NeoOPTIMIZE: An Open-Label, Phase II Trial to Assess the Efficacy of Adaptive Switching of FOLFIRINOX or Gemcitabine/Nab-Paclitaxel as a Neoadjuvant Strategy for Patients With Resectable and Borderline Resectable/Locally Advanced Unresectable Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma, Stage 0 Pancreatic Cancer American Joint Committee on Cancer v8, Stage I Pancreatic Cancer American Joint Committee on Cancer v8, Stage III Pancreatic Cancer American Joint Committee on Cancer v8, Stage IV Pancreatic Cancer American Joint Committee on Cancer v8
Sponsor: OHSU Knight Cancer Institute

 
1 
 
 
Official Study Title: 
NeoOPTIMIZE: an open-label, phase II trial to assess the efficacy 
of adaptive switching of FOLFIRINOX or Gemcitabine/nab-
Paclitaxel as a neoadjuvant strategy for patients with resectable 
and borderline resectable/locally advanced unresectable 
pancreatic cancer. 
Protocol Number:  STUDY00021614 
ClinicalTrials.gov ID NCT04539808 
Investigational products: FOLFIRINOX, Gemcitabine, nab-Paclitaxel, Losartan 
Version Number:  2.4 
Version Date: 20 September 2023 
Replaces: 2.3  
Principal Investigator: Charles Lopez, MD PhD 
 
Division of Hematology and Oncology 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, OC14HO 
Portland, OR 97239  
Phone: 503-494-8321 
Email: lopezc@ohsu.edu 
  
Statistician: 
Rochelle Fu, PhD  
Biostatistics Shared Resource| Knight Cancer Institute 
Oregon Health & Science University 
2730 S. Moody Ave, KR-BSR 
Phone: 503-494-6069 
Email: fur@ohsu.edu 

 
2 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline, PDAC, or LAPC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date: 20 September 2023 
PI: Charles Lopez MD, PhD 
SUMMARY OF CHANGES 
 
Version 
Section 
Summary of Changes 
Justification 
2.0 
4.1 
Inclusion criteria #9 revised to allow 
for up to 1 month of prior 
chemotherapy for the treatment of 
their pancreatic cancer per standard 
of care.  
This revision was added to 
account for logistical timing of 
consenting study participants 
and the planned start of their 
standard of care  
2.0 
8.3.2 
Frequency of blood collection 
revised to allow for PI discretion to 
reduce or omit blood collections for 
each study participant. 
This revision does provides 
logistical flexibility to the planned 
collection of blood samples.    
2.0 
Synopsis, 
1.4, 2.3, 
3.1, 4.1, 
11.3  
Addition of a locally-advanced, 
unresectable PDAC (LAPC) cohort. 
Revisions include adding 
exploratory objectives and 
endpoints for the LAPC cohort, 
eligibility definitions, and statistical 
population for analyses. 
The impact of providing an early 
switch to GA in the neoadjuvant 
setting after failing FOLFIRNOX 
has not been sufficiently 
explored in patients with LAPC. 
This exploratory cohort will be 
used as a benchmark for future 
studies. 
2.0 
2, 9.5, 11 
Corrections to endpoint definitions 
and timing of assessments 
Corrections provided for 
clarification 
2.1 
8.11 
Added footnote “E” “if screening 
CA19-9 or CEA falls outside of 
screening window, it is allowed 
per investigator discretion as long 
as a C1D1 CA19-9 is drawn” to 
CA19-9 and CEA. 
 
Clarification  
2.1 
8.4.1.2 
Height and weight will be collected 
within 45 days of C1D1.   
To account for the use of heights 
from a port placement or other 
visit that may occur prior to 
screening 
2.1 
8.2.2 
Updated lab analytes and added 
TUMOR MARKERS section.  
To clarify and align with OHSU’s 
SOC comprehensive metabolic 
panel. 
2.2 
1.6 
Addition of Correlative Studies 
Background 
Addition of correlative 
2.2 
8.3.1 
Addition of Wong Lab Address for 
shipping 
To provide shipping instructions 
2.3 
3.1, 7.6 
Multi-Disciplinary Tumor Board for 
restaging 
Clarification 
2.3 
3.2 
Study Agent 
Clarification 
2.3 
4.1 
Inclusion 5 – Baseline Imaging 
Increase flexibility 

2.3 
4.1 
Inclusion 11 – Baseline Labs 
Increase flexibility 
2.3 
4.2 
Exclusion 5 – Cardiac History 
Exclusion 9 – Study Agent 
Increase flexibility 
2.3 
6.8.6, 
8.1.8 
Administration 
To reflect study team actual 
practice 
2.3 
7.1.3 
Losartan – ACE Inhibitor or ARB 
Participants currently receiving 
ACE/ARB will remain eligible  
2.3 
Tables 7, 
8, 9 
Management of toxicity 
Align with changes to flexibility 
2.3 
7.7 
Supportive Care  
To reflect study team actual 
practice 
2.3 
8.1.5, 9.6 
Assessment window 
Align with changes to flexibility 
2.3 
8.8, 
Tables 
21, 24 
End of Treatment visit timing 
To reflect study team actual 
practice 
2.4 
4.2, 7.9  
Revision to exclusion criteria #7 and 
prohibited medication in regards 
anti-cancer treatment.  
Clarifies that concomitant 
supportive cancer care agents 
are permitted if participant is co-
consented to another trial. 
Exclusion criteria #8 removed as 
it duplicative 
2.4 
8.11 
Revisions to sample collection 
timing 
Correction to frequency of 
sample collection  
2.4 
8.1.7, 
10.1, 
10.5 
Revision of AE collection time frame 
to end of treatment visit 
AE collection for standard of care 
treatment updated to end of 
treatment visit.   
2.4 
8.9 
Revision of Follow-up visits and 
their timing 
Clarification to follow-up visits to 
coincide with standard of care 
visits, and variation to schedule 
are not considered deviations.   
2.4 
8.1.5, 
8.11 
Revision to screening window 
Clarification to screening 
window.   
2.4 
 
Revision to inclusion criteria #10 to 
specify triplicate ECG 
Clarification to ECG as triplicate 
measure  
 
 

 
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NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline, PDAC, or LAPC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date: 20 September 2023 
PI: Charles Lopez MD, PhD 
SYNOPSIS 
 
Study Title 
NeoOPTIMIZE: an open-label, phase II trial to assess the efficacy of 
adaptive switching of FOLFIRINOX or Gemcitabine/nab-Paclitaxel as a 
neoadjuvant strategy for patients with resectable and borderline 
resectable, or locally-advanced unresectable pancreatic cancer 
Protocol # 
STUDY00021614 
Coordinating Center 
OHSU, Knight Cancer Comprehensive Center    
Clinical Phase 
Phase II  
 
Study Description 
 
Mounting evidence suggests that pre-operative chemotherapy and/or 
chemoradiation confers significant survival benefit in patients with 
resectable pancreatic ductal adenocarcinoma (PDAC); including the 
potential for improving compliance to chemotherapies, down-staging 
tumors, and increasing the rate of margin-negative resections.  Either 
FOLFIRINOX or gemcitabine/nab-paclitaxel (GA) are currently used in 
the neoadjuvant setting; however, which of these is most optimal remains 
to be determined. There is preliminary evidence to suggest that for 
patients who do not respond to FOLFIRINOX, early switching to GA in the 
neoadjuvant setting has potential clinical benefit, but further studies are 
needed. The NeoOPTIMIZE trial described in this protocol intends to 
provide a flexible platform to provide early dynamic switching of 
neoadjuvant FOLFIRINOX to GA for patients with newly diagnosed 
resectable/borderline resectable, or locally-advanced unresectable PDAC 
(LAPC).  The study will use standard of care imaging and clinical 
biomarker, CA19-9, as a strategy for determining early switch from 
FOLFIRINOX to GA in order to optimize curative therapy. Underlying this 
treatment platform is the continuous administration of losartan, an ARB 
suggested to improve vascular perfusion and increase delivery of 
chemotherapy agents to the pancreas. 
 
Primary Objective 
To determine the rate of margin-negative (R0) resection  in participants 
with resectable or borderline resectable pancreatic cancer (BRPC) 
following treatment using NeoOPTIMIZE adaptive therapy 
Secondary Objectives 
1. To determine the progression free survival (PFS) of resectable or 
BRPC participants that received NeoOPTIMIZE adaptive therapy [i.e., 
FOLFIRINOX, or switch to GA] 
2. To determine the PFS  for the subset of resectable or BRPC 
participants that received NeoOPTIMIZE adaptive therapy plus 
preoperative radiation therapy [RT] 
3. To determine the disease-free survival (DFS) of resectable or BRPC  
participants that received NeoOPTIMIZE adaptive therapy [i.e., 
FOLFIRINOX, or switch to GA] 
4. To determine the DFS  for the subset of resectable or BRPC 
participants that received NeoOPTIMIZE adaptive therapy plus 
preoperative RT 
5. To determine the overall survival (OS) of resectable or BRPC 
participants that received NeoOPTIMIZE adaptive therapy  
6. To determine the OS  for the subset of resectable or BRPC  
participants that received NeoOPTIMIZE adaptive therapy plus 

 
5 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
preoperative RT 
7. To assess the surgical complications of participants that undergo 
resection after receiving NeoOPTIMIZE adaptive therapy (i.e. all 
surgical resectable or BRPC participants) 
8. To assess 30-day post-operative mortality that undergo surgical 
resection after receiving NeoOPTIMIZE adaptive therapy (i.e. all 
surgical resectable or BRPC participants) 
9. To assess safety of NeoOPTIMIZE adaptive therapy (all participants) 
Exploratory Objectives 
1. To monitor changes in CA19-9 levels (all participants) 
2. To determine the rate of margin-negative (R0) resection in 
participants with LAPC following treatment using NeoOPTIMIZE 
adaptive therapy 
3. To determine the PFS of LAPC participants that received 
NeoOPTIMIZE adaptive therapy [i.e., FOLFIRINOX, or switch to GA] 
4. To determine the PFS for the subset of LAPC participants that 
received NeoOPTIMIZE adaptive therapy plus preoperative radiation 
therapy [RT] 
5. To determine the disease-free survival (DFS) of LAPC participants 
that received NeoOPTIMIZE adaptive therapy [i.e., FOLFIRINOX, or 
switch to GA] 
6. To determine the DFS  for the subset of LAPC participants that 
received NeoOPTIMIZE adaptive therapy plus preoperative RT 
7. To determine the overall survival (OS) of LAPC participants that 
received NeoOPTIMIZE adaptive therapy  
8. To determine the OS  for the subset of LAPC participants that 
received NeoOPTIMIZE adaptive therapy plus preoperative RT 
9. To assess the surgical complications of LAPC participants that 
undergo resection (i.e. all surgical LAPC participants) 
10. To assess 30-day post-operative mortality for LAPC participants that 
undergo surgical resection (i.e. all surgical LAPC participants) 
 
Primary Endpoint 1. Proportion of resectable or BRPC participants with R0 resection 
Secondary Endpoints 
1. PFSNeoOPTMIZE for resectable or BRPC cohort 
2. PFSNeoOPTMIZE + preop-RT  for resectable or BRPC subset with  
preoperative RT 
3. DFSNeoOPTMIZE  for resectable or BRPC cohort 
4. DFSNeoOPTMIZE+ preop-RT  for resectable or BRPC subset  with  
preoperative RT 
5. OSNeoOPTMIZE  for resectable or BRPC cohort 
6. OSNeoOPTMIZE + preop-RT  for resectable or BRPC subset  with  
preoperative RT 
7. Proportion of surgical resectable or BRPC participants with peri- and 
post-operative complications [per the Clavien-Dindo classification 
system] 
8. Proportion of  surgical resectable or BRPC participants that die within 
30 days of surgery 
9. Incidence of grade ≥3 toxicities [per CTCAE v5.0] 
Exploratory Endpoints 
1. CA19-9 serum levels (U/ml) 
2. Proportion of LAPC participants with R0 resection 
3. PFSNeoOPTMIZE for LAPC cohort 
4. PFSNeoOPTMIZE + preop-RT  for LAPC subset  with  preoperative RT 

 
6 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
5. DFSNeoOPTMIZE  for LAPC cohort 
6. DFSNeoOPTMIZE+ preop-RT  for LAPC subset  with  preoperative RT 
7. OSNeoOPTMIZE  for LAPC cohort 
8. OSNeoOPTMIZE + preop-RT  for LAPC subset  with  preoperative RT 
9. Proportion of surgical LAPC participants with peri- and post-operative 
complications [per the Clavien-Dindo classification system] 
10. Proportion of surgical LAPC participants that die within 30 days of 
surgery 
 
Key Inclusion Criteria 
1. Cytologic or histologic proof pancreatic ductal carcinoma 
2. No evidence of metastatic disease 
3. Resectable, Borderline resectable, or local-advanced unresectable 
PDAC 
4. No history of previous chemotherapy 
5. Must have adequate organ function 
Key Exclusion Criteria 
1. Any other active malignancy or prior history of malignancy within 5 
years except for successfully treated cervical carcinoma in situ, lobular 
carcinoma in situ of the breast, or non-melanoma skin cancer. 
2. Medical co-morbidities that are deemed to make risk of surgery 
unacceptably high as determined by institutional standards.  
3. Personal history of any of the following conditions: syncope of 
cardiovascular etiology, ventricular arrhythmia of pathological origin 
(including, but not limited to, ventricular tachycardia and ventricular 
fibrillation), or sudden cardiac arrest. 
4. Recent major surgery (excluding laparoscopy) within 4 weeks prior to 
starting study treatment. Minor surgery within 2 weeks of starting study 
treatment. Patients must be recovered from effects of surgery. 
5. Participants receiving any other study agents. 
6. Judgment by the investigator that the patient should not participate in 
the study if the patient is unlikely to comply with study procedures, 
restrictions and requirements. 
Number of Participants 
N =60; n = 40 resectable/BRPC cohort; n=20 LAPC cohort 
Duration of Therapy 
Up to 8 cycles of FOLFIRINOX and/or GA, followed by short- or long-
course RT (1-8 weeks, per discretion of treating physician) 
Duration of Follow Up 
Up to 24 months from start of study treatment 
 
Description of Study
Intervention FOLFIRINOX and/or GA, followed by short- or long-course RT 
 
Statistical Analyses 
This is an open-label, non-randomized, phase II trial to assess the 
efficacy of an adaptive treatment strategy that allows for early switching 
of neoadjuvant systemic chemotherapy in patients with 
resectable/borderline resectable or locally-advanced unresectable 
pancreatic cancer. The primary endpoint is to estimate the proportion of 
resectable or BRPC participants with R0 resection. Assuming that the 
proportion of R0 is 60%, a sample size of 32 participants will allow us to 
estimate the proportion with an exact 95% CI (0.41, 076); that is, a width 
of 0.35 for the 95%CI.  To account for 20% lost to follow-up or ineligible 
for surgery, a total of 40 participants will be enrolled towards the primary 
endpoint of estimating the proportion of resectable or BRPC participants 

 
7 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
with R0 resection. A separate exploratory cohort of 20 participants with 
LAPC will be enrolled.  

