelines 

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NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g. 
from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the participant should be pre-medicated for 
the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Participant may be pre-medicated 
1.5h (± 30 minutes) prior to infusion 
of pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
No subsequent dosing 

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Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study 
drug treatment. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 

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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such 
as medical / surgical events or logistical reasons not related to study therapy. Participants 
should be placed back on study therapy within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the IND Sponsor. The reason for interruption should be 
documented in the subject’s study record. 
 
5.2.4 
Toxicity management for AEs associated with defactinib 
 
Overall, defactinib has been found to be well tolerated in clinical studies. GI disorders were 
the most common type of treatment-related adverse events reported to date. Nausea with 
or without vomiting and diarrhea are commonly reported with defactinib. If subjects 
experience Prophylactic medications may be used as needed if nausea is found to occur 
with administration of defactinib and cannot be managed with small amounts of food. 
 
Event Name 
Nausea 
Grade of Event Management/Next Dose 
≤ Grade 1 
No change 
Grade 2 
No change 
Grade 3 
Withhold until < Grade 2.  Discontinue defactinib if 
symptom lasts longer than 72 hours. 
Recommended management:  antiemetics. 
 
Event Name 
Vomiting 
Grade of Event Management/Next Dose 
≤ Grade 1 
No change 
Grade 2 
No change 
Grade 3-4 
Withhold until < Grade 2. Discontinue defactinib if 
symptom lasts longer than 72 hours. 
Recommended management:  antiemetics. 
 
Event Name 
Diarrhea 
Grade of Event Management/Next Dose 
≤ Grade 1 
No change  
Grade 2 
No change  
Grade 3-4 
Withhold until < Grade 2.  Discontinue defactinib if 
symptom lasts longer than 72 hours. 
Recommended management:  Anti-diarrheal therapy 
 
 
 

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Event Name 
AST / ALT elevation or Increased bilirubin 
Grade of Event Management/Next Dose 
≤ Grade 1 
No change  
Grade 2 
Withhold until < Grade 1 
Grade 3 
Withhold until < Grade 1. Discontinue defactinib if Grade 
3 elevated LFTs do not improve to < grade 2 after 
holding defactinib for two weeks. 
Grade 4 
Discontinue defactinib 
Recommended management:  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme value returned to baseline or 
is stable 
 
Event Name 
All other related AEs 
Grade of Event Management/Next Dose 
≤ Grade 1 
No change  
Grade 2 
No change for asymptomatic toxicities. Withhold until < 
Grade 1 if toxicity is symptomatic.  
Grade 3-4 
Withhold or discontinue based on the type of event*  
Recommended management:  Ensure adequate evaluation to confirm 
etiology and/or exclude other causes. 
 
* The following toxicities do not require treatment discontinuation: 
▪ Asymptomatic laboratory abnormalities or in the judgment of the 
investigator, are not clinically significant 
▪ Grade 3 fatigue that improves to Grade 2 within 7 days 
▪ Grade 3 dermatologic AEs that are considered mild in severity 
but only considered grade 3 because of >30% body surface 
involvement   
▪ Grade 3-4 hyperglycemia or grade 3 endocrinopathies where 
symptoms are controlled on hormone replacement therapy 
 
5.2.5 
Dosing Delays 
 
Treatment delays for standard of care chemotherapy (e.g. gemcitabine, nab-paclitaxel and 
capecitabine or chemotherapy per treating oncologist preference for parts two and five of 
study) are at the discretion of the treating medical oncologist or study team. Subjects are 
considered to have completed neoadjuvant chemotherapy when they have completed two, 
28-day cycles of chemotherapy in part two of the study, or have completed at least two 
months of standard chemotherapy. Adjuvant chemotherapy cycles are determined by 
treating oncologist and as tolerated by patient. Delays during adjuvant chemotherapy can 
occur at discretion of treating oncologist.  
 

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The first cycle of neoadjuvant immunotherapy and FAK inhibition, with pembrolizumab and 
defactinib or pembrolizumab alone should optimally be administered within one week of 
completing last cycle of neoadjuvant chemotherapy and second EUS biopsy. However, if 
necessary due to resolving adverse events related to chemotherapy or any other reason, 
the first cycle of pembrolizumab and defactinib or pembrolizumab alone can be delayed 
up to three weeks. If the first cycle of pembrolizumab and defactinib or pembrolizumab 
alone is delayed by more than three weeks from completion of neoadjuvant chemotherapy, 
the Principal Investigator must be contacted for further instructions on continued treatment 
versus preceding to definitive resection.   
 
The second cycle of immunotherapy is to be administered within 7 days of completing last 
cycle of immunotherapy. If the second cycle is delayed by more than 1 week, due to 
adverse events relates to immunotherapy or FAK inhibition or any other reason, the 
Principal Investigator must be contacted for further instructions on continued treatment 
versus preceding directly to definitive resection. If delay is not due to FAK inhibition, 
defactinib can continue until next cycle of pembrolizumab. 
 
Surgical resection should occur between 10 to 25 days from the administration of cycle 2 
of immunotherapy. Defactinib should continue until 2 days preceding surgery (last dose of 
defactinib 48 hours prior to surgery). If surgery is delayed beyond the aforementioned 
treatment window, the Principal Investigator must be contacted for further instructions 
regarding defactinib, if the subject is on Arm A. Additionally, if patient does not receive 
second cycle of immunotherapy they can proceed to surgery following surgical evaluation 
and completion of cycle 1 of immunotherapy and will remain on study. Timing of this will 
be determined by Principal Investigator and treating surgeon but will occur as soon as 
possible. If patient is unable to receive one cycle of immunotherapy they will proceed 
directly to surgery off study. 
 
In part six of the study, during maintenance immunotherapy each successive cycle of 
pembrolizumab and defactinib or pembrolizumab alone should be administered within one 
week from the completion of the preceding cycle. If the subsequent cycle is delayed by 
more than 1 week, the Principal Investigator must be contacted for further instructions on 
continued treatment on study versus discontinuation. If delay is not due to FAK inhibition, 
defactinib can continue until the next cycle of pembrolizumab. The first dose of 
immunotherapy following completion of adjuvant therapy in part five, should be 
administered within 6 weeks of completing last cycle of adjuvant therapy. However, if 
necessary due to resolving adverse events related to chemotherapy or for any other 
reason, immunotherapy is delayed by more than 6 weeks, the Principal Investigator must 
be contacted for further instructions on continued treatment. 
 
Additional delays or modifications to the treatment schedule must be approved by the 
Principal Investigator or the IND Sponsor. 
 
5.3 
Trial Blinding and masking 
 

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This is an open-label trial; therefore, the IND sponsor, investigators and subjects will know 
the treatment administered. The subjects will be notified of their assigned arm after they 
have enrolled in the study. 
 
5.4 
Randomization or Treatment Allocation 
 
36 subjects will be randomized to the two treatment arms via the Research Electronic Data 
Capture (REDCap) application in a 1:1 ratio to pembrolizumab and defactinib or to 
pembrolizumab alone.  
 
5.5 
Stratification 
 
To ensure comparability of the two study arms, randomization will be stratified by age (≥65, 
<65).   
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
5.6.1 
Neoadjuvant Chemotherapy (Gemcitabine and Nab-Paclitaxel) 
 
Acute reactions will be managed used standard therapy guidelines for acute drug reactions 
as per institutional guidelines. Neoadjuvant SOC therapy will be through local oncologist.  
 
5.6.2 
Pembrolizumab 
 
Pembrolizumab is a humanized monoclonal antibody. Subjects should be closely 
monitored for potential adverse reactions during antibody infusion and potential adverse 
events throughout the study.  
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 
hours if clinically indicated and monitored as necessary to determine if event meets toxicity 
criteria. 
 
5.6.2.1 
Infusion Reactions 
 
Pembrolizumab infusion reactions may consist of fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, rash, vomiting, myalgia, dizziness 
or hypertension.  Severe reactions may include acute respiratory distress syndrome, 
myocardial infarction, ventricular fibrillation, and cardiogenic shock.  Subjects should be 
closely monitored for such reactions.  Guidelines for subjects who experience an infusion 
related or allergic reaction during or after infusion with pembrolizumab are shown below in 
(Section 5.2.2, Table 4). 
 
5.6.2.2 
Immune-Related Adverse Events (IRAEs) for Pembrolizumab  
 

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Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. Suggested supportive care measures for the management of 
adverse events with potential immunologic etiology are outlined below. Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as 
well as additional anti-inflammatory agents if symptoms do not improve with administration 
of corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
 
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below).  It may be necessary 
to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
 
▪ Pneumonitis: 
 
▪ For Grade 2 events, treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
▪ For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed. 
▪ Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
▪ Diarrhea/Colitis: 
 
▪ Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in 
stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus). 
 
▪ All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion. 
For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
▪ For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
▪ For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids. 
▪ When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 

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▪ Type 1 diabetes mellitus (T1DM) (if new onset, including diabetic 
ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with 
ketosis (ketonuria) or metabolic acidosis (DKA) 
 
▪ For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
▪ Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 
▪ Hypophysitis: 
 
▪ For Grade 2 events, treat with corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
▪ For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
 
▪ Hyperthyroidism or Hypothyroidism: 
 
▪ Thyroid disorders can occur at any time during treatment. Monitor 
patients for changes in thyroid function (at the start of treatment, 
periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
▪ Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In 
hyperthyroidism, 
non-selective 
beta-blockers 
(e.g. 
propranolol) are suggested as initial therapy.  
▪ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
▪ Grade 3-4 hyperthyroidism 
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
▪ Hepatic: 
 
▪ For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).  
▪ Treat with IV or oral corticosteroids 

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▪ For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 
48 hours.  
▪ When symptoms improve to Grade 1 or less, a steroid taper should 
be started and continued over no less than 4 weeks. 
 
▪ Renal Failure or Nephritis: 
 
▪ For Grade 2 events, treat with corticosteroids. 
▪ For Grade 3-4 events, treat with systemic corticosteroids. 
▪ When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
▪ Elevated CK: 
 
▪ For Grade 2 events, treat with corticosteroids. 
▪ For Grade 3-4 events, treat with systemic steroids.  
▪ When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
▪ All other drug-related toxicity: 
▪ For Grade 3-4 events, treat with systemic steroids.  
▪ When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
5.6.3 
Defactinib  
 
Defactinib is a potent and selective ATP-competitive, reversible inhibitor of recombinant 
human FAK.  
Overall, defactinib has been found to be well tolerated in clinical studies at doses ranging 
from 2.5 mg to 750 mg BID (with 400 mg BID being the dose selected for further clinical 
development). 
Gastrointestinal dysfunction symptoms were the most common type of treatment-related 
adverse events reported to date, with nausea being the most common individual study 
drug-related adverse event and diarrhea and vomiting being among the most common. 
Other common drug-related adverse events included fatigue, hyperbilirubinemia and 
decreased appetite. 
Gastrointestinal Effects  
Nausea with or without vomiting and diarrhea are commonly reported with defactinib. In 
clinical studies, nausea and diarrhea were reported more commonly in subjects on 
defactinib than in subjects who received placebo, whereas the incidence of vomiting was 
relatively similar. These events are generally mild or moderate (Grade 1 or 2) in intensity 
and non-serious, although serious cases have been reported. Prophylactic medications 

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may be used as needed if nausea is found to occur with administration of defactinib and 
cannot be managed with small amounts of food. Diarrhea should be managed per 
institutional guidelines.  
Increased Bilirubin  
Increased bilirubin has been observed with defactinib. These increases are generally 
asymptomatic and not associated with increases in AST or ALT. Increased bilirubin often 
resolves spontaneously, even with continued drug treatment.  
Significant Drug Interactions 
 
Defactinib is a potent inhibitor of OATP1B1 and OATPIB3 with IC50 values of 0.2 and 8.5 
uM.  Therefore, drugs that are substrates of these hepatic uptake transporters may be 
subjected to DDI.  The blood levels of these substrate drugs might increase to unsafe 
levels. (Example – sartans) (see Appendix 3 for comprehensive list). 
Defactinib may have the potential to increase warfarin exposure due to a potential drug-
drug interaction affecting warfarin’s metabolism. Based on a review of information from all 
clinical studies, an increased level of caution is recommended. If subjects can safely stop 
taking warfarin, they will be asked to do so. If subjects require anti-coagulation, an 
alternative to warfarin will be considered. Subjects who require anti-coagulation but cannot 
discontinue warfarin, will be monitored closely and have their INRs checked more 
frequently whilst on defactinib. For subjects requiring the start of anti-coagulation therapy 
during the course of the study, alternatives to warfarin will be recommended.  
Additionally, concomitant use of strong inhibitors and inducers of CYP3A4 or CYP2C9 
should be avoided. For strong inhibitors and inducers of CYP3A4 or CYP2C9 (Appendix 
3). 
5.6.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination 
rests with the investigator. 
 
5.6.5 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 

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medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.6. 
 
5.6.6 
Prohibited and Restricted Therapies 
 
Subjects may not use any of the following agents during the study: 
 
• Any non-study anticancer or immunotherapy agent (investigational or non-
investigational) 
 
• Any other investigational agents, other than defactinib and pembrolizumab. 
 
• Any other immunotherapy treatment, including, but not limited to: IL-2, 
interferon, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-
CD40, or anti-CTLA-4 antibodies. 
 
• Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.  The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
IND Sponsor. Steroid treatment should be completed at least 14 days prior to 
resuming study-related treatments. Further, if patients require high dose 
steroids, while on study, pembrolizumab can be re-administered if the steroids 
are tapered over a 12-week period.   
 
• Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF). 
Use of these agents during SOC therapies, as long as they are >14 days from 
the administration of study therapies (pembrolizumab and defactinib) are 
allowed. 
 
• Live vaccines (examples of live vaccines include, but are not limited to: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid [oral] 
vaccine). Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
 
• Participants who, in the assessment by the investigator, require the use of any 
of the aforementioned treatments for clinical management should be removed 
from the study.  All treatments that the Investigator considers necessary for a 
participant’s welfare may be administered at the discretion of the Investigator in 
keeping with the community standards of medical care.   
• Medications or vaccinations specifically prohibited in the exclusion criteria are 
not allowed during the ongoing study.  If there is a clinical indication for any 

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medication 
or 
vaccination 
specifically 
prohibited 
during 
the 
study, 
discontinuation from study therapy or vaccination may be required.  The final 
decision on any supportive therapy or vaccination rests with the investigator 
and/or the participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the 
investigator, the IND Sponsor, and the participant. 
• Strong inhibitors or inducers of CYP3A4, CYP2C9, OATP1B1 or OATPIB3 
(Appendix 3). 
 