 
8 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline, PDAC, or LAPC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date: 20 September 2023 
PI: Charles Lopez MD, PhD 
SCHEMATIC OF STUDY DESIGN  
 
 
 
 
 

 
9 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline, PDAC, or LAPC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date: 20 September 2023 
PI: Charles Lopez MD, PhD 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................................................................... 2 
SYNOPSIS ................................................................................................................................. 4 
SCHEMATIC OF STUDY DESIGN ............................................................................................. 8 
TABLE OF CONTENTS ................................................... ERROR! BOOKMARK NOT DEFINED. 
LIST OF TABLES ..................................................................................................................... 18 
LIST OF ABBREVIATIONS ...................................................................................................... 19 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................... 21 
1.1 
Background .............................................................................................................. 21 
1.2 
Neoadjuvant Therapy For (Borderline) Resectable Pancreatic Cancer ..................... 21 
 Gemcitabine-based Neoadjuvant Regimens ........................................................ 21 
 FOLFIRINOX Neoadjuvant Regimens .................................................................. 22 
 Improving Drug Delivery in PDAC ........................................................................ 23 
 Predictive and Prognostic Biomarkers in PDAC ................................................... 24 
 
CA19-9 ................................................................................................. 24 
1.3 
Study Rationale ........................................................................................................ 25 
1.4 
Exploratory Studies Background ............................................................................... 25 
 Locally-advanced unresectable PDAC (LAPC) Exploratory Cohort ...................... 25 
 PDAC Tumor Biology ........................................................................................... 26 
1.5 
Risk/Benefit Assessment .......................................................................................... 26 
 Known Potential Risks .......................................................................................... 26 
 Known Potential Benefits ..................................................................................... 26 
2. OBJECTIVES AND ENDPOINTS ........................................................................................ 27 
2.1 
Primary Objective and Endpoint ................................................................................ 27 
2.2 
Secondary Objectives and Endpoints ....................................................................... 27 
2.3 
Exploratory Objectives and Endpoints ...................................................................... 28 
3. STUDY DESIGN AND ENDPOINTS .................................................................................... 30 
3.1 
Description of the Study Design ................................................................................ 30 
3.2 
Justification for Rationale of Study Design ................................................................ 32 
 Justification for Dose ............................................................................................ 32 
3.3 
End of Study Definition ............................................................................................. 32 
4. STUDY POPULATION ......................................................................................................... 33 

 
10 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
4.1 
Participant Inclusion Criteria ..................................................................................... 33 
4.2 
Participant Exclusion Criteria .................................................................................... 35 
4.3 
Participant Screening and Enrollment ....................................................................... 36 
 Screen Failures .................................................................................................... 36 
4.4 
Strategies for Recruitment and Retention ................................................................. 36 
 Accrual Estimates ................................................................................................ 37 
 Inclusion of Children ............................................................................................. 38 
5. STUDY ENROLLMENT AND WITHDRAWAL ..................................................................... 38 
5.1 
Registration Procedures ........................................................................................... 38 
 OHSU Registration ............................................................................................... 38 
 Multicenter Registration ........................................................................................ 38 
5.2 
Participant Withdrawal or Discontinuation from the Study ......................................... 39 
 
Study Discontinuation and Closure ........................................................................... 39 
 Handling Participant Discontinuation from Study .................................................. 40 
 
Participant replacement ....................................................................... 40 
 
Lost to Follow-up ...................................................................................................... 40 
6. STUDY INTERVENTION ...................................................................................................... 40 
 
Fluorouracil ............................................................................................................... 40 
 Acquisition ............................................................................................................ 41 
 Formulation .......................................................................................................... 41 
 Storage and Stability ............................................................................................ 41 
 Compatibility ........................................................................................................ 41 
 Handling ............................................................................................................... 41 
 Preparation .......................................................................................................... 41 
 Administration ...................................................................................................... 41 
 Special Consideration for Administration .............................................................. 41 
 
Folinic Acid ............................................................................................................... 41 
 Acquisition ............................................................................................................ 41 
 Formulation .......................................................................................................... 41 
 Storage and Stability ............................................................................................ 42 
 Compatibility ........................................................................................................ 42 
 Handling ............................................................................................................... 42 
 Preparation .......................................................................................................... 42 
 Administration ...................................................................................................... 42 

 
11 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 Special Consideration for Administration .............................................................. 42 
 
Irinotecan .................................................................................................................. 42 
 Acquisition ............................................................................................................ 43 
 Formulation, Appearance, Packaging and Labeling ............................................. 43 
 Product Storage and Stability ............................................................................... 43 
 Compatibility ........................................................................................................ 43 
 Handling ............................................................................................................... 43 
 Preparation .......................................................................................................... 43 
 Administration ...................................................................................................... 43 
 Special Consideration for Administration .............................................................. 43 
 
Oxaliplatin ................................................................................................................. 43 
 Acquisition ............................................................................................................ 44 
 Formulation, Appearance, Packaging and Labeling ............................................. 44 
 Product Storage and Stability ............................................................................... 44 
 Compatibility ........................................................................................................ 44 
 Handling ............................................................................................................... 44 
 Preparation .......................................................................................................... 44 
 Administration ...................................................................................................... 44 
 Special Consideration for Administration .............................................................. 44 
6.5 
Gemcitabine ............................................................................................................. 44 
 Acquisition ............................................................................................................ 45 
 Formulation, Appearance, Packaging and Labeling ............................................. 45 
 Product Storage and Stability ............................................................................... 45 
 Compatibility ........................................................................................................ 45 
 Handling ............................................................................................................... 45 
 Preparation .......................................................................................................... 45 
 Administration ...................................................................................................... 45 
6.6 
Nab-Paclitaxel ........................................................................................................... 45 
 Acquisition ............................................................................................................ 45 
 Formulation, Appearance, Packaging and Labeling ............................................. 46 
 Product Storage and Stability ............................................................................... 46 
 Compatibility ........................................................................................................ 46 
 Handling ............................................................................................................... 46 
 Preparation .......................................................................................................... 46 
 Administration ...................................................................................................... 46 

 
12 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 Special Consideration for Administration .............................................................. 46 
6.7 
Capecitabine ............................................................................................................. 46 
 Acquisition ............................................................................................................ 46 
 Formulation .......................................................................................................... 47 
 Storage and Stability ............................................................................................ 47 
 Compatibility ........................................................................................................ 47 
 Handling ............................................................................................................... 47 
 Preparation .......................................................................................................... 47 
 Administration ...................................................................................................... 47 
6.8 
Losartan .................................................................................................................... 47 
 Acquisition ............................................................................................................ 47 
 Formulation, Appearance, Packaging and Labeling ............................................. 47 
 Product Storage and Stability ............................................................................... 48 
 Handling ............................................................................................................... 48 
 Preparation .......................................................................................................... 48 
 Administration ...................................................................................................... 48 
 
Accountability (all Study Agents) ............................................................................... 48 
 Destruction and Return (all study agents) ................................................................. 48 
7. TREATMENT PLAN............................................................................................................. 48 
7.1 
Dosage and Administration ....................................................................................... 48 
 mFOLFIRINOX ..................................................................................................... 49 
 Gemcitabine and nab-Paclitaxel (GA) .................................................................. 49 
 Losartan ............................................................................................................... 50 
7.2 
Dosing Delays and Modifications .............................................................................. 50 
 Recommended mFOLFIRINOX Toxicity Management ......................................... 50 
 Recommended GA Toxicity Management ............................................................ 52 
 Hematologic dose modifications during days 8 and 15 of cycle ............................ 53 
 Hepatic Impairment .............................................................................................. 53 
 Recommended Losartan toxicity management ..................................................... 54 
 
Cycle 1 ................................................................................................. 54 
 
Cycle 2+ ............................................................................................... 54 
7.3 
Radiation Therapy .................................................................................................... 55 
 Dose specifications .............................................................................................. 55 
 
Short-course RT dose specifications .................................................... 55 
 
Long-course RT dose specifications .................................................... 55 

 
13 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 Localization, Simulation and Planning .................................................................. 57 
 
Treatment Volumes .............................................................................. 57 
 
Treatment Planning Simulation ............................................................ 57 
 Quality Assurance ................................................................................................ 58 
 Chemotherapy During Radiation Therapy ............................................................ 58 
 
Capecitabine ........................................................................................ 58 
 
Fluorouracil .......................................................................................... 58 
 
Recommended dose modifications for fluorouracil (5FU) or 
capecitabine given concurrently with radiation ..................................... 59 
7.4 
Surgery ..................................................................................................................... 60 
7.5 
Discontinuation from Study Intervention .................................................................... 60 
7.6 
Treatment Period and Maintenance .......................................................................... 61 
7.7 
Concomitant Medication and Supportive Care Guidelines ........................................ 61 
 Clinically Significant Dehydration.......................................................................... 62 
 Gastrointestinal .................................................................................................... 62 
 Acute cholinergic syndrome ................................................................................. 62 
 Infection Prophylaxis ............................................................................................ 62 
 Treatment of fever and neutropenia ..................................................................... 62 
 Growth Factor support .......................................................................................... 62 
 Blood Products ..................................................................................................... 63 
 Dysarthria ............................................................................................................. 63 
 Contraception ....................................................................................................... 63 
 
Use in Pregnancy ............................................................................................ 63 
 
Use in Nursing Women .................................................................................... 63 
7.8 
Precautionary Medications, Treatments, and Procedures ......................................... 63 
 5-FU ..................................................................................................................... 64 
 Oxaliplatin ............................................................................................................ 64 
 Irinotecan ............................................................................................................. 64 
 Nab-Paclitaxel ...................................................................................................... 64 
 Capecitabine ........................................................................................................ 64 
 Losartan ............................................................................................................... 65 
7.9 
Prohibited Medications, Treatments, and Procedures ............................................... 65 
8. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE ................................................ 65 
8.1 
Study-Specific Procedures ........................................................................................ 65 
 Medical history ..................................................................................................... 66 
 Disease Assessment ............................................................................................ 66 

 
14 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 Medication history ................................................................................................ 66 
 Physical examination ............................................................................................ 66 
 
Vital signs ............................................................................................ 66 
 
Height and weight ................................................................................ 66 
 
Performance status .............................................................................. 66 
 Radiographic or other imaging assessments ........................................................ 67 
 Electrocardiogram (ECG) ..................................................................................... 67 
 Adverse event evaluation ..................................................................................... 67 
 Assessment of study agent adherence ................................................................. 67 
8.2 
Laboratory Procedures and Evaluations ................................................................... 67 
 Hematology .......................................................................................................... 67 
 Biochemistry ........................................................................................................ 68 
 Urinalysis ............................................................................................................. 68 
 Coagulation panel ................................................................................................ 68 
 Pregnancy test ..................................................................................................... 68 
 Tumor Markers ..................................................................................................... 68 
8.3 
Exploratory Studies ................................................................................................... 68 
 Biological Sample Collection ................................................................................ 68 
 
Pretreatment Biospecimen Collection................................................... 69 
 
Excess tumor collection at time of planned surgery (only for 
participants with resectable or borderline resectable disease 
undergoing planned surgery) ............................................................... 69 
 Blood Collection For Research ............................................................................. 70 
8.4 
Screening Assessments ........................................................................................... 70 
8.5 
Baseline Assessments .............................................................................................. 70 
8.6 
Assessments During Treatment ................................................................................ 71 
8.7 
Early Termination Visit .............................................................................................. 71 
8.8 
End of Treatment Visit .............................................................................................. 71 
8.9 
Follow-up .................................................................................................................. 71 
8.10 Unscheduled Visits ................................................................................................... 71 
8.11 Schedule of Events ................................................................................................... 72 
9. EFFICACY MEASURES ...................................................................................................... 77 
9.1 
Margin Status............................................................................................................ 77 
9.2 
Imaging Response .................................................................................................... 77 
9.3 
Progression-Free Survival (PFS) .............................................................................. 77 
9.4 
Disease-free Survival (DFS) ..................................................................................... 77 

 
15 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
9.5 
Overall Survival (OS) ................................................................................................ 77 
9.6 
Surgical Complications ............................................................................................. 77 
10. SAFETY ............................................................................................................................ 78 
10.1 Specification Of Safety Parameters .......................................................................... 78 
10.2 Definitions ................................................................................................................. 78 
 
Adverse Event (AE) ......................................................................................... 78 
 
Serious Adverse Event (SAE) .......................................................................... 79 
 
Unanticipated Problems (UP) .......................................................................... 79 
 
Severity of Event ............................................................................................. 79 
 
Assessment of Causality Relationship To Study intervention ........................... 80 
10.3 Expectedness ........................................................................................................... 80 
10.4 Adverse Event Lists .................................................................................................. 80 
 
Adverse Event List for mFOLFIRINOX ............................................................ 80 
 
Adverse Event List for GA ............................................................................... 82 
 
Adverse Events List for Losartan ..................................................................... 84 
10.5 Time Period And Frequency For Event Assessment And Follow-Up ......................... 85 
10.6 Reporting Procedures ............................................................................................... 86 
 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events ............ 86 
 
MedWatch Reporting ....................................................................................... 86 
 
Reporting Of Pregnancy .................................................................................. 86 
10.7 Study Stopping Rules ............................................................................................... 87 
11. STATISTICAL CONSIDERATIONS .................................................................................. 87 
11.1 Statistical Hypothesis ................................................................................................ 87 
11.2 Sample Size Determiniation ...................................................................................... 87 
11.3 Populations for Analyses .......................................................................................... 87 
 
Cohorts and subgroups ................................................................................... 88 
 
Safety Analysis Set .......................................................................................... 88 
 
Efficacy Analysis Set ....................................................................................... 88 
11.4 Description of Statistical Methods ............................................................................. 88 
 
Descriptive Statistics........................................................................................ 88 
 
Baseline Descriptive Statistics ............................................................. 88 
 
On-study Treatment Summaries .......................................................... 89 
 
Analysis of Primary Endpoint ........................................................................... 89 
 
Analysis Of The Secondary Endpoints ............................................................. 89 
 
Analysis Of The Exploratory Endpoints ............................................................ 89 

 
16 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
Safety Analyses ............................................................................................... 90 
11.5 Handling of Missing Data .......................................................................................... 90 
12. CLINICAL MONITORING .................................................................................................. 90 
12.1 OHSU Knight Comprehensive Cancer Center Data & Safety Monitoring Plan .......... 90 
12.2 Clinical Data & Safety Monitoring .............................................................................. 91 
12.3 Quality Assurance & Quality Control ......................................................................... 91 
13. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............. 92 
13.1 Source Data/Documents ........................................................................................... 92 
 
Participant & Data Confidentiality..................................................................... 92 
 
Data Collection & Storage: Privacy, Confidentiality & Security ......................... 93 
 
Future Use of Stored Specimens and Data ...................................................... 94 
 
Maintenance of Records .................................................................................. 94 
13.2 Publication and Data Sharing Policy ......................................................................... 94 
 
Data Sharing Policy for Genome-Wide Association Studies (GWAS) .............. 94 
 
Data Sharing with Exploratory Observational Studies ...................................... 94 
13.3 Conflict of Interest Policy .......................................................................................... 95 
14. ETHICS/PROTECTION OF HUMAN PARTICIPANTS ...................................................... 95 
14.1 Ethical Standard ....................................................................................................... 95 
14.2 Institutional Review Board......................................................................................... 95 
14.3 Informed Consent ..................................................................................................... 95 
 
Consent Procedures and Documentation ........................................................ 95 
14.4 Protocol Review ........................................................................................................ 96 
14.5 Changes to Protocol ................................................................................................. 96 
15. REFERENCES .................................................................................................................. 96 
APPENDIX A: PERFORMANCE STATUS ............................................................................. 100 
APPENDIX B: CONTRACEPTION ......................................................................................... 101 
APPENDIX C: EXPLORATORY RESEARCH ........................................................................ 102 
A-1. Exosome Profiling ................................................................................................... 102 
A-2. Mutational Gene Profiling ........................................................................................ 102 
A-3. Microsatellite Instability ........................................................................................... 102 
A-4. Multiplex Immunohistochemistry and Cyclic Immunofluorescence .......................... 103 
A-5. Whole Exome and transcriptome Sequencing ......................................................... 105 
A-6. High Resolution Structural Analysis ........................................................................ 105 

 
17 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
A-7. Live Cell Propagation and Growth Inhibition ........................................................... 105 
A-8. Fusion Gene Profiling ............................................................................................. 106 
A-9. Cell free Tumor DNA (cfDNA) ................................................................................. 106 
A-10. Circulating Tumor DNA ........................................................................................... 107 
A-11. Reverse Phase Protein Arrays (RPPA) ................................................................... 107 
A-12. Circulating Tumor Cell (CTC) Profiling .................................................................... 107 
A-13. Dielectrophoresis (DEP) CHIP ................................................................................ 108 
A-14. Patient-Derived Xenograft (PDX) Models ................................................................ 108 
 

 
18 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline, PDAC, or LAPC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date: 20 September 2023 
PI: Charles Lopez MD, PhD 
LIST OF TABLES 
 
Table 1. Guidelines for mFOLFIRINOX to GA Switching ...........................................................30 
Table 2. Adequate Organ Function Laboratory Values ..............................................................34 
Table 3. Population Demographics - Oregon (%) ......................................................................37 
Table 4. Recommended mFOLFIRINOX Treatment regimen* ...................................................49 
Table 5. GA Treatment regimen*...............................................................................................49 
Table 6. Recommended mFOLFIRINOX Dose Levels ..............................................................50 
Table 7. Recommended Dose Modifications for mFOLFIRINOX Toxicities ...............................51 
Table 8. Recommended Dose Modifications for mFOLFIRINOX-related Hepatic Toxicities ......52 
Table 9. Recommended Dose Modifications for mFOLFIRINOX-related Renal Impairment ......52 
Table 10. Recommended GA Dose Levels ...............................................................................52 
Table 11. Recommended Dose Modifications for GA Toxicities ................................................52 
Table 12. Recommended Dose Modifications for GA-related Hematological Toxicities .............53 
Table 13. Recommended Dose Modifications for GA-related Hepatic Toxicities .......................54 
Table 14. Recommended Dose Modifications for GA-related Renal Toxicities ..........................54 
Table 14. Recommended Losartan Dose Levels .......................................................................54 
Table 15. Long-course RT Dose Prescriptions ..........................................................................56 
Table 16. Dosimetric Objectives and constraints for 15# RT Regimen ......................................56 
Table 17. Dosimetric Objectives and constraints for 25# RT Regimen ......................................56 
Table 18. Normal tissue dose-volume constraints .....................................................................57 
Table 19. Recommended Management of 5FU or Capecitabine Hematologic Toxicity ..............59 
Table 20. Recommended Management of 5FU or Capecitabine Non-hematologic Toxicity.......59 
Table 21. Study Assessments for mFOLFIRINOX Regimen ......................................................72 
Table 22. Study Assessment for GA Regimen ..........................................................................73 
Table 23. Study Assessments for RT Regimens .......................................................................74 
Table 24. Surgery, End of treatment (EOT), and Follow-up Assessments .................................75 
Table 24. Classification of Surgical Complications ....................................................................77 
Table 25. Common and Severe AEs for drug agents comprising mFOLFIRINOX regimen .......80 
Table 28. Common and Severe AEs for drug agents comprising GA regimen ..........................82 
Table 29. Less Common AEs for losartan* ................................................................................85 
Table 28. Summary protein panel for evaluation by mIHC and cycIF ...................................... 103 
 

 
19 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline, PDAC, or LAPC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date: 20 September 2023 
PI: Charles Lopez MD, PhD 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BRPC 
Borderline resectable PDAC 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell (count) 
CFR 
United States Code of Federal Regulations  
CRMS 
Clinical research management system 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CRF 
Case report form 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DFS 
Disease-free survival 
DLT 
Dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
FCBP 
Female of childbearing potential 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPPA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational new drug application 
IRB 
Institutional Review Board 
IV 
Intravenous 
LAPC 
Locally-advanced, unresectable PDAC 
LDH 
Lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
mOS 
Median Overall Survival 
MRI 
Magnetic resonance imaging 
N/A 
Not applicable 
NCI 
National Cancer Institute 
OHRP 
Office for Human Research Protections 
OHSU 
Oregon Health & Science University 
OS 
Overall Survival 
PDAC 
Pancreatic adenocarcinoma 
PET 
Positron emission tomography 
PI 
Principle Investigator 
PO 
Per os (by mouth, orally) 
RNI 
Reportable new information 
RT 
Radiation therapy 
SAE 
Serious adverse event 

 
20 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
TSMP 
Trial Specific Monitoring Plan 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 

 
21 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline, PDAC, or LAPC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date: 20 September 2023 
PI: Charles Lopez MD, PhD 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
1.1 
BACKGROUND 
 
Pancreatic Ductal Adenocarcinoma (PDAC) is the most common cancer affecting the exocrine 
pancreas, with an estimated 56,770 new PDAC cases and 45,750 deaths expected the United 
States in 2019.1  By the year 2030 PDAC is expected to be the second-leading cause of cancer-
related death and highlights the need to improve treatment outcomes.2,3  Surgical resection of 
the primary tumor followed by adjuvant therapy remains the current gold standard for a curative 
therapy; however, only 5-25% of patients have disease that is amendable to surgical 
intervention.4  Even so, post-operative complications, worsening performance status, and 
disease progression results in only 55% of surgical patients receiving adjuvant chemotherapy.5,6  
Moreover, patients with R0 and microscopically residual PDAC disease (i.e., R1) that receive 
gemcitabine-based adjuvant chemotherapy have a median overall survival of 20 to 26 months, 
which is marginally improved to 28 months with the addition of capecitabine.7,8  These dismal 
outcomes have given cause to rethink the treatment strategy of patients with borderline 
resectable pancreatic cancer (BRPC) or upfront resectable pancreatic cancer that emphasizes a 
neoadjuvant approach.  
 
1.2 
NEOADJUVANT THERAPY FOR (BORDERLINE) RESECTABLE PANCREATIC 
CANCER 
 
Results from two separate phase III trials demonstrated substantial improvement in progression-
free survival (PFS) and overall survival (OS) of patients with metastatic pancreatic cancer that 
received multi-agent chemotherapy regimens that combine 5-fluorouracil (5-FU), oxaliplatin, and 
irinotecan (FOLFIRINOX) or the combination of nab-paclitaxel and gemcitabine compared to 
standard gemcitabine.9-11  Among those receiving FOLFIRINOX, median (m)PFS was 6.4 
months compared to 3.3 months for those given gemcitabine monotherapy. Median (m)OS was 
also greatly improved (11.1 vs. 6.8 months).11  Likewise, subjects receiving the combination of 
nab-paclitaxel plus gemcitabine (GA) had a mPFS of 5.5 and a mOS of 9.7 months, compared 
to 3.7 and  6.6 months, respectively, for those administered gemcitabine alone.9  In addition to 
these studies, there is mounting evidence to suggest that gemcitabine-based regimens and 
multi-agent chemotherapy (i.e., FOLFIRINOX, FOLFOX) are promising therapies in the 
neoadjuvant setting.12-17  As to which of these is the optimal neoadjuvant regimen remains 
unknown.   
 
 GEMCITABINE-BASED NEOADJUVANT REGIMENS 
 
Sohal et al18 reported on final results of the phase II trial, SWOG S1505 (NCT02562716), in 
which patients with resectable PDAC were randomized to receive either 12 weeks of 
perioperative FOLFIRINOX or GA. The primary outcome was 2-year OS.  Among the 147 
participants enrolled, 102 were evaluable for analysis, of which 55 received perioperative 
FOLFIRINOX and 47 received GA.  The majority of participants, regardless of treatment 
assignment to FOLFIRINOX or GA, completed their perioperative chemotherapy (84% and 
85%, respectively) and underwent surgical resection (73% and 70%, respectively).  The authors 
observed no statistical difference in the 2-year survival rate (41.6% vs 48.8%) and median OS 
(22.4 vs. 23.6 months) for those treated with FOLFIRINOX or GA.  Similarly, there was no 
statistical significance in the median disease-free survival (DFS) after resection between those 
given FOLFIRINOX or GA (10.9 vs. 14.2 months, p=0.87).   
 
In the phase III PREOPANC trial, participants with resectable and borderline resectable PDAC 
that were randomized to receive neoadjuvant gemcitabine-based therapy for 6 cycles followed 
by surgery (Arm A) or perioperative treatment regimen consisting of 2 cycles of gemcitabine, 

 
22 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
plus gemcitabine-based chemoradiation at a dose of 36 Gy/2.4 per fraction over 3 weeks, 
followed by surgery and 4 additional cycles of adjuvant gemcitabine (Arm B).19  Compared to 
those receiving neoadjuvant gemcitabine alone, those receiving a perioperative treatment 
regimen had a nearly double OS benefit (Arm A, median OS = 16.8 months; Arm B, median OS 
= 29.9 months, p<0.001). 
 
Jang et al14 reported on results of a phase 2/3 trial in which 50 BRPC evaluable patients were 
randomized to receive a neoadjuvant gemcitabine-based chemoradiation regimen followed by 
surgery and adjuvant chemoradiation (n = 27), or upfront surgery followed by a chemoradiation 
approach (n = 23).  Those in the neoadjuvant treatment group had a 2-year survival rate of 
40.7% and a median survival of 21 months.  In comparison, the 2-year survival rate and median 
survival among patients that received upfront surgery was 26.1% and 12 months, respectively. 
The rate of R0 resection was also significantly improved among patients in the neoadjuvant 
treatment group compared to those receiving upfront surgery (n = 14, 51.8% vs n = 6, 26.1%, P 
= 0.004).  This significantly improved outcome in the neoadjuvant treatment group led to early 
study termination.  
 