• There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.7 
Unacceptable Toxicities 
 
 
Unacceptable toxicities are defined as any AE that is related to study drug administration 
(pembrolizumab and defactinib) and is not due to the subject’s underlying malignancy and 
for which there is no clear evidence for an alternative etiology and meets one of the 
following NCI CTCAE criteria: 
 
1. Hematologic toxicities deemed an unacceptable toxicity are: 
▪ Grade 4 anemia  
▪ Grade 3 or 4 neutropenia lasting ≥ 14 days  
▪ Grade ≥ 3 febrile neutropenia  
▪ Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically 
significant bleeding  
 
2. Any > grade 3 non-hematologic toxicities.  Exceptions include: 
 
▪ Asymptomatic laboratory abnormalities or in the judgment of the investigator, 
are not clinically significant 
▪ Grade 3 fatigue that improves to Grade 2 within 7 days 
▪ Grade 3 dermatologic AEs that are considered mild in severity but only 
considered grade 3 because of >30% body surface involvement   
▪ Diarrhea, nausea, or vomiting that resolves to < grade 3 within 72 hours of 
intervention 
▪ Grade 3-4 hyperglycemia or grade 3 endocrinopathies where symptoms are 
controlled on hormone replacement therapy 
▪ Grade 3 elevated LFTs that improve to < grade 2 after holding defactinib for two 
weeks. 
 
3. Grade 3 transaminase elevation in the presence of a total bilirubin elevation 
greater than 2x ULN 
 

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4. Grade ≥ 2 eye pain or reduction of visual acuity that does not respond to topical 
therapy and does not improve to ≤ grade 1 severity within 2 weeks of starting 
therapy, or requires systemic therapy 
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 
hours if clinically indicated and monitored as necessary to determine if event meets toxicity 
criteria. 
 
The proportion of unacceptable toxicities will be monitored. If the toxicity levels are 
unacceptable (high probability that it is >33% of subjects), then enrollment will be 
suspended until further review and consideration by the IND Sponsor.  
 
Events meeting unacceptable toxicity criteria should be reported via email to the IND 
Sponsor (lzheng6@jhmi.edu) and GIsafetyreporting@jhmi.edu within 24 hours. 
 
5.8 
Criteria for Removal from Study Treatment  
 
Subjects will be removed from study treatment when any of the criteria listed below 
applies.  The reason for study treatment removal and the date the subject was removed 
must be documented in the Case Report Form. 
 
A subject must be discontinued from the trial for any of the following reasons: 
 
• The subject or legal representative (such as a parent or legal guardian) 
withdraws consent, or 
 
• Subject is lost to follow-up. 
 
A subject must be discontinued from treatment (but may continue to be monitored in the 
post-treatment follow-up portion of the trial) for any of the following reasons: 
 
• The subject or legal representative (such as a parent or legal guardian) 
withdraws consent for treatment, 
 
• Subject completes all cycles of planned treatment and assessments, 
 
• Development of local recurrence or distant metastatic disease, 
 
• Subjects who were found to have unresectable disease intraoperatively, 
 
• ≥ Grade 3 infusion-related or hypersensitivity reaction, 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• Unacceptable adverse event(s) (see Section 5.7), 

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• Severe or life-threatening pembrolizumab or defactinib-related AE(s) (Section 
5.2.3 and 5.2.4). 
 
• Subject meets the exclusion criteria listed in Sections 2.13 and 2.1.6, 
 
• Need for >2 dose delays due to the same toxicity as per the dose delay 
guidelines. 
 
• Inability to reduce corticosteroid dose for immune-related adverse reactions to 
≤10 mg prednisone or equivalent per day, 
 
• More than 90 days have elapsed since the last immunotherapy treatment in the 
adjuvant setting. >90 days between neoadjuvant and adjuvant immunotherapy 
does not apply. 
 
• Subjects who do not proceed to surgery within four weeks from completion of 
second cycle of pembrolizumab (21 day cycle) (for patients who receive only 1 
dose of neoadjuvant therapy, if they do not proceed to surgery within 4 weeks 
from end of cycle), 
 
• If in the opinion of the Investigator, a change or temporal or permanent 
discontinuation of therapy would be in the best interest of the patient.  The IND 
Sponsor should be included in this decision, 
 
• Noncompliance with trial treatment or procedure requirements, or 
 
• Subject becomes pregnant. 
 
 
5.9 
End of Treatment (EOT) Visit 
 
After a subject is discontinued from treatment or has completed all study related therapies, 
a mandatory EOT Visit should be performed 30 days (± 7 days) after the last dose of any 
study medication (pembrolizumab or defactinib, or within 7 days prior to initiation of a new 
anti-cancer treatment, whichever comes first). An in-person visit is preferred, however, if 
the patient is unable to return for an EOT visit (e.g. disease/clinical progression, poor 
health, intercurrent illness, or initiation of a new anti-cancer therapy), or if the EOT visit 
occurs early, an assessment of adverse events should be made by telephone or 
telemedicine visit on day 30 (± 7) after the last study drug in place of the PE/PS/vitals. 
Clinical laboratory values should still be collected. Additionally, for those subjects who do 
not have scans within 6 weeks prior to EOT a repeat scan should be collected and an in-
person EOT visit is recommended. Procedures and assessments performed at this visit 
should follow the respective guidelines described in Section 6 and 7.5.3.1 as appropriate. 

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The patient will be monitored for adverse events up to the mandatory EOT Visit or to 
resolution of toxicity to Grade 0-1, whichever occurs later.   
 
5.10 
Duration of Follow Up   
 
5.10.1  
Safety Follow-up 
 
Subjects who discontinue treatment should be contacted by telephone or email at 90 days 
(+ 14-day reporting window) from their last dose of study drug or within 7 days before 
initiation of a new antineoplastic treatment (whichever comes first) to assess for treatment 
related toxicities. Serious Adverse Events (SAEs) that occur within 90 days of the last 
infusion of pembrolizumab, administration of defactinib or before initiation of a new 
antineoplastic treatment should also be followed and recorded. 
 
Subjects who are discontinued from the study treatment due to an unacceptable drug-
related AE will be monitored for safety until the resolution of the AE to ≤ grade 1 or 
stabilization or until initiation of a new therapy for their cancer, whichever occurs first. 
  
5.10.2  
Survival Follow-up 
 
Subjects who complete or discontinue from treatment will be contacted directly or their 
treating oncologist or designee (by phone, email, telemedicine, medical record search, or 
scheduled visit) per standard of care after completion of the EOT Visit for up to 2 years or 
study closure to monitor overall survival. Information of disease status, survival, other 
cancer therapies after discontinuation from the study treatment and adverse events will 
also be collected. 
 
All subjects should continue to be monitored for disease status by radiologic imaging.  
Disease monitoring should continue to be assessed per standard of care until: 1) start of 
a new antineoplastic therapy (information of the new cancer therapy will be collected), 2) 
until death, 3) withdrawal of consent, or 4) study closure, whichever occurs first.  
 
If serious adverse events in the survival follow-up phase (beyond 90 days from last study 
drug administration) are determined to be secondary to study drugs (pembrolizumab or 
defactinib), they will also be followed, reported, and recorded.  
 
6.0 
TRIAL FLOW SHEET 
 
1) 
Consent - Study consent should be obtained prior to the initiation of any therapy for 
pancreatic cancer. Randomization will occur after consent and eligibility are verified. 
Eligibility determination, randomization and enrollment can occur up to 1 week after 
initiating SOC chemotherapy, as long as all screening procedures were completed 
prior to starting therapy. 
 
2) 
Standard of Care Neoadjuvant chemotherapy - After consenting to the study and 
eligibility is verified, the subject will receive two, 28 day cycles of neoadjuvant 

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standard of care chemotherapy with gemcitabine and nab-paclitaxel. This phase will 
occur through local oncologist. 
 
3) 
Pre-immunotherapy (after neoadjuvant chemotherapy) - within two weeks after the 
last dose of standard of care chemotherapy, the subject should receive a CT scan 
and EUS guided Core Biopsy. Before proceeding to next phase on study, eligibility 
criteria as outlined in Section 2.1.3 must be satisfied.   
 
4) 
Neoadjuvant Immunotherapy and FAK inhibition – The subject will begin neoadjuvant 
immunotherapy within three weeks of completing neoadjuvant chemotherapy and 
after EUS guided biopsy (within 1 week from biopsy). They will receive two, three-
week cycles of immunotherapy with pembrolizumab and FAK inhibition with 
defactinib or pembrolizumab alone. FAK inhibition will continue up until 2 days prior 
to surgery (last dose 48 hours prior to surgery). 
 
5) 
Surgical evaluation - After the last dose of neoadjuvant pembrolizumab the subject 
will be reassessed for surgical resection. If the subject is still deemed to be a surgical 
candidate, they will proceed to surgery outside of the study protocol. Surgical 
resection will occur between 10-25 days from the administration of second dose of 
immunotherapy. If patient does not receive second dose of immunotherapy in 
neoadjuvant setting, patient can still proceed to surgery on study after surgical 
evaluation, which can occur after end of first cycle of immunotherapy. At the time of 
surgery, if the subject is found to have unresectable disease intraoperatively, core 
biopsies will be performed intraoperatively for research purposes. 
 
6) 
Standard of Care Adjuvant Chemotherapy – The subject may choose to receive this 
standard chemotherapy through a local oncologist. All follow-up visits, blood work, 
and interval surveillance scans during this portion of the study will be scheduled at 
the discretion of the subject’s local oncologist. This portion of the study will be off 
protocol. Before proceeding to next phase on study, eligibility criteria as outlined in 
Section 2.1.6, must be satisfied. 
 
7) 
Adjuvant Maintenance Immunotherapy and FAK inhibition – The subject will begin 
neoadjuvant immunotherapy within 6 weeks of completion of standard of care 
adjuvant chemotherapy. They will receive eight, three-week cycles of immunotherapy 
with pembrolizumab and FAK inhibition with defactinib or pembrolizumab alone.  
 
8) 
End of Treatment (EOT) – A mandatory EOT Visit should be performed 30 days (± 7 
days) after last dose of study drug (pembrolizumab or defactinib). An in-person visit is 
preferred, however, if the patient is unable to return for an EOT visit (e.g. 
disease/clinical progression, poor health, intercurrent illness, or initiation of a new 
anti-cancer therapy), or if the EOT visit occurs early, an assessment of adverse 
events should be made by telephone or telemedicine visit on day 30 (± 7) after the 
last study drug in place of the PE/PS/vitals. Clinical laboratory values should still be 
collected. Additionally, for those subjects who do not have scans within 6 weeks prior 
to EOT a repeat scan should be collected and an in-person EOT visit is 

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recommended. After the EOT visit, subjects or treating oncologists will be contacted 
(by phone, email, telemedicine, medical record search, or scheduled visit) oer 
standard of care to monitor OS until death, adverse events, disease status, 
withdrawal of consent, or study closure.  
  
 
 

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6.1  
Screening, Standard of Care Neoadjuvant Chemotherapy/Pre 
Immunotherapy Phase Study Calendar 
 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for inperson clinical trial visits or portions of clinical trial visits where determined to be 
appropriate and where determined by the investigator not to increase the participants risks. Prior 
to initiating telemedicine for study visits the study team will explain to the participant, what a 
telemedicine visit entails and confirm that the study participant is in agreement and able to 
proceed with this method. Telemedicine acknowledgement will be obtained in accordance with 
the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed 
feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted 
using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
1: 
Longer delays to be approved by the IND sponsor. 
Procedure 
Screening/ 
Baseline 
Procedures and 
Enrollment 
Neoadjuvant 
SOC 
Chemotherapy 
Post-SOC 
Neoadjuvant 
Chemotherapy/ Pre-
immunotherapy 
Evaluation 
Visit Window1 
-21 to 1 
- 
 21 days2 
Standard Neoadjuvant 
Chemotherapy 
Gemcitabine/Nab-Paclitaxel 
 
X3 
 
 
Inclusion/exclusion criteria 
X 
 
X4 
Randomization and Enrollment  
X19 
 
 
Demographics 
X 
 
 
Medical History5 
X 
 
X6 
Medications 
X 
 
X 
Physical Exam7 
X 
 
X 
Vital Signs and pulse ox8 
X 
 
X 
Height9 
X 
 
 
Weight 
X 
 
X 
Performance Status 
X 
 
X 
Hematology profile10 
X 
 
X 
Complete Metabolic Profile10 
X 
 
X 
TSH11  
 
 
X 
Serum/Urine Pregnancy12 
X 
 
X 
CEA 
X 
 
X 
CA 19-9 
X 
 
X 
Total Bilirubin 
X 
 
 
CT or MRI14 
X 
 
X  
Pathology Review 
X 
 
 
Whole blood for PBMC15, 18 
X 
 
 
Whole blood for serum15, 18 
X 
 
 
Whole blood for plasma15, 18 
X 
 
 
EUS Core Biopsy18 
X16 
 
X17   
Surgical Evaluation 
X 
 
 

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2:   This visit should occur within 21 days from C2D15 of chemotherapy with gemcitabine/nab-
paclitaxel (cycle length 28 days). Ideally day +7-14 from last dose of chemotherapy. 
3: 
Eligibility determination, enrollment and randomization can occur up to 1 week after initiating 
neoadjuvant chemotherapy as long as all screening procedures were completed before 
starting treatment. Longer delays will need will require notification of the IND sponsor and 
continuation on study will be at discretion of the IND sponsor. 
4:  Criteria defined in Sections 5.1.3 and 5.1.4. 
5:  Includes history of autoimmune disease, lung disease, HIV, hepatitis B or C infection, and 
complete cancer history, including primary site of cancer, gross location of primary tumor, 
histology, histologic grade, date of initial diagnosis, and prior cancer therapy regimens. 
6:  This can be a focused history, and should include ongoing symptoms from neoadjuvant 
chemotherapy. 
7:  Complete physical exam will be completed at baseline; focused physical examinations will be 
conducted thereafter.  Exams, concomitant medication, AE assessments can be made up to 
3 days prior to study visit. 
8: 
Temperature, respiration rate, blood pressure, pulse, and pulse oximetry.  
9: 
Height will be obtained at or prior to baseline only. 
10: See Table 5.  
11: Total T3 and FT4 to be checked reflexively if TSH is abnormal and clinically indicated. 
12: For WOCBP: serum pregnancy test is required at screening; urine pregnancy tests are 
required thereafter. Pregnancy tests must be done within 7 days of the first treatment and 
then will be repeated with each subsequent therapy (collected within a window of up to 3 days 
prior to dosing). 
13: Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, 
and specific gravity. 
14: Radiologic evaluations (CT pancreas protocol, Chest, abdomen, and pelvis with contrast).  
Non-contrast CT Chest and MRI Abdomen/pelvis will be done for those with contrast allergies. 
Imaging will occur: 1. at time of diagnosis, 2. after the completion of neoadjuvant 
chemotherapy and prior to start of immunotherapy (window 21 days, from last dose of 
neoadjuvant SOC chemotherapy), and 3. following the last dose of neoadjuvant 
immunotherapy before surgical resection  
15: See Section 7.3.2 on correlative studies. These studies only apply after time of consent. 
16: If a diagnostic biopsy has been already done prior to enrollment we will request the archival 
tissue. If no biopsy has been completed, we will obtain EUS diagnostic core biopsy. 
17: EUS Guided biopsy (4-6 core biopsies) if amenable and safe to do so, will be obtained for 
research purposes and archival tissue collection for organoid culture. Biopsy will occur within 
21 days from last dose of standard of care neoadjuvant chemotherapy.  
18. Research samples will be collected at the discretion of the PI based on availability of supplies 
and safety of patient and staff. 
19. Eligibility determination, enrollment and randomization can occur up to 1 week after initiating 
neoadjuvant chemotherapy as long as all screening procedures were completed before 
starting treatment. 
 