 FOLFIRINOX NEOADJUVANT REGIMENS 
 
Authors of a systematic review of 24 studies comprising 313 BRPC patients treated with 
FOLFIRINOX in the neoadjuvant setting reported a resection rate was 67.8% (95% confidence 
interval [CI], 60.1% to 74.6%), of which the R0-resection rate was 83.9% (95% CI, 76.8% to 
89.1%).  Treatment with neoadjuvant FOLFIRINOX ranged between 4 to 9 cycles, with mOS 
varying from 11.0 to 34.2 months.  Further analysis across 20 studies containing patient-level 
data for 283 BRPC patients revealed that neoadjuvant FOLFIRINOX was associated with a 
mPFS of 18 months (95% CI, 14.5 to 21.5 months) and a mOS of 22.2 months (95% CI, 18.8 to 
25.6 months).  The authors found that the highest pooled event rates for grade III–IV adverse 
events (AEs) were for neutropenia (17.5 per 100 patients, 95% CI, 10.3% to 28.3%), diarrhea 
(11.1 per 100 patients, 95% CI, 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI, 8.1 to 
14.2).  No deaths were attributed to FOLFIRINOX across all reports includes in this study.  
 
In a single site retrospective study of patients with unresectable locally-advanced pancreatic 
cancer (LPAC), Hosein et al16 identified 18 BRPC and LAPC patients that were treated with 
neoadjuvant FOLFIRINOX with growth factor support.  The authors found that following a 
median of 8 cycles per patient (range 3-17 cycles), 7 (39 %) patients were converted to 
resectable (per radiological criteria); 5 had R0 resections, 1 patient had an R1 resection, and 1 
patient had unresectable disease.  Of the 11 patients that remained unresectable, 3 patients 
achieved R0 resection following additional chemoradiation. Altogether, the authors reported an 
overall R0 resection rate of 44%.  With a median follow-up of 13.4 months, the 1-year PFS rate 
was 83 % (95 % CI 59-96 %) and the 1-year OS rate was 100 % (95 % CI 85-100 %). The 
authors noted that neutropenia (22 %), neutropenic fever (17 %), thrombocytopenia (11 %), 
fatigue (11 %), and diarrhea (11 %) were common grade 3/4 chemotherapy-related toxicities.  
 
In a similar single-site retrospective study, Blazer et al17 reported on 43 patients (20 BRPC and 
23 LAPC) that received modified (m) FOLFIRINOX (i.e., irinotecan at 165 mg/m2; oxaliplatin at 
85 mg/m2; 5-fluorouracil (5FU) at 2,400 mg/m2 over 46 hours and pegfilgrastim on day 4 of 
each 2-week cycle).  Patients also received gemcitabine-based chemoradiation (36 Gy in 15 
fractions) if their best response was stable disease after 4 months of mFOLFIRINOX.  Of the 19 
evaluable patients with BRPC, treatment with neoadjuvant mFOLFIRINOX led to resection in 12 
(63.2%) patients, of which 10 (53.6%) attained R0.  Among those 20 evaluable patients with 
LAPC initially considered unresectable, resection was achieved in 9 (45%) patients, of which 8 
(40%) were noted to be R0.  
 

 
23 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Murphy et al20 reported on a single arm phase II trial in which 48 patients (27 male, 21 female) 
with newly diagnosed BRPC were given eight cycles of neoadjuvant FOLFIRINOX.  Thirty-four 
(79%) of patients completed the planned 8 cycles, with 27 (56%) and 17 (35%) of patients 
receiving short-course or long-course chemoradiation, respectively.  R0 resection was achieved 
in 31 of 48 patients (65%), and among those that underwent resection, the R0 resection rate 
was 97%.  The authors observed a PFS of 14.5 months, and a 2-year PFS rate of 43%.  The 
OS was 37.7 months, and the 2-year OS rate was 56%.  Among those patients that underwent 
surgical resection, PFS was 48.6 months (95%CI, 14.4 to not reached), with 2-year PFS and 2-
year OS rates reaching 55% and 72%, respectively.   
 
 IMPROVING DRUG DELIVERY IN PDAC 
 
A desmoplastic-rich extracellular matrix is a common hallmark of pancreatic cancer.  Dense 
deposits of extracellular collagen and hyaluronan create physical pressures that compress 
blood vessels thus limiting the ability for cytotoxic agents to reach cancer cells.21  Coupled with 
diminished blood vessel density that is inherent to PDAC, drug delivery in these patients is 
largely ineffective and is a significant contributing factor to their poor survival outcomes.22   
 
The renin-angiotensin system has an essential role in maintaining cardiovascular homeostasis, 
and uses a variety of signal effectors (e.g., angiotensin, renin, Angiotensin-converting enzyme 
[ACE]) to manage arterial blood pressure, and fluid and electrolyte balance.  Preclinical and 
clinical studies also point to the renin-angiotensin system being dysregulated in numerous 
malignancies, including PDAC, where overexpression of several pathway components are 
associated with promoting cancer cell proliferation, as well as increasing invasiveness, 
angiogenesis, and metastases.23,24  In fibroblasts, a dysregulated renin-angiotensin system 
elicits activation of the transforming growth factor β (TGF-β) pathway, which in turn increases 
tumor fibrosis and desmoplasia.  Studies using PDAC mouse models have shown that vascular 
perfusion and consequently drug delivery can be improved with agents that modify the stroma 
by antagonizing the renin-angiotensin system.25-28  Particularly, losartan, an angiotensin II 
receptor blocker (ARB), is capable of inhibiting TGF-β pathway activity and reduce the levels of 
collagen and hyaluronan in an orthotopic PDAC mouse models.  This modification to the tumor 
stroma also increased the amount of 5-FU or doxil that perfused tumor vessels. Whereas, 
administration of 5FU, doxil, or losartan alone minimally impacted tumor growth, the 
combination of 5-FU or doxil with losartan resulted in significant tumor shrinkage.27,28 
 
Building on the above findings, Murphy et al29 recently reported on a phase II trial in which 49 
patients with untreated locally advanced unresectable pancreatic cancer received 8-cycles of 
FOLFIRINOX along with losartan (up to 50 mg PO QD).  A total of 39 (80%) patients completed 
all 8 planned cycles of FOLFIRINOX and losartan, while 10 patients received 1 to 7 cycles of 
the study regimen.  Hypotension was observed in 3 patients, and toxicity noted in 2 patients.  Of 
the 49 eligible patients, 45 (92%) proceeded to receive either short-course or long-course CRT.  
Seven (16%) patients received short-course chemoradiotherapy  comprising of 25 GyE in 5 GyE 
per fraction proton treatment or 30 Gy in 10 fractions photon treatment, and capecitabine (825 
mg/m2 BID), given Monday through Friday for 2 weeks.  Thirty-eight (84%) patients received 
long-course chemoradiotherapy consisting of 50.4 Gy in 28 fractions using intensity modulated 
radiotherapy, along with capecitabine (825 mg/m2 BID) or 5-FU continuous infusion (225 
mg/m2/day) given Monday through Friday during the course of radiotherapy.  Of the 49 
evaluable patients, 34 (64%) underwent resection and 15 remained unresectable.  Among the 
34 patients that underwent surgery, 30 (88%) had an R0 resection, of which 5 required vessel 
resection with reconstruction.  PFS overall and for those that underwent resection was 17.5 
months (95% CI: 13.9-22.7) and 21.3 months (95% CI, 16.6-28.2), respectively.  OS overall and 
for those that underwent surgery was 31.4 months (95% CI, 18.1-38.5) and 33.0 months (95% 
CI, 31.4 to not reached), respectively.   

 
24 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
 PREDICTIVE AND PROGNOSTIC BIOMARKERS IN PDAC 
 
As ongoing clinical trials attempt to identify optimal neoadjuvant therapeutic regimen(s), there 
remains an equally unmet need to have effective biomarkers that can predict the clinical benefit 
of a given neoadjuvant treatment strategy.  Several predictive markers including microsatellite 
instability, BRCA mutational status, secreted protein acidic and rich in cysteine (SPARC), 
human equilibrate nucleoside transporter 1 (hENT1), among others have been examined in 
clinical trials.30  To date, only detection of BRCA mutation has gained approval from the Food 
and Drug Administration (FDA) for guiding treatment in PDAC.  Specifically, PDAC patients who 
have inherited BRCA1 or BRCA2 genes mutations are eligible to receive olaparib, a poly-ADP-
ribose polymerase (PARP) inhibitor, to treat those with metastatic pancreatic cancer that have 
completed at least 16 weeks of initial platinum-based chemotherapy without demonstrable 
disease progression.31  This was based on results from the POLO trial, in which patients with 
BRCA mutation positive metastatic PDAC that received olaparib following standard 
chemotherapy had a mPFS of 7.4 months compared with a mPFS of 3.8 months for those who 
received a placebo after chemotherapy.  No improvement in OS was observed among patients 
who received olaparib (olaparib = 18.9 months vs. placebo = 18.1 months).  Moreover, the 
broader applicability of using this biomarker is unfortunately limited, as only 4-7% of PDAC 
patients have a BRCA mutation.   
 
 CA19-9 
 
The most widely used biomarker for PDAC is carbohydrate antigen 19-9 (CA19-9).  As a 
prognostic marker, higher median preoperative levels of CA19-9 are strongly associated more 
advanced stages of disease.32-34  In a review of 1500 PDAC patients that underwent surgical 
resection, Hartwig et al.34 observed that compared to patients with the low CA19-9 (<37 U/ml), 
those with high CA19-9 (≥4000 U/ml) had lower rates of resectability (80% vs 38%), as well as 
dramatically reduced OS (28.5 versus 14.4 months, respectively.  Similarly, in the post-
operative setting OS among those with low CA19-9 levels was 2.5-times greater than those with 
high CA19-9 levels (36.8 months vs. 14.6 months).  In a separate study, Berardi et.al  observed 
that high levels of CA 19-9 were an independent unfavorable prognostic factor as OS decreased 
from 18.49 months for those with CA19-9 ≤37 U/mL to 9.21 months for those with CA19-9 levels 
>37 U/mL.32   
 
Although the above studies establish the prognostic value of CA19-9 in PDAC patients, its use 
as biomarker to guide multimodal therapies remains unclear.  In a retrospective analysis, Wong 
et al35 evaluated 75 patients with metastatic PDAC that received fixed-dose gemcitabine to 
determine if decreases in CA19-9 levels were surrogates for time-to-progression (TTP) and OS.  
Using a 50% decline in CA19-9 as the cut-off, the authors observed a significant correlation 
between the percent decline in CA19-9 levels and TTP (0-50% decline in CA19-9, TTP = 3.6 
months; >50% decline in CA19-9, TTP = 6.2 months).  The OS was 9.2 months for patients with 
more than a 50% decline in CA19-9, 6.8 months for those with 0% to 50% decline, and 3.5 
months for those with no decline.   
 
Tsai et al36 conducted a retrospective analysis to assess CA19-9 levels among 131 patients with 
PDAC that received neoadjuvant therapy and surgery.  The authors observed OS to be nearly 
double among patients that had normalized CA19-9 levels either pre- or post-operatively, 
compared to those that failed to normalize CA19-9 (preoperative = 46 vs. 24 months; 
postoperative 43 vs. 20 months).  Compared with patients with normal preoperative CA19-9 
levels, failure to normalize pre- or post-operative levels of CA19-9 was associated with a 2.77-
fold and 4.03-fold increased risk of death, respectively (P < 0.003).  Instead of relying on the 
magnitude of change of CA19-9 levels, these findings suggest that following neoadjuvant 

 
25 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
therapy normalization of CA19-9 is a stronger prognostic marker of survival.  Continued efforts 
to bolster the utility of CA19-9 include studies combining it with other biomarkers such as 
intercellular adhesion molecule 1, and osteoprotegerin, among others.37 
 
1.3 
STUDY RATIONALE 
 
Mounting evidence suggests that pre-operative chemotherapy and/or chemoradiation confers 
significant survival benefit in the resectable PDAC population.38-40  Benefits of an early treatment 
strategy includes the potential for improving compliance to chemotherapies, down-staging 
tumors, and increasing the rate of margin-negative resections.38  Either FOLFIRINOX or 
gemcitabine plus nab-paclitaxel (GA) is currently used in the first-line treatment setting for 
advanced PDAC.41,42  However, until more information is available, most clinical decisions 
involving the choice of one treatment over another will continue to be based on a factors such 
as patient comorbidities, performance status, and individual patient preference.  Unfortunately, 
individual patients are often resistant or sensitive to one or both chemotherapy regimens; thus 
underscoring the significant clinical need to identify and validate biomarkers that can be used to 
optimize treatment regimens to individual cancer patients.  
 
In single-institution retrospective cohort study, Vreeland et al43 investigated the oncologic 
outcomes for patients with pancreatic cancer that underwent an early switch from FOLFIRINOX 
to GA in the neoadjuvant setting.  Twenty-five patents were identified that underwent an early 
switch from FOLFIRINOX to GA citing failure to respond (16 [64%]), poor tolerance (6 [24%]), or 
both poor response and tolerance as reasons for the treatment change.  The treatment change 
to GA was made after a median of 4 cycles of FOLFIRINOX, which coincided with initial re-
staging.  Of the 25 patients that underwent a switch to GA, 21 (84%) responded, of which 11 
proceeded to undergo surgical resection.  Of those underwent surgery, 9 (81.8%) had an R0 
resection, and 3 (27.3%) were N0.  At a median follow-up of 17.0 months, the estimated PFS 
was nearly double for patients that responded to GA and underwent resection (15.2 months), 
compared to those that responded to GA but did not undergo resection (6.5 months) or those 
that did not respond to GA (1.4 months).  Barring the limitations of a retrospective study, these 
findings suggest that for patients who do not respond to FOLFIRINOX, early switching to GA in 
the neoadjuvant setting is warranted.   
 
Altogether, the above findings strongly point to the need for early identification of possible 
resistance during the course neoadjuvant treatment of PDAC.  The NeoOPTIMIZE trial 
described in this protocol intends to provide a flexible platform to provide dynamic switching of 
established neoadjuvant therapies for patients with newly diagnosed resectable/borderline 
resectable PDAC.  Coupled with robust scientific correlative studies, the study aims to identify 
biomarker(s) that predict sensitivity of a given chemotherapy regimen.  Specifically, the current 
study will use overall participant disposition, radiographic imaging, as well as changes in levels 
of the standard of care biomarker, CA19-9, as a means to enrich for patients that are 
responders to FOLFIRINOX or GA in order to optimize curative therapy.  Underlying this 
treatment platform is the continuous administration of losartan, an ARB suggested to improve 
vascular perfusion and increase delivery of chemotherapy agents to the pancreas.27,29   
 
1.4 
EXPLORATORY STUDIES BACKGROUND 
 
 LOCALLY-ADVANCED UNRESECTABLE PDAC (LAPC) EXPLORATORY COHORT 
 
The potential for systemic chemotherapy to downstage LAPC has been evaluated in several 
studies.20,44-47 Notably, Murphy et al29 reported that LAPC downstaging by total neoadjuvant 
therapy with FOLFIRINOX, losartan, and chemoradiotherapy achieved an R0 resection rate of 
61%. However, for LAPC patients who do not respond to FOLFIRINOX, it is unclear if early 

 
26 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
switching to GA in the neoadjuvant setting can confer similar clinical benefit.  As such, the 
flexibility of the NeoOPTIMIZE trial platform will be used to separately examine patients with 
LAPC as part of an exploratory to cohort to assess if dynamic switching of established 
neoadjuvant therapies can improve clinical outcomes.  
 
 PDAC TUMOR BIOLOGY 
The exploratory objectives of this study are to better understand the biological underpinnings of 
PDAC tumorigenesis and assess mechanisms of resistance following therapy. To this end, 
tumor biopsy and blood samples may be used to assess aberrant genomic, transcriptomic, 
proteomic, and metabolomic characteristics of PDAC, as well as dynamic interactions with the 
tumor and immune environment.  These broad goals will be accomplished using a variety of 
cellular and molecular assays, and advanced imaging techniques described in Appendix C.  
 
1.5 
RISK/BENEFIT ASSESSMENT 
 
 KNOWN POTENTIAL RISKS  
 
Systemic chemotherapy using FOLFIRINOX or GA has become routinely used in the 
neoadjuvant setting for patients with resectable and borderline-resectable PDAC.  At OHSU, 
FOLFIRINOX or GA, followed by RT and surgery is a standard of care neoadjuvant approach to 
treating patients with resectable/borderline resectable PDAC.  Even so,  clear superiority of a 
neoadjuvant treatment regimen and alternating between two specific treatment modalities, has 
yet to be defined.  A neoadjuvant treatment strategy carries the possible risk of over-treating 
patients with systemic chemotherapy and unnecessarily subjecting them to its associated 
toxicities.  The associated risk of each chemotherapy regimen is well-defined, however.1110,16  
Another potential risk to utilizing a neoadjuvant treatment strategy in patients with clearly 
resectable disease is the possibility of missing the “window” for curative intent-resection in these 
patients.  
 
 KNOWN POTENTIAL BENEFITS 
 
A neoadjuvant treatment strategy that provides dynamic switching between chemotherapy 
regimens based on CA19-9 profiling may provide access to a new treatment modality not 
previously available to patients with resectable PDAC.  It cannot, however, be guaranteed that 
participants in this study will directly benefit from treatment during participation, as the clinical 
trial is designed to provide information about the safety and effectiveness of the investigational 
approach. 
 
1.6 
CORRELATIVE STUDIES BACKGROUND 
 
The Wong research group has recently discovered that macrophages (MФs) fuse with cancer 
cells to form a hybrid cancer cell that retains genotypes and phenotypes of both the parental 
cancer cell and MФ.39  The resulting tumor cell hybrid displays hallmarks of metastatic cancer 
cells but appears to have greater "stem cell"-like behavior.  Interestingly, these cells represent a 
unique population of circulating tumor cells (CTCs) that are termed circulating hybrid cells 
(CHCs), which exist in blood at a log-fold higher than conventionally isolated CTCs in late stage 
disease.  While enumeration of CHCs tracks with disease burden in CRC, the Wong group has 
also developed panels of antibodies that differentiate CHCs derived from inflamed tissue from 
cancer-derived CHCs.  Based upon this novel biologic finding, an exploratory component of this 
study will evaluate and characterize CHCs as a potential measure of tumor response to 
therapeutic delivery and risk for recurrence or progression.   

 
27 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
 
Objective 
Endpoint 
Start  
End  
To determine the rate of 
margin-negative (R0) resection 
in participants with resectable 
or BRPC following treatment 
using NeoOPTIMIZE adaptive 
therapy 
[i.e., FOLFIRINOX alone, or 
switch to GA] 
Proportion of resectable or 
BRPC participants with R0 
resection 
 
 
Start of 
neoadjuvant 
therapy  
[i.e., Day 1] 
Time of 
Surgery 
 
 
 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Start  
End  
1. To determine the 
PFS of resectable 
or BRPC 
participants that 
received 
NeoOPTIMIZE 
adaptive therapy 
[i.e., FOLFIRINOX, 
or switch to GA] 
1. PFSNeoOPTMIZE for 
resectable or BRPC 
cohort 
Start of 
neoadjuvant 
therapy  
[i.e., Day 1] 
Time of tumor 
progression, or 
death due to any 
cause [up to  24 
months from 
start of study 
treatment] 
2. To determine the PFS 
for the subset of 
resectable or BRPC 
participants that 
received 
NeoOPTIMIZE 
adaptive therapy  plus 
preoperative radiation 
therapy [RT] 
2. PFSNeoOPTMIZE + preop-RT 
for resectable or 
BRPC subset 
3. To determine the 
disease-free survival 
(DFS) of resectable or 
BRPC participants that 
received 
NeoOPTIMIZE 
adaptive therapy [i.e., 
FOLFIRINOX, or 
switch to GA] 
3. DFSNeoOPTMIZE for 
resectable or BRPC 
cohort 
Date of surgery 
Time of tumor 
progression, or 
death due to any 
cause [up to  24 
months from 
start of study 
treatment] 

 
28 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
4. To determine the DFS 
for the subset of 
resectable or BRPC 
participants that 
received 
NeoOPTIMIZE 
adaptive therapy plus 
preoperative RT 
4. DFSNeoOPTMIZE + preop-RT 
for resectable or 
BRPC subset 
5. To determine the OS 
of resectable or BRPC 
participants that 
received 
NeoOPTIMIZE 
adaptive therapy  
5. OSNeoOPTMIZE for 
resectable or BRPC 
cohort 
Start of 
neoadjuvant 
therapy  
[i.e., Day 1] 
Death by any 
cause [up to  24 
months from 
start of study 
treatment] 
6. To determine the OS 
for the subset of 
resectable or BRPC 
participants that 
received 
NeoOPTIMIZE 
adaptive therapy plus 
preoperative RT 
6. OSNeoOPTMIZE + preop-RT 
for resectable or 
BRPC subset 
7. To assess the surgical 
complications of 
resectable or BRPC 
participants that 
undergo surgical 
resection  
7. Proportion of 
resectable or BRPC 
participants with peri- 
and post-operative 
complications [per 
the Clavien-Dindo 
classification 
system48] 
Date of surgery 
Within 30 days 
from date of 
surgery 
8. To assess 30-day 
post-operative 
mortality of 
participants with 
resectable or BRPC 
that undergo surgical 
resection  
8. Proportion of 
resectable or BRPC 
participants that die 
within 30 days of 
surgery 
Date of surgery 
30-days post 
surgery 
9. To assess safety of 
NeoOPTIMIZE 
adaptive therapy (all 
participants) 
9. Incidence of grade ≥3 
toxicities [per CTCAE 
v5.0] 
Start of 
neoadjuvant 
therapy  
[i.e. Day 1] 
90 days after last 
dose of protocol-
directed therapy   
 
2.3 
EXPLORATORY OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Start  
End  
To monitor changes in CA19-9 
levels (all participants) 
CA19-9 serum levels 
(U/ml) 
Day 0 
[i.e., Baseline] 
24 months 
after start of 
therapy 

 
29 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
To determine the rate of 
margin-negative (R0) resection 
in patients with LAPC, following 
treatment using NeoOPTIMIZE 
adaptive therapy 
[i.e., FOLFIRINOX alone, or 
switch to GA] 
Proportion of LAPC 
participants with R0 
resection 
 
 
Start of 
neoadjuvant 
therapy  
[i.e., Day 1] 
Time of 
Surgery 
 
 
To determine the PFS of LAPC 
participants that received 
NeoOPTIMIZE adaptive 
therapy [i.e., FOLFIRINOX, or 
switch to GA] 
PFSNeoOPTMIZE for LAPC 
cohort 
Start of 
neoadjuvant 
therapy  
[i.e., Day 1] 
Time of 
tumor 
progression, 
or death 
due to any 
cause [up to  
24 months 
from start of 
study 
treatment] 
To determine the PFS for the 
subset of LAPC participants 
that received NeoOPTIMIZE 
adaptive therapy plus 
preoperative radiation therapy 
[RT] 
PFSNeoOPTMIZE + preop-RT for 
LAPC subset 
 
 
To determine the disease-free 
survival (DFS) of LAPC 
participants that received 
NeoOPTIMIZE adaptive 
therapy [i.e., FOLFIRINOX, or 
switch to GA] 
DFSNeoOPTMIZE for LAPC 
cohort 
Date of 
surgery 
 
 
 
Time of 
tumor 
progression, 
or death 
due to any 
cause [up to  
24 months 
from start of 
study 
treatment] 
To determine the DFS for the 
subset of LAPC participants 
that received NeoOPTIMIZE 
adaptive therapy plus 
preoperative RT 
DFSNeoOPTMIZE + preop-RT for 
LAPC subset 
To determine the OS of LAPC 
participants that received 
NeoOPTIMIZE adaptive 
therapy  
OSNeoOPTMIZE for LAPC 
cohort 
Start of 
neoadjuvant 
therapy  
[i.e., Day 1] 
Death due 
to any 
cause [up to  
24 months 
from start of 
study 
treatment] 
To determine the OS for the 
subset of LAPC participants 
that received NeoOPTIMIZE 
adaptive therapy plus 
preoperative RT 
OSNeoOPTMIZE + preop-RT for 
LAPC subset 
To assess the surgical 
complications of LAPC 
participants that undergo 
surgical resection  
Proportion of LAPC 
participants with peri- and 
post-operative 
complications [per the 
Clavien-Dindo 
classification system48] 
Date of 
surgery 
Within 30 
days from 
date of 
surgery 

 
30 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
To assess 30-day post-
operative mortality of LAPC 
participants who undergo 
surgical resection  
Proportion of LAPC 
participants who die within 
30 days of surgery 
Date of 
surgery 
30-days 
post-
surgery 
 
3. STUDY DESIGN AND ENDPOINTS 
 
3.1 
DESCRIPTION OF THE STUDY DESIGN 
 
Refer to Section 11, Statistical Analysis for additional information regarding statistical methods 
used in this study. 
 
This is an open-label, non-randomized, phase II trial to assess the efficacy of an adaptive 
treatment strategy that allows for early switching of neoadjuvant systemic chemotherapy in 
patients with resectable and borderline resectable pancreatic cancer, or patients with locally-
advanced, unresectable pancreatic cancer (LAPC).  Participants must meet the inclusion 
criteria, have none of the exclusion criteria, and have provided written informed consent before 
the conduct of any screening tests not performed routinely in their treatment.  Approximately 60 
participants will be enrolled into this study. A total of 40 participants with resectable or BRPC will 
accrued towards the primary endpoint of estimating the proportion of individuals achieving R0 
resection. A separate cohort comprised of 20 participants with LAPC will be enrolled to this 
study as part of an exploratory objective to similarly estimate the proportion of R0 resection that 
can be achieved using an early switching approach of neoadjuvant systemic chemotherapy.  
 
Eligible participants enrolled into this study will initially receive approximately 2 months of 
preoperative mFOLFIRINOX (approximately 4 cycles) to be administered in accordance with 
institutional standards.  Participants will then undergo disease restaging consistent with 
standard of care, including imaging (e.g., ultrasound, CT, MRI, PET-CT [per institutional 
standards]), CA19-9 serum levels, and performance status (i.e., Eastern Cooperative Group 
[ECOG]).  Keeping with institutional standards, results of the disease reassessment (Re-Stage 
I) may be reviewed by the treating physician in conjunction with the investigator and institutional 
multi-disciplinary tumor board if warranted (comprised of radiologists, and medical, surgical, and 
radiation oncologists). A participant may be switched to GA from FOLFIRINOX prior to the 
imaging time point (and therefore prior to Restage 1 and the TB discussion); or a patient may be 
switched to GA from FOLFIRINOX after the imaging time point but without needing to be 
presented at a TB conference. The algorithm shown in Table 1 should be used to aid in the 
decision of whether a participant will continue to receive mFOLFIRINOX or proceed with early 
switching to GA; however, the ultimate decision to continue or switch therapy is at the discretion 
of the treating physician in consultation with the multi-disciplinary tumor board.  Treatment 
response at Re-Stage I will be defined as either radiographic or serologic:  
i) a radiographic response is defined as “response” of any kind as noted in the radiology 
clinical report.   
ii)  a serological response is defined as any decrease in serum CA19-9 of at least 25% 
from baseline.   
a. Because serum CA19–9 levels may be influenced by elevations in bilirubin, 
consideration of changes in CA19-9 levels may be excluded from response 
assessment if, at the time of the CA19–9 assessment, the participants total bilirubin 
level is > 2.0 mg/dL (in the absence of stenting).   
 