 

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6.2  
Neoadjuvant Immunotherapy Phase Study Calendar 
 
Procedure 
Cycle 1 
Pembrolizumab ± 
Defactinib 
Cycle 2 
Pembrolizumab ± 
Defactinib 
Post Immunotherapy/ 
Pre-surgical 
Evaluation3 
C1D1 
C1D2-21 
C2D1 
C2D-2117 
 
Visit Window1 
+21 
Days2 
- 
+7 days 
- 
 
Pembrolizumab 
X4 
 
X5 
 
 
Defactinib (Arm A Only)18 
X 
X 
X 
X6 
X 
Medications7 
X 
 
X 
 
X 
Physical Exam7 
X 
 
X 
 
X 
Vital Signs, pulse ox8 
X 
 
X 
 
X 
Weight 
X 
 
X 
 
X 
Performance Status 
X 
 
X 
 
X 
Hematology Profile9 
X10 
 
X11 
 
X 
Complete Metabolic 
Profile9 
X10 
 
X11 
 
X 
TSH12  
X10 
 
X11 
 
X 
Urine Pregnancy13 
X10 
 
X11 
 
X 
CEA 
X10 
 
X11 
 
X 
CA19-9 
X10 
 
X11 
 
X 
Phone Call 
 
 
 
X17 
 
Adverse event evaluation7 
X 
 
X 
 
X 
CT or MRI14 
 
 
 
 
X 
Whole blood for PBMC15, 
19 
X 
 
 
 
X 
Whole blood for serum15, 19 
X 
 
 
 
X 
Whole blood for plasma15, 
19 
X 
 
 
 
X 
Surgical Evaluation16 
 
X 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for inperson clinical trial visits or portions of clinical trial visits where determined to be 
appropriate and where determined by the investigator not to increase the participants risks. Prior 
to initiating telemedicine for study visits the study team will explain to the participant, what a 
telemedicine visit entails and confirm that the study participant is in agreement and able to 
proceed with this method. Telemedicine acknowledgement will be obtained in accordance with 
the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed 
feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted 
using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
 

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1:   Longer delays to be approved by the IND sponsor. 
2:   C1D1 can occur on the same day following post SOC neoadjuvant chemotherapy visit, as 
long as imaging studies and EUS have also been completed prior to immunotherapy. 
3: 
This visit will occur as close as possible to the second cycle of immunotherapy, however can 
occur any time prior to surgical resection. 
4: 
The first cycle of pembrolizumab will begin within 21 days of C2D15 even if patient does not 
receive dose on D15. If delayed further, please see Section 5.2.5. Pembrolizumab can only 
be administered after imaging scans, EUS biopsy, and post-SOC neoadjuvant chemotherapy 
visit are complete.  
5: 
The second cycle of pembrolizumab will begin within 7 days of completing the last cycle of 
pembrolizumab. If delayed further, please see Section 5.2.5. 
6: 
Defactinib will continue up until 2 days  prior to surgery (last dose given 48 hours prior to 
surgery) and surgery will occur 10-25 days from the administration of the second cycle of 
pembrolizumab. If second cycle of immunotherapy is not administered due to toxicity or other 
reasons, patient can proceed with surgical evaluation and be considered for surgery. If 
delayed further, please see Section 5.2.5. 
7: 
Focused physical examination for Cycle 1 and 2. Complete physical exam during the pre-
surgical evaluation. Exams, concomitant medication, AE assessments can be made up to 3 
days prior to infusion. 
8: 
Temperature, respiration rate, blood pressure, and pulse should be taken prior to and at the 
end of the pembrolizumab infusion. Pulse oximetry should be taken prior to each 
pembrolizumab infusion. 
9: 
See Table 5. 
10: If these labs were obtained at the post SOC neoadjuvant chemotherapy visit and are not >7 
days old, they do NOT need to be repeated.  If lab parameters are not met on earlier labs at 
post neoadjuvant chemotherapy visit they can be repeated on C1D1.  
11: Labs may be collected within a window of up to 3 days prior to dosing. Unexpected Grade 3 
or greater laboratory abnormalities should be repeated within 24-72 hours if clinically indicated 
and monitored as necessary to determine if event meets toxicity criteria. 
12: Total T3 and FT4 to be checked reflexively if TSH is abnormal and clinically indicated. 
13: For WOCBP. Urine pregnancy tests must be done within 7 days of the first treatment and then 
will be repeated with each subsequent therapy (collected within a window of up to 3 days prior 
to dosing). 
14: Radiologic evaluations (CT pancreas protocol, Chest, abdomen, and pelvis with contrast).  
Non-contrast CT Chest and MRI Abdomen/pelvis will be done for those with contrast allergies. 
Imaging will occur: 1. at time of diagnosis, 2. after the completion of neoadjuvant 
chemotherapy and prior to start of immunotherapy (window + 14 days, from completion of 
neoadjuvant chemotherapy) and 3. following the last dose of neoadjuvant immunotherapy and 
before surgical resection (i or after cycle 1 of immunotherapy and before surgical evaluation 
for those patients who do not receive second dose of immunotherapy) If surgical evaluation 
is <4 weeks from last scan, it does not need to be repeated.  
15: See Section 7.3.2 on correlative studies. These research studies can be obtained earlier +/- 
7 days from C1D1, but should ideally be obtained on C1D1. Prior to surgery, these labs can 
be obtained +/-14 days from day of surgery, but ideally should be obtained at preoperative 
visit regardless of receiving one or two cycles of neoadjuvant immunotherapy.  
16:  An option surgical initial planning visit as part of standard of care may occur at any point during 
immunotherapy treatment and after chemotherapy, at discretion of surgical team.  
17:  Subjects are planned to receive 21 days of defactinib. However, administration of defactinib 
can be prolonged until 23 days or discontinued prior to 21 days depending on planned date 

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of surgery. Defactinib will continue up until 2 days prior to surgery (last dose given 48 hours 
prior to surgery). Study team will notify patient when to stop drug.  
18:  Defactinib should be administered within 30 minutes of a meal. 
19. Research samples will be collected at the discretion of the PI based on availability of supplies 
and safety of patient and staff. 
 
 
 

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6.3  
Surgery, Standard of Care Adjuvant Chemotherapy Phase Study 
Calendar 
 
Procedure 
 
Surgery1 
Adjuvant 
chemotherapy 
Post Standard of Care Adjuvant 
Chemotherapy/Pre-Maintenance 
Immunotherapy Evaluation 
Visit Window 
- 
- 
X2 
SOC Chemotherapy 
 
X 
 
Medications 
 
 
X 
Inclusion/Exclusion Criteria 
 
 
X3 
Complete Physical Exam 
 
 
X 
Vital Signs and pulse ox4 
 
 
X 
Weight 
 
 
X 
Performance Status 
 
 
X 
Hematology profile5,6 
 
 
X 
Complete Metabolic Profile5,6 
 
 
X 
TSH6,7 
 
 
X 
Urine Pregnancy8 
 
 
X 
CEA6 
 
 
X 
CA19-96 
 
 
X 
Surgical Tumor Specimen12, 13 
X 
 
 
Pathology Review 
 
 
X 
Adverse Event Evaluation 
X9 
X9 
X9 
CT or MRI10 
 
 
X 
Whole blood for PBMC11, 13 
 
 
X 
Whole blood for serum11, 13 
 
 
X 
Whole blood for plasma11, 13 
 
 
X 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for inperson clinical trial visits or portions of clinical trial visits where determined to be 
appropriate and where determined by the investigator not to increase the participants risks. Prior 
to initiating telemedicine for study visits the study team will explain to the participant, what a 
telemedicine visit entails and confirm that the study participant is in agreement and able to 
proceed with this method. Telemedicine acknowledgement will be obtained in accordance with 
the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed 
feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted 
using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
 

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1: 
Surgery will be scheduled within 10-25 days from the second dose of neoadjuvant 
pembrolizumab. 
2: 
Post Standard of Care Adjuvant Chemotherapy/Pre-Maintenance Immunotherapy evaluation 
should occur within 6 weeks from completion of standard of care adjuvant chemotherapy or 
after final administered dose of adjuvant therapy. This visit can coincide with the first dose in 
the maintenance immunotherapy phase (C3D1).  
3: 
Criteria defined in Sections 5.1.5 and 5.1.6. 
4:  Temperature, respiration rate, blood pressure, pulse, and pulse oximetry. 
5: 
See Table 5. 
6: 
Labs may be collected within a window of up to 3 days prior to dosing. Unexpected Grade 3 
or greater laboratory abnormalities should be repeated within 24-72 hours if clinically indicated 
and monitored as necessary to determine if event meets toxicity criteria. 
7: 
Total T3 and FT4 to be checked reflexively if TSH is abnormal and clinically indicated. 
8: 
For WOCBP. Urine pregnancy tests must be done within 7 days of the first treatment and then 
will be repeated with each subsequent therapy (collected within a window of up to 3 days prior 
to dosing). 
9:  Collection of pembrolizumab and defactinib related toxicities. See Section 7.6.5 and 8.2.1 for 
the surgical toxicities that will be collected. 
10: CT Chest, abdomen, pelvis with pancreas protocol with contrast or Non-contrast CT chest 
and MRI Abd, pelvis for those with contrast allergies. CT at the start of immunotherapy in the 
adjuvant phase will need to occur before start of C1 of pembrolizumab. This should occur at 
the end of adjuvant SOC chemotherapy and prior to the first cycle of pembrolizumab (6 week 
window) but as close as possible to administration of first dose of immunotherapy in the 
maintenance phase (cycle 3). 
11: See section on correlative studies, Section 7.3.2. If research bloods are collected at the 
Post SOC Adjuvant Chemotherapy/Pre-Maintenance Immunotherapy Evaluation they do not 
need to be collected again at C3D1. 
12.  If patient is a surgical candidate, resected specimen will be obtained intraoperatively for 
research. If patient is noted to have metastases at the time of surgery, a research biopsy will  
be performed. If it is determined at the pre-surgical evaluation that the patient is not a 
candidate for surgery, a research biopsy will be performed via EUS if safe and amenable to 
do so. 
13. Research samples will be collected at the discretion of the PI based on availability of supplies 
and safety of patient and staff.

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6.4  
Maintenance Immunotherapy Phase Study Calendar 
 
 
Procedure 
 
Combination immunotherapy1 on 3-week cycles 
EOT2 
90 Day 
Safety FU 
Visit 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
 
+14 
D1 
D 
2-21 
D1 
D 
2-21 
D1 
D 
2-21 
D1 
D 
2-21 
D1 
D 
2-21 
D1 
D 
2-21 
D1 
D 
2-21 
D1 
D 
2-21 
 
 
Visit Window 
+73 
 
+7 
 
+7 
 
+7 
 
+7 
 
+7 
 
+7 
 
+7 
 
X2 
 
SOC Chemotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Defactinib (Arm A) Only12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pembrolizumab 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Medications 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Focused Physical Exam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital Signs, pulse ox4 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Weight 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Performance Status 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematology profile5,6 
X7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Complete Metabolic 
Profile5,6 
X7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
TSH6,8 
X7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine Pregnancy6,9 
X7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
CEA6 
X7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CA19-96 
X7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Adverse Event Eval 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CT or MRI10 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Whole blood for PBMC11, 
13 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Whole blood for serum11, 
13 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Whole blood for 
plasma11, 13 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 

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In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for inperson clinical trial visits 
or portions of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the 
participants risks. Prior to initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit 
entails and confirm that the study participant is in agreement and able to proceed with this method. Telemedicine acknowledgement 
will be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed 
feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA compliant method 
approved by the Health System and within licensing restrictions. 
 
1: 
Subjects will receive combination immunotherapy and defactinib or pembrolizumab alone on a 21-day cycle. Each subsequent 
cycle of pembrolizumab should start within 7 days after the completion of the last cycle on a 21-day cycle with visit (window + 7 
days) occurring prior to administration of pembrolizumab. If delayed further, please see Section 5.2.5. Unexpected Grade 3 or 
greater laboratory abnormalities should be repeated within 24-72 hours if clinically indicated and monitored as necessary to 
determine if event meets toxicity criteria. 
2: 
End of Treatment (EOT) Evaluation: 30 days (±7 days) after their last dose of study drug or within 7 days prior to initiation of a 
new anti-cancer treatment, whichever comes first. An in-person visit is preferred, however, if the patient is unable to return for an 
EOT visit (e.g. disease/clinical progression, poor health, intercurrent illness, or initiation of a new anti-cancer therapy), or if the 
EOT visit occurs early, an assessment of adverse events should be made by telephone or telemedicine visit on day 30 (± 7) after 
the last study drug in place of the PE/PS/vitals. Clinical laboratory values should still be collected. Additionally, for those subjects 
who do not have scans within 6 weeks prior to EOT a repeat scan should be collected and an in-person EOT visit is recommended. 
The EOT scan and research labs do not need to be repeated if they occurred within 6 weeks of the EOT evaluation. Patients who 
discontinue from treatment should be contacted (by phone, email, telemedicine, medical record search, or scheduled visit) per 
standard of care for up to 24 months or study closure to monitor overall survival.  Information of other cancer therapies after 
discontinuation from the study treatment will be collected.  
3: 
Patients must have eligibility reconfirmed prior to initiation of Cycle 3 of adjuvant immunotherapy (Please see Sections 5.1.1, 
5.1.2 and 2.1.6 for criteria). Cycle 3 of adjuvant immunotherapy should begin within 6 weeks from completion of standard of care 
adjuvant chemotherapy. Further dosing of study medications will be based on visits prior to each adjuvant immunotherapy cycle. 
This visit can coincide with the post-surgery/SOC adjuvant chemotherapy visit.  
4: 
Temperature, respiration rate, blood pressure, and pulse should be taken prior to and at the end of the pembrolizumab infusion. 
Pulse oximetry should be taken prior to each pembrolizumab infusion. 
5: 
See Table 5. 
6: 
Labs may be collected within a window of up to 3 days prior to dosing. Unexpected Grade 3 or greater laboratory abnormalities 
should be repeated within 24-72 hours if clinically indicated and monitored as necessary to determine if event meets toxicity 
criteria. 
7: 
If these labs were obtained at the post-surgery/SOC adjuvant chemotherapy visit and are not >7 days old, they do NOT need to 
be repeated. 
8: 
Total T3 and FT4 to be checked reflexively if TSH is abnormal and clinically indicated. 

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9: 
For WOCBP. Urine pregnancy tests must be done within 7 days of the first treatment and then will be repeated with each 
subsequent therapy (collected within a window of up to 3 days prior to dosing). 
10: CT Chest, abdomen, pelvis with pancreas protocol with contrast or non-contrast CT chest and MRI Abd, pelvis for those with 
contrast allergies. Imaging at the start of immunotherapy in the adjuvant phase will need to occur before start of C1 of 
pembrolizumab. The first scan in the immunotherapy maintenance phase can occur at the post-surgery/SOC adjuvant 
chemotherapy visit. Subsequent scans will approximately on C6D1 and C10D1, with a window of -14 day window. 
11: Research blood should coincide with imaging studies, and are to occur on C3D1, C6D1 and C10D1, with a window of -14 day 
window.  See section on correlative studies, Section 7.3.2. 
12:  Defactinib should be administered within 30 minutes of a meal. 
13. Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff. 

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7.0 
TRIAL PROCEDURES 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at 
each visit.  Individual trial procedures are described in detail below.  It may be necessary 
to perform these procedures at unscheduled time points if deemed clinically necessary by 
the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the IND 
Sponsor and/or Merck/Verastem for reasons related to participant safety. In some cases, 
such evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained from 
the participant.  In these cases, such evaluations/testing will be performed in accordance 
with those regulations. 
 
7.1 
Administrative Procedures 
 
7.1.1  
Informed Consent 
 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
 
7.1.1.1  
General Informed Consent 
 
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
 
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in 
the trial.  The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the 
participant’s dated signature or by the participant’s legally acceptable representative’s 
dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form template 
at the protocol level.   
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and 
regulations, and IND Sponsor requirements. 
 

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7.1.2  
Inclusion/Exclusion Criteria 
 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.  
 
7.1.3  
Registration Guidelines and Procedures 
 
Eligible patients will be entered on study centrally at the Sidney Kimmel Comprehensive 
Cancer Center at the Johns Hopkins University by the Coordinating Center. All sites should 
email GITrialRegistration@jhmi.edu to verify ongoing study enrollment status.  The 
Registration Form and Eligibility Checklist will be supplied to each participating site. 
 
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible. 
 
To register a patient, the following de-identified documents should be completed by the 
Research Nurse or Study Coordinator at the participating site and e-mailed to 
GITrialRegistration@jhmi.edu: 
• Fax cover sheet 
• Registration Form 
• Signed patient consent form 
• HIPAA authorization form  
• Eligibility Screening Checklist 
• Copy of required screening tests and scans 
 
The Research Nurse or Study Coordinator at the participating site will then e-mail 
GITrialRegistration@jhmi.edu to verify eligibility.  To complete the registration process, the 
Coordinating Center at JHU will: 
• Assign a patient study number 
• Register the patient on the study 
• Fax or e-mail the patient study number to the participating site 
• Call or e-mail the research nurse or data manager at the participating site and 
verbally confirm registration. 
 
7.1.4  
Medical History 
 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the 
subjects PDAC, for which the participant has enrolled in this study will be recorded 
separately and not listed as medical history.   
 
7.1.5 
Prior and Concomitant Medications Review 
 

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7.1.5.1  
Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the 
participant within 28 days before starting the trial.  Treatment for the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as a prior 
medication.  
 
7.1.5.2 
Concomitant Medications 
 
The investigator or qualified designee will record medication, if any, taken by the 
participant during the trial.  All medications related to reportable SAEs and ECIs should be 
recorded as defined in Section 7.6. 
 
7.1.6  
Disease Details and Treatments 
 
7.1.6.1 
Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding 
subjects PDAC.  
 
7.1.6.2 
Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
7.1.6.3 
Subsequent Anti-Cancer Therapy Status 
 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy 
within 30 days after the last dose of trial treatment, the 30 day Safety Follow-up visit must 
occur before the first dose of the new therapy.  Once new anti-cancer therapy has been 
initiated the participant will move into survival follow-up.  
 
7.1.7  
Assignment of Screening Number 
 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation. 
Each subject will be assigned only one screening number. Screening numbers must not 
be re-used for different subjects.  
 
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.  
 

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Specific details on the screening visit requirements (screening/rescreening) are provided 
in Section 7.6.1.  
 
7.1.8  
Assignment of Randomization Number 
 
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number. The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization. Once a treatment/randomization 
number is assigned to a subject, it can never be re-assigned to another subject.  
 
A single subject cannot be assigned more than 1 treatment/randomization number.  
 
7.1.9 
Trial Compliance (Medication/Diet/Activity/Other) 
 
Interruptions from the protocol specified treatment for greater than 4 weeks between study 
treatment of pembrolizumab for non-drug-related or administrative reasons require 
consultation between the investigator and the IND Sponsor and written documentation of 
the collaborative decision on subject management. Interruptions from the protocol 
specified treatment for greater than 2 weeks between study treatment pembrolizumab for 
non-drug-related or administrative reasons require consultation between the investigator 
and the IND Sponsor and written documentation of the collaborative decision on subject 
management.  
 
Administration of trial medications will be witnessed by the investigator and/or trial staff 
when administered in the outpatient setting.  
 
7.2 
Clinical Procedures/Assessments 
 
7.2.1 
Adverse Event (AE) Monitoring 
 
The investigator or qualified designee will assess each participant to evaluate for potential 
new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 5.0. Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to Section 7.6 for detailed information regarding the assessment and 
recording of AEs.   
7.2.2 
Complete Physical Exam 
 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  Additional complete physical exams should be performed as specified in the Trial 
Flow Chart – Section 6.0. After the first dose of trial treatment, new clinically significant 
abnormal findings should be recorded as AEs.  

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7.2.3  
Focused Physical Exam 
 
For cycles that do not require a complete physical exam per the Trial Flow Chart – Section 
6.0, the investigator or qualified designee will perform a focused physical exam as clinically 
indicated prior to dosing ±3 days of Day 1 of each treatment cycle. New clinically significant 
abnormal findings should be recorded as AEs.  
 
7.2.4 
Vital Signs and Pulse Oximetry 
 
The investigator or qualified designee will take vital signs and pulse oximetry at screening, 
prior to and after the administration of each dose of pembrolizumab, and at treatment 
discontinuation as specified in the Trial Flow Chart (Section 6.0).  Vital signs should 
include temperature, pulse, respiratory rate, weight and blood pressure. Height will be 
measured prior to or at screening only. New clinically significant abnormal findings should 
be recorded as AEs. 
 
7.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (Appendix 1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial 
treatment as specified in the Trial Flow Chart.   
 
7.2.6 
Tumor Imaging and Assessment of Disease 
 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT) using 
JHH pancreatic protocol.  For the abdomen and pelvis, contrast-enhanced magnetic 
resonance imaging (MRI) may be used when CT with iodinated contrast is contraindicated, 
or when local practice mandates it.  The same imaging technique regarding modality, 
ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the assessment of response or progression 
based on imaging. 
 
7.2.6.1 
Tumor Imaging During the Study 
 
The first on-study imaging assessment should be performed within ±4 weeks from the date 
of randomization.  Subsequent tumor imaging should be performed every 8 weeks (56 
days ±14 days) in the neoadjuvant setting or more frequently if clinically indicated. In the 
adjuvant setting imaging will occur prior to immunotherapy or C3D1, C6D1 and 
C10D1/EOT Visit with window of - 14 day. Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts.  Imaging should continue to be performed 
until progression indicating unresectability of disease in the neoadjuvant phase, 
recurrence in the adjuvant phase or metastatic disease at any point in the study is 
identified by the Investigator.  
 

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7.2.6.2 
End of Treatment and Follow-up Tumor Imaging 
 
In participants who discontinue study treatment for any reason, tumor imaging should be 
performed at the time of treatment discontinuation (±4 week window).  If previous imaging 
was obtained within 6 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory. 
 
In participants who discontinue study treatment without documented disease progression, 
recurrence or metastatic disease, every effort should be made to continue monitoring their 
disease status by tumor imaging per standard of care to monitor disease status until the 
start of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
 
7.3 
Laboratory Procedures/Assessments 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below.  
 
7.3.1 
Basic Laboratory Testing 
 
Laboratory tests for hematology, chemistry, and others are specified in Table 5.   

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Table 5: Laboratory Tests 
 
Hematology 
Chemistry 
Other 
Hematocrit 
Albumin 
Serum β-human chorionic 
gonadotropin†; (β-hCG) 
Platelet count 
Alanine aminotransferase (ALT) 
Urine pregnancy test † 
WBC (total and differential) 
Aspartate aminotransferase (AST) Total thriiodothyronine (T3) 
Red Blood Cell Count 
Carbon Dioxide ‡ 
Free thyroxine (T4) 
Absolute Neutrophil Count 
  (CO2 or biocarbonate) 
Thyroid stimulating hormone (TSH) 
Absolute Lymphocyte Count 
Calcium 
CEA 
 
Chloride 
CA 19-9 
 
Glucose 
 
 
Potassium   
 
 
Sodium 
 
 
Total Bilirubin 
 
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
Total protein 
 
 
Blood Urea Nitrogen 
  
 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required.  Serum pregnancy test required at time of intitial 
enrollment, urine pregnancy test acceptable subsequently.  
‡ If considered standard of care in your region. 
 
 
 

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Laboratory tests for screening should be performed within 10 days prior to the first dose 
of trial treatment. Laboratory test results must be reviewed by the investigator or qualified 
designee and found to be acceptable prior to administration of each dose of trial treatment. 
New clinically significant abnormal findings should be recorded as AEs. Unresolved 
abnormal labs that are drug related AEs should be followed until resolution. Labs do not 
need to be repeated after the end of treatment if labs are within normal range.  
 
7.3.2 
Tumor Tissue Collection and Correlative Studies 
 
7.3.2.1  
Tissue Studies 
 
Four to six core tumor biopsies will be collected during scheduled endoscopies (at 
diagnosis (baseline) and after neoadjuvant chemotherapy [part 2 of study]). Archival tumor 
samples will also be collected for every subject (10 slides and/or blocks). Detailed 
instructions for tissue collection, processing, and shipment are provided in the Laboratory 
Manual. 
 
The tissue samples will be banked for the evaluation of CD8+ T Cell effectors, MHC 1 
expression, PD-L1 expression on tumor and PD-L1 on tumor-infiltrating immune cells, and 
their associated immune suppressive pathways and other immune activation pathways to 
assess the effect of treatment upon the tumor microenvironment and the correlations 
between these immune parameters and clinical response. Immunohistochemistry, flow 
cytometry, quantitative PCR assays and microarray analysis will be employed. Peripheral 
Blood Lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL), either directly from 
FFPE tumor sections or following isolation from fresh surgical tumor specimen, will be 
used for the TCR repertoire analysis by next-generation sequencing. 
 
7.3.2.2 
Translational Immune Biology Analysis 
 
Peripheral blood mononuclear cells (PBMC), plasma, and serum will be collected before 
and after chemotherapy, each cycle of immunotherapy and surgery at participating sites. 
Whole blood for PBMCs (up to 100cc) will be collected at the specified timepoints (See 
Section 6.0). Detailed instructions for blood collection, processing, and storage are 
provided in the Laboratory Manual.  Peripheral MDSCs will also be assessed before and 
after study treatments. Resected tumor specimens will be archived for research purpose. 
Tumor infiltrating immune cells will be isolated from resected PDACs. Biopsy and surgical 
resected biospecimens will be archived for tumor/stroma DNA/RNA sequencing. Tumor 
infiltrating immune cells will be isolated from resected tumors, phenotypically analyzed and 
also sorted to immune subpopulations including CD4, CD8, CD4+, CD25+, B cells, 
myeloid cells for RNA sequencing. All biospecimens will be subjected to multiplex 
immunostaining analysis and nanostring PCR analysis. 
 
• TAM, MDSC, and Treg will be particularly analyzed through multiplex IHC based 
methods.  In addition, M1 vs. M2, Th1, Th2, Th17, vs. Treg, immune checkpoint 
pathways, T effector, memory, and activation markers will be analyzed by multiplex 

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IHC. The role of FAK inhibitor on the change of immune suppressive cells and 
immune effector cells will be assessed.  
• Chemokine/cytokines and their receptors will be analyzed by RNA sequencing and 
nanostring PCR.  
• Tumor signaling, immune signaling and stroma signaling pathways will be analyzed 
through RNA sequencing and nanostring PCR. In particular, dissected stroma will 
be analyzed for the FAK signaling pathways and TCR clonality.  
• Genetic alterations in the tumor will also be analyzed. Immune response or change 
in immune parameters will be correlated to the subtypes of PDACs as defined by 
genetic alterations and transcriptome.  
• Stromal fibroblast density, activity (SMA expression) and FAP expression will be 
assessed by immunohistochemistry. 
• Immunogenic cell death markers (calreticulin) and signaling pathways will be 
assessed in the post-chemo and pre-immunotherapy biopsy specimens through 
immunohistochemistry and nanostring PCR analysis. 
• TCR clonality analysis will be assessed in the pre-immunotherapy biopsy 
specimens and post-immunotherapy resected tumor specimens, pre- and post-
immunotherapy peripheral blood.  
• Plasma will be collected for ctDNA analysis; serum will be collected for serum 
proteomic analysis for predictive biomakers  
• Microsatellite instability (MSI), a form of genomic instability, occurs through the 
insertion or deletion of repeating nucleotides during DNA replication and failure of 
the mismatch repair system to correct errors in nucleotide repeat markers. This can 
confer tumor responses to anti-PD1 therapy. All MSI testing will be performed 
retrospectively for mismatch repair deficiency (MRD) or MSI using IHC, PCR, or 
next generation sequencing (NGS) in all study subjects. MMRd or MSI status is 
determined by examining either 1) protein expression by IHC of 4 MMR enzymes 
(MLH1/MSH2/MSH6/PMS2) or 2) 3-5 tumor microsatellite loci using PCR-based 
assay, respectively. 
 