Table 1. Guidelines for mFOLFIRINOX to GA Switching 
Continued mFOLFIRINOX at Re-Stage I will be based on the following considerations*: 

 
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Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
1. If the participant is considered to have a radiographic response (per radiology clinical 
report), then they will proceed to receive an additional 2 months of mFOLFIRINOX 
(approximately 4 cycles).  This treatment response may be considered independent of any 
possible increases in serum CA19-9 levels, or 
2. In the absence of radiographic disease progression (per radiology clinical report), 
participants may continue to receive an additional 2 months of mFOLFIRINOX 
(approximately 4 cycles) if: 
a. serum CA19-9 levels have decreased ≥ 25% (from baseline), or 
b. serum CA19-9 levels remain unchanged (from baseline), or 
c. serum CA19-9 levels have increased <30% (from baseline) 
Switch to GA at Re-stage I will be guided by the following considerations*: 
1. Participants should be switched to receive up to 2 months of preoperative GA 
(approximately 2 cycles) if there is evidence of radiographic disease progression (per 
radiology clinical report), or 
2. In the absence of radiographic disease progression (per radiology clinical report), 
participants may be switched to receive 2 months of preoperative GA (approximately 4 
cycles) if serum CA19-9 levels have increased ≥30% (from baseline), 
3. Participants responding to FOLFIRINOX but, per assessment of treating physician, are 
unlikely to physically tolerate additional courses, will also proceed to having treatment 
switched to GA.  
*The decision to continue or switch therapy at Re-Stage I is at the discretion of the treating physician in 
consultation with the multi-disciplinary tumor board. There is no protocol deviation if the above 
algorithm is not explicitly followed. Reasons for alternate treatment decisions that are consistent with 
the general guidelines of the neoadjuvant treatment should be recorded.   
 
After completing an additional 2 months of treatment with mFOLFIRINOX or GA participants will 
undergo disease restaging consistent with institutional standard of care (e.g., imaging, CA19-9 
serum levels, and performance status).  The results of the disease reassessment (Re-Stage II) 
will be reviewed by the treating physician in conjunction with the institutional multi-disciplinary 
tumor board.  In the absence of disease progression, participants may undergo RT or planned 
surgery based on whether there was tumor involvement with pancreatic vasculature at baseline 
as follows: 
1. If there was no vascular involvement at the outset (i.e., no evidence of either arterial or 
venous tumor contact), then participants will proceed to planned surgical resection of 
their disease.  
2. If tumor involvement was present at baseline, but Re-stage II shows resolution of tumor 
contact with pancreatic vasculature, then participants will receive short-course RT (30 
Gy/10 fractions), per institutional guidelines.  
3. If tumor contact with pancreatic vasculature at baseline still persists at Re-stage II, then 
participants will undergo CRT (15-25 fraction) per institutional guidelines. The concurrent 
use of capecitabine or continuous infusion 5-fluorouracil (CIV-5-FU), per institutional 
guidelines, is permitted at the discretion of the treating physician.  
 
*Note that participants with any clinically-relevant condition that, in opinion of the treating 
physician, would contraindicate RT may proceed to undergo surgery (if eligible).*   
 
For participants that undergo RT, surgical resection should be performed 1 to 4 weeks after 
completing their RT regimen.  For all participants that proceed to surgery, the tumor resection 
margins will be evaluated and scored.  Following surgery, participants will considered off-
protocol-directed therapy and will proceed to the follow-up portion of the trial.  Throughout the 

 
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NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
trial, any participant showing disease progression will discontinue study treatment, undergo 
surgery (if eligible), and proceed to longitudinal follow-up as described in Section 8.9.  
Subsequent management of the participant’s disease will be in accordance with institutional 
standards.  
 
Starting on Cycle 1 Day 1, all participants will initiate concurrent treatment with losartan.  The 
administration of losartan will be continuous throughout the participant’s chemotherapy (i.e., 
FOLFIRINOX or GA) and planned RT.  Losartan administration will be discontinued after 
completion of the RT regimen.   
 
3.2 
JUSTIFICATION FOR RATIONALE OF STUDY DESIGN 
 
There is clear evidence to show that pre-operative chemotherapy and/or chemoradiation 
confers significant survival benefit in the resectable PDAC population, including down-staging 
tumors, and increasing the rate of margin-negative resections.38-40  Moreover, there is 
retrospective clinical data to show that early switching from mFOLFIRINOX to GA has clinical 
benefit for patients that failed initial mFOLFIRINOX treatment because of a lack of response, 
poor tolerability, or both.43  However, a prospective study is needed to empirically evaluate the 
potential clinical benefit of early switching of neoadjuvant treatments.  The NeoOPTIMIZE trial is 
designed to provide a flexible platform to allow for early switching of standard of care therapies 
by monitoring changes in both radiographic and serological response.  Additionally, losartan is 
suggested to improve vascular perfusion and increase delivery of chemotherapy agents to the 
pancreas, and its continuous administration (if assigned) during the course of the study will also 
be assessed.27,29 Participants currently receiving an angiotensin-converting enzyme (ACE) 
inhibitor or angiotensin II receptor blocker (ARB) will remain eligible for study participation. In 
such cases, losartan will not be assigned as part of the study intervention. These participants 
will continue to receive their ACE inhibitor or ARB per standard-of-care. The ACE inhibitor or 
ARB type should be recorded as a concomitant medication (including dose and frequency).    
 
 JUSTIFICATION FOR DOSE 
 
The dosing regimens and schedules for both mFOLFIRINOX and GA are well established.10,11  
All systemic chemotherapy will be administered at doses consistent with institutional standard of 
care for the treatment of pancreatic cancer.  Likewise, all RT will be administered at the 
discretion of treating radiation oncologist in accordance with institutional standards.  
 
The administration of losartan in this study is based on a prior report of patients with locally 
advanced PDAC that received concomitant FOLFIRINOX and short-or long-course 
chemoradiotherapy (5 GyE x 5 protons).29  In a previous trial, losartan was administered at a 
starting dose of 25 mg PO QD for the first 7 days of (i.e., Cycle 1, Day 1-7).  Provided that the 
participants’ systolic blood pressure is >100 mm Hg, then the losartan dose was increased to 50 
mg PO QD for the remainder of the study in combination with FOLFIRINOX.  Results from the 
study showed that of the 49 eligible patients, 39 (80%) received all 8 cycles of FOLFIRINOX 
and losartan. Of which only 3 patients experienced hypotension after losartan treatment, but all 
continued on the study.  Based on these findings, the NeoOPTIMIZE trial will adapt a similar 
dosing strategy in which participants will receive losartan at a reduced dose 25 mg PO QD for 
the first 14 days, and if well-tolerated (i.e., maintain systolic BP > 100 mm Hg) then dose will 
increase to 50 mg PO QD.   
 
3.3 
END OF STUDY DEFINITION 
 

 
33 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
A participant is considered to have completed the study they have completed all phases of the 
study including the last scheduled follow-up (i.e. up to 24 months after initiating study therapy).  
 
4. STUDY POPULATION 
 
4.1 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Ability to understand and the willingness to sign a written informed consent document. 
2. Age ≥ 18 years  
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (see Appendix A) 
4. Cytologic or histologic proof pancreatic ductal carcinoma is required prior to study entry 
a. If a biopsy (e.g., EUS-guided FNA) is planned per standard of care, the participant may 
be asked to consent to the additional collection of tumor tissue for research.  
5. No evidence of metastatic disease as determined by chest computed tomography (CT) 
scan, abdomen/pelvis Computed tomography (CT) scan (or magnetic resonance imaging 
[MRI] with gadolinium and/or manganese) within the 45-day window of study entry or prior to 
the one cycle of SOC administered before study entry, which is consistent with the standard 
of care.  
Note: On a case by case basis, for participants who enroll on trial after having received up to 
1 month of Standard of Care chemotherapy per Investigator discretion, baseline 
radiographic imaging performed per institutional guidelines prior to SOC chemotherapy 
treatment may be used per investigator discretion to fulfill baseline radiographic imaging 
criteria even if performed >45 days prior to official study entry. 
6. Diagnostic staging laparoscopy is not required for study eligibility. 
a. If staging laparoscopy is planned per standard of care, the participant may be asked to 
consent to the collection of tumor tissue for research. 
7. At time of screening, per NCCN criteria, must have either: 
a. Resectable PDAC, defined as no arterial tumor contact (celiac axis [CA], superior 
mesenteric artery [SMA], or common hepatic artery [CHA]), or  
b. Node positive disease as defined by CT, MRI, or EUS imaging, or 
c. Borderline resectable PDAC, defined as: 
i. For tumors of the head or uncinate process: 
• 
Solid tumor contact with the SMV or portal vein of >180 degrees with contour 
irregularity of the vein or thrombosis of the vein, but with suitable vessel proximal 
and distal to the site of involvement, allowing for safe and complete resection and 
vein reconstruction. 
• 
Solid tumor contact with the inferior vena cava. 
• 
Solid tumor contact with the common hepatic artery without extension to the 
celiac axis or hepatic artery bifurcation, allowing for safe and complete resection 
and reconstruction. 
• 
Solid tumor contact with the SMA ≤180°. 
• 
Solid tumor contact with variable anatomy (e.g., accessory right hepatic artery, 

 
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PI: Charles Lopez MD, PhD 
replaced right hepatic artery, replaced common hepatic artery, and the origin of 
replaced or accessory artery), and the presence and degree of tumor contact 
should be noted if present, as it may affect surgical planning. 
ii. For tumors of the body/tail: 
• 
Solid tumor contact with the celiac axis of ≤180 degrees. 
• 
Solid tumor contact with the celiac axis >180 degrees without involvement of the 
aorta and with an intact and uninvolved gastroduodenal artery, thereby permitting 
a modified Appleby procedure (although some members of the consensus 
committee preferred this criterion to be in the unresectable category). 
d. Locally-advanced, unresectable disease as defined by NCCN guidelines as follows: 
i. Tumors of the head with SMA ≥180°, or any celiac abutment, unreconstractable SMV 
or portal occlusion, or aortic invasion or encasement  
ii. Tumors of the body with SMA or celiac encasement ≥180°, unreconstractable SMV 
or portal occlusion, or aortic invasion 
iii. Tumors of the tail with SMA or celiac encasement ≥180° 
iv. Irrespective of location, all tumors with evidence of nodal metastasis outside of the 
resection field that are considered unresectable.   
8. Must be deemed fit to undergo planned curative resection as determined by institutional 
standards. 
9. No history of previous chemotherapy for pancreatic cancer. At the discretion of the PI, 
patient that have received no more than 1 month of systemic chemotherapy (e.g., 
mFOLFIRINOX), per standard of care, for the treatment of their PDAC may be eligible to 
participate.   
10. For participants who will get INV losartan, baseline systolic blood pressure (BP) > 100 mm 
Hg taken as the average of 3 blood pressure readings. 
11. Must have adequate organ (as defined in Table 2) prior to the one month of standard of 
care chemotherapy allowed by the protocol or within 4 weeks of screening. 
Note: On a case by case basis, for participants who enroll on trial after having received up to 
1 month of Standard of Care chemotherapy per Investigator discretion, labs prior to initiation 
of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening 
lab requirements even if performed >4 weeks prior to official study entry and/or there are 
more recent labs available from during chemotherapy treatment. 
Table 2. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Hemoglobin 
> 9 g/dL with no blood transfusion within 28 days of starting 
treatment; 
Absolute neutrophil count (ANC)a 
≥1.0 x 109/L (> 1000 cells/mm3); 
Platelet count  
≥100 x 109/L (>100,000 per mm3); 
Renal 
Creatinine OR 
Measured or calculatedb 
creatinine clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 mg /dl, OR  
≥30 mL/min/1.73m2 for participants with 
creatinine levels >1.5 x institutional ULN 

 
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Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Hepatic 
Serum bilirubin  
≤1.5 x institutional upper limit of normal (ULN); or ≤2 x ULN or 2 
down-trending values for individuals who have undergone biliary 
stenting. 
AST (SGOT) and ALT (SGPT)  
≤ 2.5 x ULN, OR two consecutive down-trending values for 
individuals who have undergone biliary stenting. 
a May be waived on a case-by-case basis for patient populations recognized to have normal baseline values 
below this level.  
b Creatinine clearance should be calculated per institutional standard. For participants with a baseline calculated 
creatinine clearance below normal institutional laboratory values, a measured baseline creatinine clearance 
should be determined. Individuals with higher values felt to be consistent with inborn errors of metabolism will be 
considered on a case-by-case basis. 
 