Genomic sequencing library construction, whole genome/exome sequencing, whole 
transcriptome sequencing, T cell receptor and B cell receptor sequencing, neoepitope 
prediction, mutation burden, CITE-seq, ChIP-seq, ATAC-seq, and MBD-seq, and 
bioinformatic analysis will be performed either at an on-campus laboratory or at an off-
campus sequencing service. These assays will allow us to explore the effects of therapy 
on tumor and tumor infiltrating immune cells. 
 
All the samples will be de-identified before sending to any laboratory for sequencing. The 
FASTQ files, BAM files and VCF files will be generated and analyzed. Genomic 
sequencing data will be stored and computations conducted using a JH IT managed 
subscription of Azure. 
 
Results from the sequencing studies will not be released to the patients. These studies 
are for research purposes only and are not using a clinically validated platform. 

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7.3.2.3  
Serum and Plasma Marker Studies 
 
Sera (up to 10 cc in neoadjuvant setting and 5cc in the adjuvant setting) and plasma (up 
to 10cc) will be collected at the specified time points (Section 6) detailed in the study 
schedule to identify potential therapeutic targets, biomarkers, and predictors of response 
and autoimmune toxicity. Detailed instructions for blood collection, processing, and 
shipment are provided in the Laboratory Manual.  
 
7.3.2.4  
Diagnostic Tissues Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or 
diagnoses immune related toxicities. 
 
7.3.2.5  
Tumor Modeling for Molecular Characterization 
 
Tissue collected at the time of diagnostic biopsy, 2nd research biopsy and surgical 
specimen will also be utilized to create organoid models of each subject’s tumor. For the 
purposes of this work, one to three core needed biopsies of the tumor will be obtained 
during endoscopy. This tissue cores will be transported to the laboratory and used to 
generate organoid culture models of each subject’s tumor. In this manner, each tumor’s 
organoid model may then be utilized for gene mutation, gene expression and immune 
biology analysis as in Section 7.3.2.2-7.3.2.4. For further details, please refer to the 
laboratory analysis. 
 
7.4 
Other Procedures 
 
7.4.1 
Withdrawal/Discontinuation 
 
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.6 - Assessing 
and Recording Adverse Events.   
 
7.4.2  
Blinding/Unblinding 
 
This is an open label trial; there is no blinding for this trial.  
 
7.5  
Visit Requirements 
 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-
related details are provided above in Section 7.0 - Trial Procedures. 
 
7.5.1 
Screening 
 

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Approximately 14 days prior to treatment randomization, potential subjects will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1. 
Screening procedures may be repeated after consultation with the IND Sponsor.  
 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified 
time frame. CA19-9 level will be determined for eligibility at the time of diagnosis.  
• Laboratory tests and ECOG performance status are to be performed within 14 days prior 
to randomization. 
• Baseline scan is to be performed within 21 days prior to randomization.  
• For women of reproductive potential, a serum pregnancy test will be performed within 72 
hours prior to the first dose of trial treatment.  
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in 
lieu of repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. Subjects may not rescreen more than 1 time without 
consulting with the IND Sponsor. Subjects who are rescreened will retain their original 
screening number.  
7.5.2. 
Treatment Period 
 
Visit requirements are outlined in the Trial Flow Chart (Section 6.0). Specific procedure- 
related details are provided above in the Trial Procedures (Section 7.0)  
 
7.5.3 
Post-Treatment Follow-up Visits 
 
7.5.3.1  
End of Treatment (EOT) Visit 
 
The mandatory EOT Visit should be conducted 30 days (± 7 days) after the last dose of 
study treatment (pembrolizumab or defactinib) or within 7 days before the initiation of a 
new anti-cancer treatment, whichever comes first. Procedures and assessments 
performed at this visit should follow the respective guidelines described in Sections 5.9 
and 6.4. 
 
7.5.3.2  
Safety Follow-up Visit 
 
See Section 5.10.1.  
 
7.5.3.3  
Survival Follow-up 
 
See Section 5.10.2. 
 

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7.6 
Assessing and Recording Adverse Events 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to 
the medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a pre-existing condition that is 
temporally associated with the use of the study treatments, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.   
 
Study treatments include any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including 
placebo or active comparator medication) or marketed, manufactured by, licensed by, 
provided by or distributed by Merck or Verastem for human use. 
 
Adverse events may occur during the course of the use of drug product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
 
▪ All AEs, SAEs and other reportable safety events that occur after the consent form 
is signed but before treatment allocation/randomization must be reported by the 
investigator if the event caused the participant to be excluded from the study, or is 
the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, or a procedure.  
▪ All AEs from the time of treatment allocation/randomization through 30 days 
following cessation of study treatment must be reported by the investigator.  
o Chemotherapy is considered standard of care (SOC). Patients will be 
considered off investigational therapy/ies during neoadjuvant chemotherapy. 
Patients will also be off investigational therapy/ies during adjuvant 
chemotherapy. Only AEs and SAEs related to pembrolizumab or defactinib 
that occur during this off treatment period will be recorded and reported.  
o Surgery is also considered SOC. Adverse events  will  be  reviewed  to  
ensure  that  pembrolizumab  and  defactinib  are  not  contributing  to  
postoperative complications. Section 7.6.5 outlines which surgical 
complications will be recorded as adverse events. Adverse events and 
serious adverse events related to either pembrolizumab or defactinib will 
also be recorded and reported. 
▪ All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following 

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cessation of study treatment if the participant initiates new anticancer therapy, 
whichever is earlier must be reported by the investigator.  
▪ Events of clinical interest as defined in Section 7.6.3.2.  
▪ All pregnancies and exposure during breastfeeding, that occur from the time of 
treatment allocation/randomization through 120 days following cessation of study 
treatment, or 30 days following cessation of study treatment if the participant 
initiates new anticancer therapy must be reported by the investigator. All 
pregnancies will be followed through pregnancy completion or termination.  
▪ Additionally, any SAE brought to the attention of an investigator at any time outside 
of the time period specified above must be reported immediately by the investigator 
if the event is considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, 
the investigator must promptly notify Merck and Verastem. 
 
7.6.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the IND Sponsor, Merck, and Verastem 
Pembrolizumab: 
 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available 
on the treatment of overdose of pembrolizumab. In the event of overdose, pembrolizumab 
should be stopped and the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other serious 
criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect” on the ECI Reporting Form (Appendix 5) to 
the IND Sponsor (e-mail: lzheng6@jhmi.edu and GIsafetyreporting@jhmi.edu) within 24 
hours and to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215-661-6229) 
within 2 business days. 
 
All reports of overdose with an adverse event must be reported using the SAE Reporting 
Form 
(Appendix 
6) 
to 
the 
IND 
Sponsor 
(e-mail: 
lzheng6@jhmi.edu 
and 
GIsafetyreporting@jhmi.edu) within 24 hours and to Merck Global Safety (Attn: Worldwide 
Product Safety; FAX 215-661-6229) within 2 business days. 
 

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Defactinib: 
 
For purposes of this study, if the subject was given (accidentally or intentionally) a dose of 
1600 mg or greater (≥4 times the indicated dose) of defactinib, it is considered an 
overdose.  No specific information is available on the treatment of overdose of defactinib. 
In the event of overdose, defactinib should be stopped and the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
if clinically indicated. 
 
If an adverse experience(s) is associated with (“results from”) the overdose of test drug, 
the adverse experience(s) is reported as a serious adverse experience, even if no other 
serious criteria are met. 
If a dose of defactinib meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as 
a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect” on the ECI Reporting Form (Appendix 5) 
within 
24 
hours 
to 
the 
IND 
Sponsor 
(e-mail: 
lzheng6@jhmi.edu 
and 
GIsafetyreporting@jhmi.edu) 
and 
Verastem 
local 
safety 
representative 
(drugsafety@verastem.com or faxed to +1 781 465 7936). 
 
All reports of overdose with an adverse experience must be reported using the SAE 
Reporting Form (Appendix 6) within 24 hours to the IND Sponsor (e-mail: 
lzheng6@jhmi.edu and GIsafetyreporting@jhmi.edu) and Verastem local safety 
representative (drugsafety@verastem.com  or faxed to +1 781 465 7936). 
 
7.6.2 
Reporting of Pregnancy and Lactation to the IND Sponsor, Merck, and 
Verastem 
 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events unless there is cause to believe that the investigational product may have interfered 
with the effectiveness of a contraceptive medication or if the outcome of the pregnancy 
meets serious criteria, it is the responsibility of investigators or their designees to report 
any pregnancy or lactation in a participant (spontaneously reported to them) that occurs 
during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form 
is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the participant to be excluded from the trial, or are the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.   
 
Pregnancies and infant exposures during breastfeeding that occur from the time of 
treatment allocation/randomization through 120 days following cessation of the 
investigational product, or 30 days following cessation of treatment if the participant 
initiates new anticancer therapy, whichever is earlier, must be reported by the investigator.  
All reported pregnancies must be followed to the completion/termination of the pregnancy. 

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Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be 
reported as serious adverse events (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
 
Such events must be reported using the SAE Reporting Form (Appendix 6) within 24 
hours to the IND Sponsor (e-mail: lzheng6@jhmi.edu and GIsafetyreporting@jhmi.edu), 
Verastem (drugsafety@verastem.com or faxed to +1 781 465 7936), and to Merck Global 
Safety (Attn: Worldwide Product Safety; FAX 215-661-6229) within 2 business days. 
 
7.6.3 
Immediate Reporting of Adverse Events to the IND Sponsor, Merck, and 
Verastem 
 
7.6.3.1 
Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
study product that: 
• Results in death; 
• Is life threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe); 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization ≥ 24 hours (see note 
below for exceptions); 
• Is a congenital anomaly/birth defect; 
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.);  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the IND Sponsor, 
Verastem, and Merck in the same timeframe as SAEs to meet certain local 
requirements. Therefore, these events are considered serious by the IND Sponsor, 
Verastem, and Merck for collection purposes: 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose 
• Is a pregnancy or pregnancy outcome of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, or stillbirth. 
 

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Events not considered to be SAEs are hospitalizations for:  
• 
Visits to the emergency room or other hospital department for <24 hours, that does 
not result in admission (unless considered an important medical or life-threatening 
event) 
• 
Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
• 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required in 
these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
 
Refer to Table 6 for additional details regarding each of the above criteria. 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause that occurs to any participant must be reported 
within 24 hours to the IND Sponsor and Verastem, and within 2 business days to Merck 
Global Safety if it causes the participant to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, whichever is earlier, any serious adverse 
event, or follow up to a serious adverse event, including death due to any cause whether 
or not related to the study product, must be reported to the IND Sponsor and Verastem 
within 24 hours, and to Merck Global Safety within 2 business days. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to study product that is brought to the attention of the investigator 
at any time following consent through the end of the specified safety follow-up period 
specified in the paragraph above, or at any time outside of the time period specified in the 
previous paragraph also must be reported immediately to the IND Sponsor, Verastem, and 
Merck Global Safety. 
 
All participants with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to the IND 
Sponsor (lzheng6@jhmi.edu), GIsafetyreporting@jhmi.edu, Merck Global Safety 
(facsimile 
number: 
+1-215-661-6229) 
and 
to 
Verastem 
(email 
address:  
drugsafety@verastem.com or faxed to +1-781 465 7936) using the SAE Reporting 
Form found in Appendix 6. 

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Investigators will submit a copy of any Expedited Safety Reports submitted to the FDA 
(Section 7.6.5.3.1) to Verastem (email: drugsafety@verastem.com) and Merck (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
7.6.3.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported to the IND Sponsor (lzheng6@jhmi.edu), 
GIsafetyreporting@jhmi.edu, and Verastem (email:  or faxed to +1 781 465 7936) within 
24 hours, and to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215-661-
6229) within 2 business days using the ECI Reporting Form in Appendix 5. 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant 
must be reported to the IND Sponsor and Verastem within 24 hours and to Merck Global 
Safety within 2 business days if it causes the participant to be excluded from the trial, or 
is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to 
an ECI, whether or not related to Merck product, must be reported within 24 hours to the 
IND sponsor and Verastem, and to Merck Global Safety within 2 business days. 
 
Events of clinical interest for this trial include: 
1. an overdose of Verastem or Merck product, as defined in Section 7.6.1, that is not 
associated with clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
 
7.6.3.3 
Unacceptable Toxicities 
Any event meeting unacceptable toxicity criteria as defined in Section 5.7 should be 
reported 
via 
email 
to 
the 
IND 
Sponsor 
(lzheng6@jhmi.edu) 
and 
GIsafetyreporting@jhmi.edu within 24 hours. 
 

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7.6.4 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to 
the NCI Common Terminology for Adverse Events (CTCAE), version 5.0. Any adverse 
event which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 
• 
No (unrelated, not related, no relation):  The time course between the administration 
of study drug and the occurrence or worsening of the adverse event rules out a 
causal 
relationship 
and 
another 
cause 
(concomitant 
drugs, 
therapies, 
complications, etc.) is suspected.  
 
• 
Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, complications, etc.) 
can be identified. 
 
The expectedness of an AE is to be assessed by the investigator according to the following 
definitions:  
 
• Unexpected AE: An AE, which varies in nature, intensity or frequency from 
information on the investigational drug/agent provided in the product IB, package 
insert or safety reports. Any AE that is not included in the IB, package insert, safety 
reports or informed consent is considered “unexpected”.  
 
• Expected (known) AE: An AE, which has been reported in the IB, package insert or 
safety reports. An AE is considered “expected”, only if it is included in the IB 
document in the Reference Safety Information.

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Table 6: Evaluating Adverse Events 
An investigator, who is a qualified physician, will evaluate all adverse events against CTCAE if no adverse event grading is 
assigned: 
V5.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck or Verastem product that: 
 
†Results in death; or 
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it 
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of 
length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective 
procedure to treat a pre-existing condition that has not worsened is not a serious adverse event.  A pre-existing condition is a 
clinical condition that is diagnosed prior to the use of a Merck product and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the IND Sponsor and 
Verastem within 24 hours and to Merck within 2 business days; or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event for collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event 
of clinical interest and must be reported within 24 hours to the IND Sponsor and Verastem and to Merck within 2 businesss days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the participant and 
may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  Did the adverse event cause the Verastem or Merck product to be discontinued? 
Relationship 
to Merck or 
Verastem 
Product  
Did the Merck or Verastem product cause the adverse event? The determination of the likelihood that Merck or Verastem product 
caused the adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on 
the source document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment 
of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the 
adverse event based upon the available information. 

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The following components are to be used to assess the relationship between Merck or Verastem product and the AE; the 
greater the correlation with the components and their respective elements (in number and/or intensity), the more likely Merck or 
Verastem product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to Merck or Verastem product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck or Verastem product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck or 
Verastem 
Product 
(continued)  
Dechallenge 
Was Merck or Verastem product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the investigational product; or (3) the trial is a single-dose drug trial); 
or (4) investigational product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to Merck or Verastem product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial 
is a single-dose drug trial); or (3) Investigational product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY MERCK OR VERASTEM PRODUCT, OR IF REEXPOSURE TO MERCK OR 
VERASTEM PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT, 
THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE IND SPONSOR, MERCK, AND 
VERASTEM. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck or 
Verastem product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according 
to his/her best clinical judgment, including consideration of the above elements. 
Record one of the 
following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck 
product relationship). 
Yes, there is a reasonable 
possibility of Merck or 
Verastem product 
relationship. 
There is evidence of exposure to Merck or Verastem product.  The temporal sequence of the AE onset relative 
to the administration of Merck product is reasonable.  The AE is more likely explained by Merck product than by 
another cause. 
No, there is not a 
reasonable possibility of 
Merck or Verastem product 
relationship 
Participant did not receive the Merck or Verastem product OR temporal sequence of the AE onset relative to 
administration of Merck product is not reasonable OR the AE is more likely explained by another cause than 
the Merck product.  (Also entered for a participant with overdose without an associated AE.) 

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7.6.5 
Special considerations for adverse events that occur during the surgery 
and postoperative course 
Pancreatic surgery is one of the highest-risk procedures, requires prolonged 
hospitalization, has significant toxicities and is commonly associated with complications 
and comorbidities. It is deemed to be standard of care, therefore, is not part of this 
research study. From the day of surgery through day 0 of the third immunotherapy, 
participants will be primarily followed by their primary surgeons for monitoring and 
managing the complications and comorbidities attributable to the surgery. Table 7 
summarizes complications commonly associated with the pancreatic surgery based on 
several published analyses of more than 1000 patients at Johns Hopkins Medicine and 
other institutions.6> A normal, uncomplicated postoperative course is still commonly 
associated with laboratory abnormalities (grade 1/2 AEs and occasionally grade 3 AEs) 
without need of therapeutic interventions.  At least one complication was associated with 
58.5% of patients based on a recent analysis of a consecutive series of 633 patients 
undergoing pancreaticoduodenectomy at Johns Hopkins Medicine between February 
2003 and August 2005. Grade I, II, III complications were common, in 10%, 30%, 13.5% 
of the patients, respectively. These complications and comorbidities are commonly 
associated with toxicities and laboratory abnormalities of CTCAE grade 3 and even grade 
4.  By contrast, Grade IV and V complications are relatively uncommon, in 3.0% and 2.0% 
of the patients, respectively (Table 8). 
 
Table 7: Complications after Pancreaticoduodenectomy  
 
Anastomotic leak, pancreas 
Anastomotic leak, intestinal 
Wound infection 
Gastrointestinal bleeding 
Delayed gastric emptying 
Pleural effusion 
Hemorrhage, immediate postoperative or delayed 
Pneumonitis 
Intraabdominal abscess 
Sepsis 
Fascial dehiscence or evisceration 
Acute respiratory distress syndrome  
Supraventricular arrhythmia 
Angina, cardiac ischemia 
Urinary tract infection 
Aspiration 
Anastomotic leak, biliary 
Cardiopulmonary arrest 
Pancreatitis 
Catheter-related infection 
Hypotension, shock 
Constipation 
Cellulitis 
Delirium tremens 
Clostridium difficile colitis 
Fever 
Congestive heart failure, left ventricular dysfunction Fluid imbalance 
Myocardial infarction 
Gastroesophageal reflux disease 
Renal failure 
Congestive heart failure 
Apnea or hypoxia 
Ileus 
Atelectasis 
Interstitial pneumonitis and fibrosis 
Catheter-related infection 
Prolonged intubation 
Deep venous thrombosis 
Salivary gland infection 
Dehydration 
Small bowel obstruction 
 

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Table 8: Classification of Surgical Complication Adopted for Pancreatic Surgery 
 
 
 
Pancreatic surgery is commonly associated with laboratory abnormalities in blood cell 
counts, serum electrolytes, liver function, and renal function, etc., with a range of severity 
from grade 1 to grade 4 by CTCAEv3.0 criteria. Grade I-III complications are common; 
therefore, laboratory abnormalities associated with a normal postoperative course or 
Grade I-III complications are considered to be within the commonly expected range of 
grades of severity (Table 9). Laboratory abnormalities beyond these commonly expected 
ranges of severity should be considered uncommon. Although Grade IV and V 
complications have still occurred, any SAE including laboratory abnormalities associated 
with Grade IV/V complications should be considered uncommon.   
 
 
 
 
 

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Table 9: Laboratory abnormalities commonly associated with pancreatic surgery 
 
Lab test Abnormality 
Ranges of severity by CTCAEv3.0 criteria 
Amylase 
Elevated 
Grade 1-4 
Lipase 
Elevated 
Grade 1-4 
Bilirubin 
Elevated 
Grade 1-4 
AST 
Elevated 
Grade 1-4 
ALT 
Elevated 
Grade 1-4 
Albumin 
Decreased 
Grade 1-3 
Glucose 
Elevated 
Grade 1-4 
Glucose 
Decreased 
Grade 1-4 
Alk Phosphatase 
Elevated 
Grade 1-4 
Creatinine 
Elevated 
Grade 1-3 
Glomerular filtration rate 
Decreased 
Grade 1-3 
Bicarbonate 
Decreased 
Grade 1-4 
Acidosis 
Elevated 
Grade 1-4 
Alkylosis 
Elevated 
Grade 1-4 
CPK 
Elevated 
Grade 1-4 
WBC 
Elevated 
Not graded by CTCAE 
Hemoglobin 
Decreased 
Grade 1-3 
Platelets 
Elevated 
Not graded by CTCAE 
Platelets 
Decreased 
Grade 1-3 
Sodium 
Elevated 
Grade 1-3 
Sodium 
Decreased 
Grade 1-3 
Potassium 
Elevated 
Grade 1-3 
Potassium 
Decreased 
Grade 1-3 
Magnesium 
Elevated 
Grade 1-3 
Magnesium 
Decreased 
Grade 1-3 
Phosphate 
Elevated 
Grade 1-3 
Phosphate 
Decreased 
Grade 1-4 
Calcium 
Elevated 
Grade 1-3 
Calcium 
Decreased 
Grade 1-4 
 
Therefore during this period, first, the study will be focused on monitoring and reporting 
the complications with uncommon grades of severity such as Grade IV and Grade V 
complications by criteria used at Johns Hopkins (Table 8). The severity of any SAEs 
associated with such grades of complications should be considered uncommon.  Second, 
any unusual complications not seen commonly with this operation will be reported. Third, 
the study will also be focused on monitoring and reporting any laboratory abnormality 
beyond the common ranges of severity (Table 9). Fourth, the study will also be focused 
on monitoring and reporting any type of toxicity not commonly attributable to the surgery 
or postoperative course. These events will be recorded as described in Section 7.6 and 
their severities will still be categorized by NCI CTCAEv5.0 criteria. Relationship of these 
events to the investigational drug will be determined by the principal investigator together 

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with surgical co-investigators of the study team and, if necessary, with primary surgeons, 
and will be categorized as described in Section 7.6.4. Reporting of these events will 
follow the same guidelines described in Sections 7.6 and 7.6.6. 
 
7.6.6  
IND Sponsor Responsibility for Reporting Adverse Events 
All serious adverse events that meet immediate reporting criteria will be reported by the 
IND Sponsor to regulatory authorities, IRB/IECs and investigators in accordance with all 
applicable global laws and regulations, and sent to both Verastem and Merck. 
 
7.6.6.1  
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor (or designee), Verastem, and 
Merck will notify investigators of all SAEs that are unexpected (i.e., not previously 
described in the IB), and related to pembrolizumab or defactinib. An event meeting these 
criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of an Investigator Safety Letter 
that is to be e-mailed to the principal investigator and designee as requested. Upon 
receiving such notices, the investigator must review and retain the notice with the IB and 
where required by local regulations, the investigator will submit the SUSAR to the 
appropriate IRB. The investigator and IRB will determine if the informed consent requires 
revision. The investigator should also comply with the IRB procedures for reporting any 
other safety information. 
 
7.6.6.2  
Institutional Review Board (IRB) 
 
SAEs will be reported to the IRB per institutional guidelines. The following SAEs will be 
reported to the Johns Hopkins Medicine IRB per institutional guidelines: 
 
1. Deaths, regardless of causality 
2. Serious adverse events that are both related and unexpected  
 
Follow-up information will be submitted to the IRB as soon as relevant information is 
available. 
 
7.6.6.3  
Food and Drug Administration (FDA) 
 
All reporting to the FDA for the trial will be completed by the IND Sponsor.  
 
7.6.6.3.1 Expedited IND Safety Reports 
 
7 Calendar-Day Telephone or Fax Report:   
 
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
investigational agent.  Such reports are to be emailed to the regulatory project manager 

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and faxed (301-796-9849) to the FDA within 7 calendar days of first learning of the event. 
Follow-up information will be submitted to the FDA as soon as relevant information is 
available.  
 
15 Calendar-Day Written Report:   
 
The IND Sponsor is required to notify the FDA of any SAE that is unexpected and 
assessed by the investigator as possibly related to the investigational agent in a written 
IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND 
concerning similar events should be analyzed.  The new report should contain comments 
on the significance of the new event in light of the previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA 
within 15 calendar days of first learning of the event. Follow-up information will be 
submitted to the FDA as soon as relevant information is available. 
 
7.6.6.3.2 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 days 
of the anniversary date that the IND went into effect submit a brief report of the AEs and 
progress of the investigation.  Please refer to Code of Federal Regulations, 21 CFR § 
312.33 for a list of the elements required for the annual report.  All IND annual reports will 
be submitted to the FDA by the IND Sponsor. 
 
8.0 
STATISTICAL METHODS 
 
This is a multi-center, randomized, phase II open label study to evaluate the clinical 
activity and safety of a combination of neoadjuvant immunotherapy with pembrolizumab 
and focal adhesion kinase inhibitor, defactinib or pembrolizumab alone following standard 
chemotherapy in subjects with resectable PDAC. The primary endpoint will be pathologic 
complete response. The primary correlative endpoint is immune response, defined as 
>80% increase of intratumoral infiltration of CD8+ cells for each patient. Additionally, will 
also be assessing the activity and changes in TAM (tumor associated macrophages), 
myeloid–derived suppressor cells (MDSC) and T-reg cells, as well as the activity of 
pancreatic stellate cells via α-Smooth muscle actin (αSMA) and fibroblast activate protein 
(FAP). 
  
8.1 
Study Design and Sample Size 
                 
We wish to determine whether the percent of pCR subjects after neoadjuvant 
pembrolizumab/defactinib or pembrolizumab following standard chemotherapy exceeds 
3%. A clinically meaningful improvement would be a 15% increase over that, i.e. 18% of 
subjects with pCR after neoadjuvant pembrolizumab/defactinib or pembrolizumab 

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following standard chemotherapy. Additionally, we wish to assess change in intratumoral 
expression of CD8+ cells with pembrolizumab and defactinib or pembrolizumab alone, 
following neoadjuvant chemotherapy. The primary efficacy endpoint is pathologic 
complete response (pCR). The primary correlative endpoint is immune response, defined 
as >80% increase of intratumoral infiltration of CD8+ cells for each patient. Secondary 
endpoints include safety, disease-free survival (DFS), overall survival (OS), near 
pathologic CR rate and Grade 3 pathologic response rate. We will also perform correlative 
studies (expression of TAMs, MDSCs, T-reg cells and effector T cells, as well activity of 
pancreatic stellate cells via αSMA and FAP) to evaluate the effect of FAKi with anti-PD1 
therapy on myeloid cell modulation and impact on effector T cell infiltration in the TME of 
PDAC. 
 
Approximately 16 evaluable subjects in each arm will be enrolled. Subjects will be 
considered efficacy evaluable if they have surgically resectable, biopsy proved 
adenocarcinoma of the pancreas with a CA19-9>200 at the time of randomization and 
they go to surgery after neoadjuvant treatment. The study will have 81% power to detect 
an 
increase 
of 
15% 
in 
the 
number 
of 
pCR 
subjects 
with 
neoadjuvant 
pembrolizumab/defactinib or pembrolizumab treatment at the trial’s completion based on 
a one-sided Fisher’s exact test with a type I error of 0.082. It also gives 90% power to 
detect an increase of immune response rate from 5% to 30%. Adjusting for 10% 
unevaluable patients, the trial will recruit 18 patients each arm. 
 