12. Female participants of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to initiating study therapy. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
13. Female participants of childbearing potential agree to use adequate methods of 
contraception (Appendix B) starting with the first dose of study therapy through 30 days after 
the last dose of study therapy.   
Participants of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for >1 year without an alternative medical cause.  
14. Male participants must agree to use an adequate method of contraception (Appendix B) 
starting with the first dose of study therapy through 30 days after the last dose of study 
therapy.  
15. Male patients must use a condom during treatment when having sexual intercourse with a 
pregnant woman or with a woman of childbearing potential.  Female partners of male 
participant should also use a highly effective form of contraception if they are of childbearing 
potential. 
16. Participants currently receiving an angiotensin-converting enzyme (ACE) inhibitor or 
angiotensin II receptor blocker (ARB) will remain eligible for study participation. In such 
cases, losartan will not be assigned as part of the study intervention. These participants will 
continue to receive their ACE inhibitor or ARB per standard-of-care. The ACE inhibitor or 
ARB type should be recorded as a concomitant medication (including dose and frequency).   
 
4.2 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. History of previous chemotherapy, targeted/biologic therapy, or radiation therapy for the 
treatment of their PDAC. 
2. Evidence of metastasis to distant organs (liver, peritoneum, lung, others). 
3. Any other active malignancy or prior history of malignancy with less than a 90% cure rate in 
the judgement of the investigators. 
4. Medical co-morbidities that are deemed to make risk of surgery unacceptably high as 
determined by institutional standards.  
5. Personal history of any of the following conditions: syncope of cardiovascular etiology, 

 
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ventricular arrhythmia of pathological origin (including, but not limited to, ventricular 
tachycardia and ventricular fibrillation), or sudden cardiac arrest. Patients with 
cardiovascular conditions that are well-controlled in the clinical judgement of the treating 
oncologist are eligible to participate. 
6. Recent major surgery (excluding laparoscopy) within 4 weeks prior to starting study 
treatment. Minor surgery within 2 weeks of starting study treatment. Patients must be 
recovered from effects of surgery. 
7. Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal 
therapy (Hormone replacement therapy is acceptable), not otherwise allowed in this study. 
Note: participation in other trials for supportive cancer care (e.g., cancer-related cachexia) 
interventions is permitted per PI discretion. 
8. Participants with a history of hypersensitivity reactions to study agents or their excipients. In 
cases of losartan hypersensitivity, losartan will be omitted and patient may still be eligible to 
participate. 
9. Participant is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 30 days after the 
last dose of trial therapy. 
10. Psychiatric illness/social situations, or any condition that, in the opinion of the investigator, 
would: interfere with evaluation of study treatment or interpretation of participant safety or 
study results, or substantially increase risk of incurring AEs, or compromise the ability of the 
patient to give written informed consent. 
11. Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
 
4.3 
PARTICIPANT SCREENING AND ENROLLMENT 
 
In order to participate in this study, signed informed consent must be obtained from the 
participant.  The current Institutional Review Board (IRB) approved informed consent must be 
signed and dated by each participant prior to undergoing any study procedures or before any 
prohibited medications are withheld from the participant in order to participate in this study.  The 
informed consent discussion must be documented in the participant’s medical record and a 
copy of their signed IRB approved informed consent form must be scanned into their record.  
 
Screening will begin once the participant has provided written informed consent to participate in 
the study and ends on Day 1 of the study. All screening and baseline evaluations will be 
performed during the screening phase (i.e., up to, but just before, start of treatment). Day 1 of 
the clinical trial will be when participants are started on the study intervention.   
 
 SCREEN FAILURES 
 
Any participant that has signed the consent form but does not meet the study eligibility criteria, 
or meets study eligibility criteria but terminates their participation prior to receiving study 
treatment, will be considered a screen failure and not counted towards total number of planned 
enrollments.  The reason for screen failure should be captured in the database for each 
participant failing to meet the eligibility criteria. 
 
4.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 

 
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PI: Charles Lopez MD, PhD 
This study will be conducted in the United States.  Participants for this study will primarily be 
recruited from hematology and oncology practices within OHSU and its affiliated community 
hematology and oncology (CHO) partners, but additional collaborative study sites may also be 
invited to participate in this trial.  Participants may be identified and referred to this study by their 
primary treating physician from within OHSU/CHO, collaborating study sites, or from the outside 
community.  Participants may be identified by a member of the participant’s treatment team, the 
PI, research team, or medical and surgical oncology clinics part of OHSU/CHO or collaborating 
study sites.  As a member of the treatment team, the investigator(s) will screen their 
participant’s medical records for suitable research study participants and discuss the study and 
their potential for enrolling in the research study.  Referral of potential participants to 
investigator(s) of this study is made as part of standard of care, with the referring physician 
seeking advice on the diagnosis, evaluation, and/or treatment of the participant’s malignancy.   
 
The investigator(s) may also screen the medical records of potential participants with whom the 
investigator does not have a treatment relationship.  This will be done for the limited purpose of 
identifying patients who would be eligible to enroll in the study and to record appropriate contact 
information in order to approach these potential individuals regarding the possibility of 
participating in the study.  Participants may also initiate contact with the investigator through 
information of this study posted on the clinicaltrials.gov website. 
 
 ACCRUAL ESTIMATES 
 
Up to 40 participants are planned for enrollment over approximately 36 months. 
No OHSU Knight Comprehensive Cancer Center study will focus on any particular gender, 
racial or ethnic subset.  No participant will be excluded from the study on the basis of gender, 
racial or ethnic origin.  Male, female and minority volunteers will be recruited for this study from 
the general population and approximately 50% men and 50% women will be studied.  Gender-
nonconforming and gender-fluid individuals as members of the general population will also be 
recruited. 
The projected gender, racial, and ethnic composition of the study will represent that of the state 
of Oregon.  
 
Table 3. Population Demographics - Oregon (%) 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
 
n 
% 
n 
% 
n 
% 
Hispanic or Latino 
3 
6.7 
3 
6.6 
5 
13.3 
Not Hispanic or Latino 
17 
43.7 
17 
43.0 
35 
86.7 
Ethnic Category: Total of all participants* 
20 
  
20 
  
40 
100.0 
 
Racial Category 
 
American Indian or Alaskan Native 
0 
0.9 
0 
0.9 
1 
1.8 
Asian 
1 
2.4 
1 
2.4 
2 
4.8 
Black or African American 
0 
1.1 
0 
1.1 
1 
2.2 
Native Hawaiian or other Pacific Islander 
0 
0.3 
0 
0.2 
0 
0.5 

 
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Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
 INCLUSION OF CHILDREN 
 
This protocol does not include children as the number of children with this type of cancer is rare. 
 
5. STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
REGISTRATION PROCEDURES 
 
 OHSU REGISTRATION 
 
Participants will be required to give written informed consent to participate in the study before 
any screening tests or evaluations are conducted that are not part of standard care.  
Registration from all consented participants must be entered into the OHSU electronic Clinical 
Research Management System (CRMS, e.g., eCRIS).  At a minimum, registration of OHSU 
participants will include: 
• 
Signed copies of the most recently IRB-approved, informed consent form and HIPAA 
authorization. 
• 
Investigator validation (signature and date) on participant’s inclusion and exclusion 
criteria  
 
 MULTICENTER REGISTRATION 
 
The OHSU coordinating center study team will manage the participant registration process. 
Investigators, or study team designee, at participating sites will identify eligible participants and 
send source documents that support eligibility to OHSU for review and verification before the 
participating site may enroll and treat the participant.  
 
The OHSU coordinating center team is responsible for verifying completeness of documents, 
entering registration information into the Knight CRMS, and assigning a study number/identifier 
for each individual participant.  The OHSU coordinating center will send an email to the 
participating site to indicate whether or not a participant is eligible and will assign a participant 
number/identifier.  Registration at participating research sites will include, at a minimum, signed 
copies of the most recent local IRB-approved, informed consent form and HIPAA authorization. 
 
Each participating research site is expected to maintain a screening log of all participants who 
are approached for the study.  The log documents an explanation for exclusion due to screen 
failure.  This log should be submitted to the OHSU coordinating center on a regular basis. 
Participating sites are required to retain, in a confidential manner, sufficient information on each 
participant so that the participant may be contacted should the need arise 
Table 3. Population Demographics - Oregon (%) 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
White 
17 
43.6 
17 
43.0 
35 
86.6 
Two or more races 
1 
2.0 
1 
1.9 
2 
3.9 
 
Racial Category: Total of all participants* 
20 
50.4 
20 
49.6 
40 
100* 
Source: Adapted from U.S. Census Bureau, 2019. 
*Totals may not equal 100 due to rounding. 

 
39 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
5.2 
PARTICIPANT WITHDRAWAL OR DISCONTINUATION FROM THE STUDY  
 
Participants are free to withdraw consent and discontinue participation in the study at any time 
and without prejudice to further treatment.  If a participant no longer wants to receive 
investigational product, but is willing to come for follow-up appointments, the participant’s 
request should be honored, if possible.  If a participant withdraws consent, they will be 
specifically asked if they are withdrawing consent to: 
• 
All further participation in the study including any further follow up (e.g., survival contact 
telephone calls) 
• 
Withdrawal of consent to the use of their study generated data 
• 
Withdrawal to the use of any biological samples  
 
No further participant contact should be made if the participant withdraws consent for 
participation in the study.  Information about the reason(s) for discontinuation and about any 
new or ongoing AEs should be collected at the time the participant withdraws consent.   
 
A participant may also be withdrawn from investigational product/study by the Sponsor-
Investigator, local IRB, or regulatory authorities.  Reasons for a participant to discontinue the 
study intervention may include the following: 
• 
Participant dies or is lost to follow-up 
• 
Participant withdraws consent for any further participation 
• 
The end of study is reached  
• 
Pregnancy  
**Note: In the event of a pregnancy, the study treatment will be permanently 
discontinued.  Refer to Section 10.6.3 regarding reporting of pregnancy.** 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive study drug for the intended duration of study treatment 
 
 
STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study funder, local IRB, 
and other regulatory agencies (as required).  If the study is prematurely terminated or 
suspended, the Investigator will promptly inform the IRB and will provide the reason(s) for the 
termination or suspension.  Circumstances that may warrant termination or suspension include, 
but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 

 
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NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
• 
Investigator(s) do not adhere to the study protocol, or applicable regulatory guidelines in 
conducting the study.  
• 
Participant enrollment is unsatisfactory.  
• 
Submission of knowingly false information from the study site to Sponsor or regulatory 
authorities. 
• 
Upon instruction by local or other regulatory, or oversight authority.  
 
The Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the Sponsor, IRB and/or FDA. 
 
 HANDLING PARTICIPANT DISCONTINUATION FROM STUDY 
 
When an individual discontinues participation in the study, the reason the participant is no 
longer participating, the study name, IRB study number, and the date of discontinuation must be 
documented in the participant’s medical record.  The change in study status must be 
documented in the appropriate trial management system (e.g., eCRIS) within 24 hours from 
time of participant discontinuation.  For all other reasons for discontinuation from the study 
treatment phase, the participant should return to the clinic for the end of treatment (EOT) visit 
according to Section 8.  
 
 Participant replacement 
 
  If after enrollment, any participant found to not fulfill any inclusion/exclusion criteria (per 
Sections 4.1 and 4.2), which could adversely affect safety or efficacy evaluation of that 
individual, may be replaced after discussion with the Principal Investigator.  A participant who 
receives FOLFIRINOX for less than 80% of the days during their treatment cycle and 
discontinues the study during this initial stage of treatment will not be evaluable for efficacy, and 
will be replaced by another participant.  
 
 
LOST TO FOLLOW-UP 
 
Lost to follow-up is defined by the inability to reach the participant after a minimum of three (3) 
documented phone calls, faxes, emails, and/or a registered mail letter.  The investigator should 
show "due diligence" by documenting in the source documents the steps taken to contact the 
participant.  If it is determined that the participant has died, the site may use permissible local 
methods to obtain date and cause of death. 
 
6. STUDY INTERVENTION 
 
A list of the adverse events and potential risks associated with the study intervention 
administered in this study can be found in Section 10.4, Adverse Events.  
 
 
FLUOROURACIL 
 
Fluorouracil (5-fluorouracil; 5-FU; Adrucil™; Carac™; Efudex™, Efudix™) is a fluorinated 
pyrimidine antimetabolite that is metabolized intracellularly to its active form, fluorouridine 
monophosphate (FdUMP). The active form inhibits DNA synthesis by inhibiting thymidylate 
synthetase and the normal production of thymidine. Effects on RNA (incorporation into RNA and 
RNA inhibition) occur especially with bolus administration. Fluorouracil is cell cycle phase-
specific (S-phase). Please refer to package insert for additional detail. 
 

 
41 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 ACQUISITION 
 
5-FU will be both supplied and prepared by OHSU pharmacy per manufacturer instructions. 
 
 FORMULATION 
 
5-FU is provided as a sterile, non-pyrogenic injectable solution for intravenous administration 
(50 mg/ml vial).  
 
 STORAGE AND STABILITY 
 
5-FU is stored at room temperature 15° to 30°C and protected from light. 5-FU IV admixtures 
(50 to 1000 mL NS or D5W) or (undiluted solutions in syringes) are stable for 72 hours at room 
temperature. 
 
 COMPATIBILITY 
 
Broad compatibility. Please refer to package insert.  
 
 HANDLING 
 
Appropriate care should be exercised in the handling and preparation of 5-FU infusion solutions. 
 
 PREPARATION 
 
5-FU is supplied ready for injection.  
 
 ADMINISTRATION 
 
5-FU is delivered by IV infusion per institutional standards.  
 
 SPECIAL CONSIDERATION FOR ADMINISTRATION 
 
Injection should be administered only intravenously, using care to avoid extravasation. 
 
 
 
FOLINIC ACID 
 
Also known as calcium folinate, citrovorum factor, Leucovorin® (Pfizer).  
 