8.2 
Interim Monitoring for Toxicity 
 
In each arm, toxicity will be monitored closely and continuously.  Any grade-3/4 local 
reactions attributable to pembrolizumab/defactinib or pembrolizumab or Grade 3 infusion-
related reaction or cytokine release syndrome that lasts ≥ 12 hours will be considered 
AEs for purposes of this stopping rule. If the risk of these adverse events appears to be 
higher than 33%, we will temporarily halt the study pending dose modification. 
Specifically, we apply a Bayesian toxicity monitoring rule that suspends the enrollment if 
the posterior probability of risk being larger than 0.33 is 65% or higher. The monitoring 
rule uses beta (1.5, 5.5) as prior distribution. This means that our prior guess at the 
proportion of toxicity is 21%, and there is 90% probability that this proportion is between 
3% and 49%. The decision rule for toxicity stopping is as follows:  
 
 
 
 
 
For example, we will interrupt the accrual if 3 subjects have AEs among the first 4 
receiving treatment. If 4 or more out of the first 5-7 subjects have AEs, we will suspend 
accrual.  
 
The operating characteristics of the stopping rule are shown below and are based on 
5000 simulations: 
 
Study termination if:  
3 AEs 4 AEs 
5 AEs 
6 AEs 
7 AEs 
8 AEs 
In number of patients 
between: 
3 - 4 
5 - 7 
8 - 10 
11 - 12 13 - 15 16 - 18 

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Risk of AE 
0.20 
0.25 
0.30 
0.33 
0.40 
0.45 
% of Time study 
stops 
6.7% 14.1% 24.7% 31.8% 52.1% 
65% 
Expected sample 
size 
15.4 
14.7 
13.9 
13.3 
11.5 
10.3 
 
8.2.1  
Surgical Complications/Toxicity 
 
Surgical complications will be defined based on Clavien-Dindo classification. In addition 
to toxicity monitoring, we will monitor for post-operative complications. The stopping rule 
will focus on Grade IIIa surgical complication or above, which is beyond what may be 
expected for chemotherapy or resection without immunotherapy or defactinib, and that 
may be attributable to these drugs. If the risk of Grade IIIa or higher surgical complications 
appears to be greater than 40%, the study will temporarily be halted pending feasibility 
evaluations. The study may resume after discussion between the principal investigator 
and the IND sponsor if the surgical co-investigators do not deem there is an association 
of an increased rate of high grade postoperative complication with any of the study 
treatments. Specifically, we apply a Bayesian monitoring rule that suspends the 
enrollment if the posterior probability of risk being greater than 40% is 0.5 or higher. The 
previous study showed 26% Grade IIIa or above post-operative complications in patients 
receiving neoadjuvant stereotactic body radiation therapy or chemoradiation therapy. 
Thus, a Beta (2.5, 5.5) prior, representing the prior guess of a post-operative 
complications (Grade IIIa or above) rate of 31%, will be used. Starting from the 30th 
randomized patient, surgical complications will be monitored continuously according to 
the protocol amendment. The table below shows the number of post-operative 
complications (Grade IIIa or above) that would need to be observed in order to trigger the 
stopping for each arm: 
 
The operating characteristics of the stopping rule are shown below and are based on 
5000 simulations: 
 
Risk of surgical 
complications 
0.2 
0.25 
0.3 
0.35 
0.4 
0.45 
0.5 
0.6 
% of Time study 
stops 
16% 
25% 
38% 
51% 
67% 
79% 
87% 
97% 
Expected sample 
size 
15.7 
14.7 
13.2 
11.8 
9.9 
8.4 
7.1 
4.8 
Study termination if 
number of complications 
2 
3 
4 
5 
6 
7 
8 
In number of patients 
between: 
2-3 
4 - 5 
6 - 8 
9 - 10 
11 - 13 14 - 15 16 - 18 

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8.3 
Interim Analysis for Futility 
 
No interim analyses for efficacy are planned for this study. The participating            
Investigators, the IND Sponsor, and the independent safety physician will review the 
safety profile of all subjects in the run-in phase and determine that the defined dose and 
regimen are acceptable for Phase 2. 
 
8.4 
Data Analysis 
 
The primary objective is to assess the pCR rate of neoadjuvant pembrolizumab and 
defactinib or pembrolizumab alone following chemotherapy. Pathologic response will be 
graded and defined as follows: 0: No viable residual tumor (complete response[pCR]) 1: 
Marked response (minimal residual cancer with single cells or small groups of cancer 
cells) 2: Moderate response (residual cancer outgrown by fibrosis) 3: Poor or no response 
(extensive residual cancer).The primary outcome of efficacy will be pCR. The pCR rate 
will be estimated as the proportion of subjects who have pCR after neoadjuvant 
pembrolizumab and defactinib or pembrolizumab alone following chemotherapy. Subjects 
who drop out of the study due to disease progression, death, or limiting toxicity before 
surgery may be considered as not evaluable in estimating the pCR rate. Exact binomial 
test will be used to test the increase in pCR rate compared with the null hypothesis 3% 
pCR rate. The 95% confidence interval (CI) of the pCR rate will be computed. The primary 
correlative endpoint is immune response, defined as >80% increase of intratumoral 
infiltration of CD8+ cells for each patient. We will estimate the proportion of patients who 
achieve immune response, along with 95% CI. We will also evaluate the changes of TAM, 
MDSC & T-reg, pre- vs. post-treatment.  
 
The secondary objectives include accessing the proportion of patients experiencing at 
least one grade 3/4 non-lymphopenia AE, OS, DFS, near pathologic CR rate and Grade 
3 pathologic response rate, explorative immunology endpoints (αSMA, FAP IHC), 
immunogenic cell death (calreticulin IHC) induced by different types of chemotherapy, 
CD68/CD8 ratio, changes of TAM, MDSC & T-reg, PD-L1, PD-1, pre- vs. post-treatment 
intratumoral and peripheral blood TCR clonality. Summary statistics and percentages will 
be reported for AE and toxicities.  The rate of near pathologic CR rate and Grade 3 
pathologic response rate along with 95% confidence interval (CI) will be computed for 
each arm. Changes from pre- to post-treatment will be assessed using paired-sample t 
tests or Wilcoxon signed rank tests as appropriate. Summary statistics and plots for OS, 
DFS will be computed using the Kaplan Meier estimate of the survival function. 
Comparisons between arms will be made using the log-rank test. Cox proportional 
hazards models will be used to evaluate the impact of different groups on OS and DFS. 
 
9.0 
LABELING, PACKAGING, STORAGE, AND SUPPLIES 
 
9.1 
Investigational Product  
 

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The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of investigational product in accordance with the protocol and any applicable laws 
and regulations. 
 
Pembrolizumab will be provided by Merck and defactinib will be supplied by Verastem as 
summarized in Table 10. 
 
Table 10: Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Defactinib 200 mg IR Tablet 
Tablet (white, oval) for Oral 
Administration 
 
9.2 
Packaging and Labeling Information 
 
Supplies will be labeled in accordance with regulatory requirements. 
 
9.3 
Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the participant, the trial site personnel, the IND Sponsor 
and/or designee are not blinded to treatment. Drug identity (name, strength) is included 
in the label text; random code/disclosure envelopes or lists are not provided. 
 
9.4 
Storage, Stability, and Handling Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at 
the trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
Refer to the Pharmacy Manual for storage, stability, and handling conditions. 
 
9.5 
Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck, Verastem, or designee, the amount dispensed to and returned by 
the participants, and the amount remaining at the conclusion of the trial.  
 

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Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS 
 
AE guidelines and instructions for AE reporting can be found in Section 7.6 (Adverse 
Events: List and Reporting Requirements). 
 
Dr. Zheng will be holding the IND for this study. He will comply with all regulated reporting 
requirements to the FDA. The Sponsor-Investigator will comply with FDA Regulations: 
Good Clinical Practice and Clinical Trials, 21 code federal regulations (CFR) parts 50, 54, 
56, 312.  
 
10.1 
Data Collection and Processing 
 
All information will be collected on study-specific CRFs by study staff. These data will be 
reviewed for completeness and accuracy by the Principal Investigator at each site.  
 
CRFs will be used to capture study results and data. The study coordinator or other 
authorized study personnel will transcribe data from source documents onto eCRFs. At 
any time, the IND Sponsor or designee may request copies of the CRFs for preliminary 
medical review. Once the CRFs are complete and source-verified, the investigator must 
sign and date all required pages, verifying the accuracy of all data contained within the 
CRF.  
 
Protocol Chair 
The Protocol Chair and/or designee is responsible for performing the following tasks: 
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as 
well as its subsequent amendments. 
• 
Assuring that all participating institutions are using the correct version of the 
protocol. 
• 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
• 
Reviewing and ensuring reporting of SAE 
• 
Reviewing data from all sites. 
 
Coordinating Center (Johns Hopkins University) 
The Coordinating Center (or its representative) is responsible for performing the following 
tasks: 

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• 
Ensuring that IRB approval has been obtained at each participating site prior to the 
first subject registration at that site, and maintaining copies of IRB approvals from 
each site. 
• 
Monitoring subject registration. 
• 
Collecting and compiling data from each site. 
• 
Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
• 
Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
• 
Following the protocol as written, and the guidelines of Good Clinical Practice 
(GCP). 
• 
Submitting data to the Coordinating Center. 
• 
Consent subjects promptly and randomize eligible subjects in EDC. 
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
• 
Maintaining regulatory binders on site and providing copies of all required 
documents to the Coordinating Center. 
• 
Collecting and submitting data according to the schedule specified by the protocol. 
 
10.2 
Meetings 
 
Scheduled meetings will take place weekly and will include the protocol principal 
investigator, study coordinator(s), research nurse(s), sub-investigators (as appropriate), 
collaborators (as appropriate), and biostatisticians (as appropriate) involved with the 
conduct of the protocol. During these meetings matters related to the following will be 
discussed: safety of protocol participants, validity and integrity of the data, enrollment rate 
relative to expectation, characteristics of participants, retention of participants, adherence 
to protocol (potential or real protocol violations), data completeness, and progress of data 
for objectives. 
 
Monthly teleconferences will be scheduled to include the Coordinating Center and the 
clinical trial sites. During these meetings, the Coordinating Center and clinical trial sites 
shall discuss the following: study protocol updates, safety data, enrollment status, and 
progress of data for objectives. 
 
10.3 
Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-
affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019).  The SMC 
Subcommittee will determine the level of patient safety risk and level/frequency of 
monitoring. Data monitoring of this protocol will occur on a regular basis with the 

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frequency dependent on the rate of subject accrual and the progress of the study.  
Eligibility for all sites will be monitored by the Protocol Chair. The protocol will be internally 
monitored by the Principal Investigator at each site. The PI shall internally monitor the 
progress of the trial, including review and confirmation of all safety/treatment-related 
outcomes, response assessments, safety reports and/or any related source 
documentation. IND-sponsor is ultimately responsible for external monitoring of the trial.  
External monitoring will occur according to the following guidelines: 
 
Johns Hopkins SKCCC: The protocol will be monitored externally by the SKCCC CRO in 
accordance with SKCCC guidelines. Trial monitoring and reporting will be done through 
the Safety Monitoring Committee (SMC) at SKCCC. 
 
Participating site(s): The protocol will be monitored by authorized representatives of the 
Coordinating Center.  
 
Authorized representatives of the Coordinating Center may visit the satellite sites to 
perform audits or inspections, including source data verification. The purpose of these 
audits or inspections is to systematically and independently examine all trial-related 
activities and documents to determine whether these activities were conducted and data 
were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), and any applicable regulatory requirements. 
 
Additional data and safety monitoring oversight will also be performed by the SKCCC 
Safety Monitoring Committee (SMC - as defined in the DSMP) and a Data Safety 
Monitoring Board as detailed below.  
 
Interim analysis of toxicity, outcome and ongoing scientific investigations will be 
performed every 6 months by the Sidney Kimmel Comprehensive Cancer Center Data 
Safety Monitoring Board (SKCCC DSMB). The SKCCC DSMB will review aspects of this 
trial that are outlined in the responsibilities section of the Data and Safety Monitoring 
Board (DSMB) Guidance. If the committee decides that amendments should be made to 
this trial, recommendations will be made in writing to the Study Principal Investigator.  The 
study team will submit modifications to the IRB within 60 days of receipt from the DSMB.  
The Associate Director of Clinical Research, will arbitrate any disagreements between 
the DSMB and the study Principal Investigator. These changes may include early 
termination of accrual if deemed appropriate.  
 

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subtypes of pancreatic cancer. Nature. 2016;531(7592):47-52. 
doi:10.1038/nature16965 
29.  Carlsson A, Jonsson Y, Svensson K, Stahl B, Twetman S. Pit and fissure sealing 
and mutans streptococci levels in saliva. Am J Dent. 1992;5(5):280-282. 
doi:10.1146/annurev.immunol.26.021607.090331 
30.  Yoshimura K, Laird LS, Chia CY, et al. Live attenuated Listeria monocytogenes 
effectively treats hepatic colorectal cancer metastases and is strongly enhanced 
by depletion of regulatory t cells. Cancer Res. 2007;67(20):10058-10066. 
doi:10.1158/0008-5472.CAN-07-0573 
31.  Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates 
with tumor aggressiveness and postoperative recurrence in human hepatocellular 
carcinoma. Clin Cancer Res. 2009;15(3):971-979. doi:10.1158/1078-0432.CCR-
08-1608 
32.  Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of 
the programmed death-1 ligand/programmed death-1 pathway in human 
pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-2157. doi:10.1158/1078-
0432.CCR-06-2746 
33.  Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency. N Engl J Med. 2015;372(26):2509-2520. 
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34.  Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non–
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doi:10.1056/NEJMoa1501824 
35.  Robert C, Schachter J, Long G V., et al. Pembrolizumab versus Ipilimumab in 
Advanced Melanoma. N Engl J Med. 2015;372(26):2521-2532. 
doi:10.1056/NEJMoa1503093 
36.  Kunk PR, Bauer TW, Slingluff CL, Rahma OE. From bench to bedside a 
comprehensive review of pancreatic cancer immunotherapy. J Immunother 
Cancer. 2016;4(1):14. doi:10.1186/s40425-016-0119-z 
37.  Laklai H, Miroshnikova YA, Pickup MW, et al. Genotype tunes pancreatic ductal 
adenocarcinoma tissue tension to induce matricellular fibrosis and tumor 
progression. Nat Med. 2016;22(5):497-505. doi:10.1038/nm.4082 
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39.  Jiang H, Hegde S, Knolhoff BL, et al. Targeting focal adhesion kinase renders 
pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 
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role of focal-adhesion kinase in cancer - A new therapeutic opportunity. Nat Rev 
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41.  Serrels A, Lund T, Serrels B, et al. Nuclear FAK Controls Chemokine 
Transcription, Tregs, and Evasion of Anti-tumor Immunity. Cell. 2015;163(1):160-
173. doi:10.1016/j.cell.2015.09.001 
42.  Zhao XK, Cheng Y, Liang Cheng M, et al. Focal adhesion kinase regulates 

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fibroblast migration via integrin beta-1 and plays a central role in fibrosis. Sci Rep. 
2016;6(1):19276. doi:10.1038/srep19276 
43.  Stokes JB, Adair SJ, Slack-Davis JK, et al. Inhibition of Focal Adhesion Kinase by 
PF-562,271 Inhibits the Growth and Metastasis of Pancreatic Cancer 
Concomitant with Altering the Tumor Microenvironment. Mol Cancer Ther. 
2011;10(11):2135-2145. doi:10.1158/1535-7163.MCT-11-0261 
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adenocarcinoma. Mol Cancer Ther. 2007;6(4):1186-1197. doi:10.1007/s11214-
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46.  Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD. Cancer-associated 
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clinical applications. Nat Rev Cancer. 2014;14(9):598-610. doi:10.1038/nrc3792 
48.  Luo M, Guan JL. Focal adhesion kinase: A prominent determinant in breast 
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doi:10.1016/j.canlet.2009.07.005 
49.  Jiang H, Hegde S, Knolhoff BL, et al. Targeting focal adhesion kinase renders 
pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 
2016;22(8):851-860. doi:10.1038/nm.4123 
50.  D’Angelo RC, Wicha MS. Stem cells in normal development and cancer. Prog Mol 
Biol Transl Sci. 2010;95(C):113-158. doi:10.1016/B978-0-12-385071-3.00006-X 
51.  Buczacki S. Cancer Stem Cells. Encycl Cell Biol. 2015;3:807-812. 
doi:10.1016/B978-0-12-394447-4.30119-5 
52.  Shapiro IM, Kolev VN, Vidal CM, et al. Merlin deficiency predicts FAK inhibitor 
sensitivity: A synthetic lethal relationship. Sci Transl Med. 2014;6(237):237ra68. 
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53.  Zhang Y, Liu D, Chen X, et al. Secreted Monocytic miR-150 Enhances Targeted 
Endothelial Cell Migration. Mol Cell. 2010;39(1):133-144. 
doi:10.1016/j.molcel.2010.06.010 
54.  Wang-Gillam A, Lockhart AC, Tan BR, et al. Phase I study of defactinib combined 
with pembrolizumab and gemcitabine in advanced cancer. J Clin Oncol. 
2017;35(4_suppl):TPS505-TPS505. doi:10.1200/JCO.2017.35.4_suppl.TPS505 
55.  Lutz ER, Kinkead H, Jaffee EM, Zheng L. Priming the pancreatic cancer tumor 
microenvironment for checkpoint-inhibitor immunotherapy. Oncoimmunology. 
2014;3(11):e962401-1-e962401-3. doi:10.4161/21624011.2014.962401 
56.  Tsujikawa T, Kumar S, Borkar RN, et al. Quantitative Multiplex 
Immunohistochemistry Reveals Myeloid-Inflamed Tumor-Immune Complexity 
Associated with Poor Prognosis. Cell Rep. 2017;19(1):203-217. 
doi:10.1016/j.celrep.2017.03.037 
57.  Fokas E, Liersch T, Fietkau R, et al. Tumor regression grading after preoperative 
chemoradiotherapy for locally advanced rectal carcinoma revisited: Updated 
results of the CAO/ARO/AIO-94 trial. J Clin Oncol. 2014;32(15):1554-1562. 

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doi:10.1200/JCO.2013.54.3769 
58.  Donohoe CL, O’Farrell NJ, Grant T, et al. Classification of pathologic response to 
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59.  Asa M, Baldrati L, Rinaldi C, et al. Electric field control of magnetic properties and 
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60.  Gillen S, Schuster T, Büschenfelde CM Zum, Friess H, Kleeff J. 
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meta-analysis of response and resection percentages. PLoS Med. 2010;7(4). 
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61.  Chuong MD, Frakes JM, Figura N, et al. Histopathologic tumor response after 
induction chemotherapy and stereotactic body radiation therapy for borderline 
resectable pancreatic cancer. J Gastrointest Oncol. 2016;7(2):221-227. 
doi:10.3978/j.issn.2078-6891.2015.075 
62.  Von Hoff DD, Ervin T, Arena FP, et al. Increased Survival in Pancreatic Cancer 
with nab-Paclitaxel plus Gemcitabine. N Engl J Med. 2013;369(18):1691-1703. 
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63.  Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus Gemcitabine for 
Metastatic Pancreatic Cancer. N Engl J Med. 2011;364(19):1817-1825. 
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64.  Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for 
pembrolizumab for oncology indications. J Immunother Cancer. 2017;5(1):43. 
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65.  Jones SF, Siu LL, Bendell JC, et al. A phase i study of VS-6063, a second-
generation focal adhesion kinase inhibitor, in patients with advanced solid tumors. 
Invest New Drugs. 2015;33(5):1100-1107. doi:10.1007/s10637-015-0282-y 
66.  Shimizu T, Fukuoka K, Takeda M, et al. A first‑in‑asian phase 1 study to evaluate 
safety, pharmacokinetics and clinical activity of vs‑6063, a focal adhesion kinase 
(FAK) inhibitor in japanese patients with advanced solid tumors. Cancer 
Chemother Pharmacol. 2016;77(5):997-1003. doi:10.1007/s00280-016-3010-1 
67.  Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive 
pancreaticoduodenectomies. Ann Surg. 2006;244(1):10-15. 
doi:10.1097/01.sla.0000217673.04165.ea 
 
 
 
 

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Appendix 1: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
% 
Description 
0 
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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Appendix 2: Contraceptive Guidance and Pregnancy Testing 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
 
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to one of the following during the protocol defined time frame from first visit 
through 120 days after the final administration of any study therapy.  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
● Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 11 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration. 
 
Female Participants: 

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Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective method of contraception consistently and correctly as described in 
Table 11 during the protocol-defined time frame from first visit through 120 days after the 
final administration of any study therapy.  
 
Table 11: Highly Effective Contraception Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should 
be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used 
consistently and correctly).  

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b) If hormonal contraception efficacy is potentially decreased due to interaction with 
study treatment, condoms must be used in addition to the hormonal contraception 
during the treatment period and for at least 60 days. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable hormonal contraceptives are limited to those which inhibit 
ovulation.  
 
Pregnancy Testing 
 
WOCBP should only be included after a negative highly sensitive urine or serum 
pregnancy test.  
 
Following initiation of treatment, pregnancy testing will be performed whenever an 
expected menstrual cycle is missed or when pregnancy is otherwise suspected; at the 
time points specified in the Schedule of Activities, and as required locally. 
 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
 
 

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Appendix 3: Substrates, Inhibitors, Inducers of CYP2C9, CYP3A4, OATP1B1 and 
 
OATPIB3 
 
Examples1 of Substrates of CYP2C9 and CYP3A4  
 
Substrates of CYP2C9  
Substrates of CYP3A4 
Celecoxib 
Phenytoin 
Tolbutamide  
Warfarin 
 
Alprazolam 
Astemizole 
Buspirone 
Calcium Channel Blockers 
Carbamazepine 
Cisapride 
Cyclosporine 
Doxorubicin 
Erythromycin 
Etoposide 
Felodipine 
Fentanyl 
HIV protease inhibitors 
Ifosphamide 
Lovastatin (not prevastatin) 
Midazolam 
Nifedipine 
Pimozide 
Quinidine 
Quinine 
Simvastatin 
Tacrolimus 
Terfenadine 
Triazolam 
1Note that this is not an exhaustive list.  Additional information on drugs and possible 
interactions can be found at http://www.drugs.com. 
 
 
 

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Examples1 of Strong Inhibitors and Inducers of CYP2C9 and CYP3A4 
 
Inhibitors of CYP2C9  
Inhibitors of CYP3A4 
fluconazole 
miconazole 
amentoflavone (constituent of Ginkgo 
biloba and St. John’s Wort) 
sulfaphenazole 
valproic acid 
boceprevir  
clarithromycin 
conivaptan 
grapefruit juice  
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
Inducers of CYP2C9 
Inducers of CYP3A4 
rifampicin 
secobarbital 
carbamazepine 
phenytoin 
oxcarbazepine 
phenobarbital 
St. John's wort 
rifampicin 
rifabutin 
efavirenz 
nevirapine 
pioglitazone 
troglitazone 
glucocorticoids 
modafinil 
1Note that this is not an exhaustive list.  Additional information on drugs and possible 
interactions can be found at http://www.drugs.com. 
 

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Examples of Substrates for OATP1B1 and OATPIB3 
Substrates of OATP1B1 
Substrates of OATPIB3 
Atorvastatin 
Atrasentan 
Benzylpenicillin 
Bosentan 
Caspofungin 
Cerivastatin 
Enalapril 
Ezetimibe glucuronide 
Fexofenadine 
Fluvastatin 
Methotrexate 
Olmesartan 
Pitavastatin 
Pravastatin 
Rifampicin 
Rosuvastatin 
SN-38 
Temocapril 
Troglitazone sulfate 
Valsartan 
Atrasentan 
 
Bosentan 
 
Digoxin 
 
Docetaxel 
 
Enalapril 
 
Erythromycin  
Fexofenadine 
 
Fluvastatin 
 
Imatinib 
 
Methotrexate  
Olmesartan  
Ouabain 
 
Paclitaxel 
 
Pitavastatin  
Pravastatin  
Rifampicin 
 
Rosuvastatin  
Telmisartan  
SN-38  
Thyroxine 
 
Valsartan 
 
These are referenced from: Kalliokoski, A., & Niemi, M. (2009). Impact of OATP 
transporters on pharmacokinetics. British journal of pharmacology, 158(3), 693–705. 
doi:10.1111/j.1476-5381.2009.00430.x, and can be cross referenced in Lexicomp 
 
 

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Appendix 4: Adverse Event of Clinical Interest (ECI) Reporting Form 
 
Please notify: Dr. Lei Zheng (lzheng6@jhmi.edu AND GIsafetyreporting@jhmi.edu) within 
24 hours 
Merck within 2 business days (FAX: +1-215-661-6229) 
Verastem within 24 hours (drugsafety@verastem.com or faxed to +1 781 465 7936) 
 
 
Protocol Title: 
 
 
A randomized phase II study of pembrolizumab with or without defactinib, a 
focal adhesion kinase inhibitor following chemotherapy as a neoadjuvant and 
adjuvant treatment for resectable pancreatic ductal adenocarcinoma (PDAC) 
Protocol 
Number: 
J18140 
Signature of PI: 
 
 
 
Principal Investigator: 
 
Date: 
 
 
 
Report Type: 
 
Initial          
Follow-up          
Final Follow-up          
Addendum to: 
Section A: Subject Information 
Subject ID: 
Subject Gender: 
Male 
Female 
 
Subject Age: 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Date of First Dose: 
 
Action taken with the study 
drug: 
 
None 
Interrupted 
Discontinued 
Delayed 
Date of Last Dose prior to 
Event: 
 
Event Grade: 
Number of Total Cycles: 
 
Event Onset Date: 
Event End Date: 
 
 
 
Date Event Discovered: 
 
Section C: Study Drug Information: 
Investigational Products:  
Arm A: Pembrolizumab 200 mg IV every 3 weeks (21 days), Defactinib 400 mg BID 
Arm B: Pembrolizumab 200 mg IV every 3 weeks (21 days) 
 
Indication: High-Risk Resectable Pancreatic Adenocarcinoma 
 

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Treatment Arm: 
 Arm A 
 Arm B 
 
Relationship to: 
Pembrolizumab 
Defactinib 
Underlying Disease 
Unrelated 
 
 
 
Related 
 
 
 
Section D: Brief Description of the Event: (please include relevant procedures and laboratory 
values)  
 
Section E: Relevant Medical History 
 
Section F: Concomitant Drug (Not related to ECI) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify 
 
 
 

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Appendix 5: SAE Reporting Form 
 
Please notify: Dr. Lei Zheng (lzheng6@jhmi.edu AND GIsafetyreporting@jhmi.edu) within 
24 hours 
Merck within 2 business days (FAX: +1-215-661-6229) 
Verastem within 24 hours (drugsafety@verastem.com or faxed to +1 781 465 7936) 
 
Protocol Title: 
 
 
A randomized phase II study of pembrolizumab with or without defactinib, 
a focal adhesion kinase inhibitor following chemotherapy as a neoadjuvant 
and adjuvant treatment for resectable pancreatic ductal adenocarcinoma 
(PDAC) 
Protocol 
Number: 
J18140 
Signature of PI: 
 
 
 
Principal 
Investigator: 
 
Date of Report: 
 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all 
that apply): 
Death    
Life-threatening 
 Hospitalization or 
Elongation of Existing 
Hospitalization 
 Other Important Medical 
Event 
 Cancer 
 Overdose 
 Other:_____________ 
 
Hospital 
Admission Date: 
 
 
 
Date Event 
Discovered: 
 
Hospital 
Discharge Date:   
Section A: Subject Information 
Subject ID: 
Subject Gender: 
Male 
Female 
Subject Age: 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Event Grade: 
Cause of death (if 
applicable): 
Event Outcome: 
 
 Recovering 
 Recovered 
 Recovered with 
sequelae 
 Death 
 Unknown  
Event Onset Date (or Date of Death): 
 
 
Event End Date: 
Section C: Study Drug Information: 

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Investigational Products:  
Arm A: Pembrolizumab 200 mg IV every 3 weeks (21 days), Defactinib 400 mg BID 
Arm B: Pembrolizumab 200 mg IV every 3 weeks (21 days 
 
Indication: High-Risk Resectable Pancreatic Adenocarcinoma 
Treatment Arm:  
 Arm A 
 Arm B 
 
Number of Total Cycles: 
Action Taken with 
Study Drug: 
 
 None  
 Interrupted 
 Delayed 
 Discontinued 
Date of First Dose: 
Date of Last Dose prior to Event: 
Relationship to: 
Pembrolizumab 
Defactinib 
Underlying Disease 
Unrelated 
 
 
 
Related 
 
 
 
Section D: Brief Description of the Event 
 
Section E: Relevant Tests/Laboratory Data 
 
Section F: Relevant Medical History 
 
Section G: Concomitant Drug (Not related to SAE) 
Name of the 
Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section H: Comments 
 
Additional Documents: 
 Please specify 
 
 
 

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END OF PROTOCOL