Folinic acid is a reduced form of folic acid. As part of the FOLFIRINOX regimen, folinic acid is 
used to enhance the activity of 5-FU by binding to the enzyme thymidylate synthetase and 
decreasing intracellular levels of thymidylate. Please refer to package insert for additional 
details. 
 
 ACQUISITION 
 
Folinic acid will be both supplied and prepared by OHSU pharmacy per manufacturer 
instructions. 
 
 FORMULATION 
 

 
42 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Folinic acid is supplied as lyophilized powder for injection in 50 mg, 100 mg, and 200 mg vials. 
 
 STORAGE AND STABILITY 
 
Folinic acid injection, powder, lyophilized, for solution:  Store vials at 20° to 25°C (68° to 77° F). 
Protect from light. 
Folinic acid solution for injection: Store in refrigerator 2° to 8°C (36° to 46°F). Protect from light.  
 
 COMPATIBILITY 
 
Can be diluted in D5W, lactated ringers, water (sterile or bacteriostatic). 
 
 HANDLING 
 
No special handling required under conditions of normal product use. Follow institutional and 
manufacturer guidelines.  
 
 PREPARATION 
 
Each 50, 100, and 200 mg vial of folinic acid for injection when reconstituted with 5, 10, and 20 
mL, respectively, of sterile diluent yields a leucovorin concentration of 10 mg/ml. Folinic acid for 
Injection contains no preservative, inactive ingredient is Sodium Chloride, USP, added to adjust 
tonicity. Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP 
(benzyl alcohol preserved), or Sterile Water for Injection, USP. When reconstituted with 
Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days. If the 
product is reconstituted with Sterile Water for Injection, USP, use immediately and discard any 
unused portion. 
 
 ADMINISTRATION 
 
Administer immediately if reconstituted with sterile water for injection. Administer IV at maximum 
rate of 160 mg/min. 
 
 SPECIAL CONSIDERATION FOR ADMINISTRATION 
 
Do not administer the injectable product intrathecally. Do not mix with 5-FU in the same infusion 
as a precipitate may form. 
 
 
IRINOTECAN 
 
Also known as camptothecin-11; CPT-11; U-101440E, or Camptosar® (Pfizer).  
 
Irinotecan is a semi-synthetic derivative of camptothecin, an alkaloid extract from Camptotheca 
acuminata. Camptothecin and its analogue belong to the class of topoisomerase I inhibitors. 
Irinotecan is metabolized to its active form, SN38, in the presence of hepatic or gastrointestinal 
carboxylesterase. Irinotecan and its active metabolite, SN-38, bind to the topoisomerase DNA 
complex, preventing re-ligation of the single-strand breaks in the DNA molecule. The drug and 
its active metabolite exert their cytotoxic effects during the S-phase of cell cycle. Please see 
package insert for additional details.  
 

 
43 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 ACQUISITION 
 
Irinotecan will be both supplied and prepared by OHSU pharmacy per manufacturer 
instructions. 
 
 FORMULATION, APPEARANCE, PACKAGING AND LABELING 
 
Irinotecan is provided as a sterile, IV solution (20 mg/ml).  
 
 PRODUCT STORAGE AND STABILITY 
 
Solution is stable at room temperature and ambient fluorescent light for up to 24 hours. Solution 
diluted in D5W is stable for 48 hours when refrigerated and protected from light; use within 24 
hours. Do not refrigerate solutions diluted with NS. Use within 4 hours if solution is kept at room 
temperature. Do not freeze reconstituted of diluted solutions. Use solution immediately after 
reconstitution if possible. Complete infusion within 12 hours (if kept at room temperature) or 24 
hours (if kept refrigerated) if reconstitution and dilution are performed under strict aseptic 
conditions. 
 
 COMPATIBILITY 
 
Compatible with D5W (D5W-Dextrose 5%).  
 
 HANDLING 
 
Care should be exercised in the handling and preparation of infusion solutions prepared from 
irinotecan. The use of double gloves and gown is recommended. If a solution of irinotecan 
contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan 
contacts the mucous membranes, flush thoroughly with water. 
 
 PREPARATION 
 
Irinotecan is supplied as a sterile, pale yellow, clear, aqueous solution, and can be reconstituted 
in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final 
concentration range of 0.12 mg/mL to 2.8 mg/mL. 
 
 ADMINISTRATION 
 
Irinotecan is delivered by IV infusion per institutional standards. 
 
 SPECIAL CONSIDERATION FOR ADMINISTRATION 
 
Contraindicated in patients with a known hypersensitivity to the drug or its excipients. 
 
 
OXALIPLATIN 
 
Oxaliplatin, also known as 1-OHP; L-OHP; oxalatoplatin; oxaliplatinum, or Eloxatin® (Sanofi 
Aventis). 
  
Oxaliplatin is a platinum alkylating agent, containing platinum complexed to oxalate and 
diaminocyclohexane complex. Platinum complexes are formed intracellularly and inhibit 

 
44 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
DNA synthesis through covalent binding of DNA molecules to form intra- and inter-strand DNA 
cross-links. Oxaliplatin-induced cytotoxicity is cell-cycle nonspecific, and considered a radiation-
sensitizing agent. Please refer to package insert for additional details.  
 
 ACQUISITION 
 
Oxaliplatin will be both supplied and prepared by OHSU pharmacy per manufacturer 
instructions. 
 
 FORMULATION, APPEARANCE, PACKAGING AND LABELING 
 
Oxaliplatin is provided as a sterile, preservative-free lyophilized powder.  
 
 PRODUCT STORAGE AND STABILITY 
 
After final dilution, the Oxaliplatin shelf life is 6 hours at room temperature [20° to 25°C] or up to 
24 hours under refrigeration [2° to 8°C]. Unopened vials should be stored at 15-30°C, and 
protected from light. 
 
 COMPATIBILITY 
 
Compatible with D5W (D5W-Dextrose 5%).  
 
Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic 
solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously 
through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, 
USP prior to administration of any concomitant medication. Oxaliplatin should always be 
administered before fluorouracil.  
 
 HANDLING 
 
Care should be exercised in the handling and preparation of infusion solutions prepared from 
Oxaliplatin Injection. The use of gloves is recommended. If a solution of oxaliplatin contacts the 
skin, wash the skin immediately and thoroughly with soap and water. If oxaliplatin contacts the 
mucous membranes, flush thoroughly with water. 
 
 PREPARATION 
 
Oxaliplatin reconstituted in water or 5% Dextrose. 
 
 ADMINISTRATION 
 
Oxaliplatin is delivered by IV infusion per institutional standards. 
 
 SPECIAL CONSIDERATION FOR ADMINISTRATION 
 
Increasing infusion time to 6 hours may decrease acute toxicity such as pharyngolaryngeal 
dysesthesia. Oxaliplatin may be administered at the same time as leucovorin. 
 
6.5 
GEMCITABINE 
 

 
45 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Gemcitabine is nucleoside analogue that replaces cytidine, during DNA replication. That 
process arrests tumor growth, as only one additional nucleoside can be attached to the "faulty" 
nucleoside, resulting in apoptosis. Please refer to package insert for additional detail. 
 
 ACQUISITION 
 
Gemcitabine will be both supplied and prepared by OHSU pharmacy per manufacturer 
instructions. 
 
 FORMULATION, APPEARANCE, PACKAGING AND LABELING 
 
Gemcitabine HCl is available as a solution for intravenous administration in several formats: 38 
mg /1 ml, 100 mg /1 ml.  
 
 PRODUCT STORAGE AND STABILITY 
 
Store unopened vials at a controlled room temperature between 20 and 25°C (68 and 77°F), 
with excursions permitted between 15 and 30 degrees C (59 and 86°F) 
 
 COMPATIBILITY 
 
Gemcitabine is compatible with D5W (Dextrose 5% in water) or NS (Normal saline (Sodium 
chloride 0.9%)).  
 
 HANDLING 
 
Use appropriate precautions for receiving, handling, administration, and disposal.  Gloves 
(single) should be worn during receiving, unpacking, and placing in storage. 
 
 PREPARATION 
 
May dilute reconstituted drug in normal saline for IV infusion, resulting in a minimum final 
concentration of at least 0.1 mg/mL. 
 
 ADMINISTRATION 
 
Gemcitabine should be given by IV infusion according to institutional standards (approximately 
30 -60 minutes). 
 
6.6 
NAB-PACLITAXEL 
 
Paclitaxel is the active ingredient in the nanoparticle albumin-bound (nab) nab-paclitaxel.  
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin 
dimers and stabilizes microtubules by preventing depolymerization, which interferes with the 
normal dynamic reorganization of the microtubule network required for interphase and mitotic 
functions.  Please refer to package insert for additional detail. 
 
 ACQUISITION 
 
Nab-paclitaxel will be both supplied and prepared by OHSU pharmacy per manufacturer 
instructions. 

 
46 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
 FORMULATION, APPEARANCE, PACKAGING AND LABELING 
 
Nab-paclitaxel is presented in single-use vials containing 100 mg of paclitaxel, and are 
individually packaged in a carton. 
 
 PRODUCT STORAGE AND STABILITY 
 
Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package 
to protect from bright light 
 
 COMPATIBILITY 
 
Do not admix with other drugs. 
 
 HANDLING 
 
Care should be exercised in the handling and preparation of infusion solutions prepared from 
nab-paclitaxel. The use of double gloves and gown is recommended. If a solution of nab-
paclitaxel contacts the skin, wash the skin immediately and thoroughly with soap and water. If 
nab-paclitaxel contacts the mucous membranes, flush thoroughly with water. 
 
 PREPARATION 
 
Nab-paclitaxel should be prepared according to manufacturer instructions.  The drug agent can 
be reconstituted by slowly injecting 20 mL of 0.9% Sodium Chloride Injection, USP, over a 
minimum of 1 minute, using the sterile syringe to direct the solution flow onto the inside wall of 
the vial.  Allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the 
lyophilized cake/powder.  Gently swirl and/or invert the vial slowly for at least 2 minutes until 
complete dissolution of any cake/powder occurs. Avoid generation of foam.  No further dilution 
is required after reconstitution. Transfer reconstituted drug to an empty, sterile IV PVC or non-
PVC infusion bag. 
 
 ADMINISTRATION 
 
Nab-paclitaxel should be IV infused according to institutional standards (approximately 30 – 40 
minutes.  When administered as part of a combination chemotherapy regimen with gemcitabine, 
nab-paclitaxel should be given first, followed immediately by gemcitabine. 
 
 SPECIAL CONSIDERATION FOR ADMINISTRATION 
 
Do not substitute nab-paclitaxel for or with other paclitaxel formulations. 
 
6.7 
CAPECITABINE  
 
Capecitabine is an orally available fluoropyrimidine carbamate with antineoplastic activity. The 
drug precursor, 5’-deoxy-5-fluorouridine (5’-DFUR), is converted to 5FU. 
 
 ACQUISITION 
 
Capecitabine will be both supplied and prepared by OHSU pharmacy per manufacturer 

 
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instructions. 
 
 FORMULATION 
 
Capecitabine is supplied as biconvex, oblong film-coated tablets for oral administration. Each 
light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 
500 mg capecitabine. The inactive ingredients in capecitabine include: anhydrous lactose, 
croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium 
stearate and purified water. The peach or light peach film coating contains hydroxypropyl 
methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides. 
 
 STORAGE AND STABILITY 
 
Store tightly closed at a controlled room temperature of 25°C (77°F), with excursions permitted 
between 15 and 30°C (59 and 86°F). 
 
 COMPATIBILITY 
 
Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 
20ºC.   
 
 HANDLING 
 
Use appropriate precautions for receiving, handling, administration, and disposal.  Gloves 
(single) should be worn during receiving, unpacking, and placing in storage. 
 
 PREPARATION 
 
None. 
 
 ADMINISTRATION 
 
Capecitabine will be self-administered by the participant and should be taken with water within 
approximately 30 minutes after a meal.  The tablets should be swallowed whole and neither 
crushed or cut.  Missed or vomited doses will not be made up. 
 
6.8 
LOSARTAN 
 
Losartan is an angiotensin II receptor (type AT1) antagonist.  Please refer to package insert for 
additional detail. 
 
 ACQUISITION 
 
Losartan will be both supplied and dispensed by OHSU pharmacy. 
 
 FORMULATION, APPEARANCE, PACKAGING AND LABELING 
 
Losartan potassium is a white to off-white free-flowing crystalline powder available as tablets for 
oral administration containing either 25 mg, 50 mg or 100 mg of losartan potassium and the 
following inactive ingredients: microcrystalline cellulose, lactose hydrous, pregelatinized starch, 
magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide. 

 
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PI: Charles Lopez MD, PhD 
 
 PRODUCT STORAGE AND STABILITY 
 
Tablets should be stored at 59°F to 86°F (15°C to 30°C), and kept in a tightly closed container 
that protects the medicine from light.  
 
 HANDLING 
 
National Institute for Occupational Safety and Health (NIOSH) recommends the use of single 
gloves by anyone handling intact tablets or capsules or administering from a unit-dose package. 
 
 PREPARATION 
 
None. 
 
 ADMINISTRATION 
 
Losartan will be self-administered by the participant and may given with or without food.  Missed 
or vomited doses will not be made up. Participants will receive instruction on how to administer 
the study drug from a physician, clinical research nurse, or other designated, qualified 
healthcare provider. At each visit the Investigators seeing the participants ask directly whether r 
not the participant has been taking the study agent as prescribed and if any doses have been 
missed. This is then documented in the participant’s research note and added into the office 
visit note for that cycle.   
 
 
ACCOUNTABILITY (ALL STUDY AGENTS) 
 
Responsibility for drug accountability at the study site rests with the Investigator; however, the 
Investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
designee. Inventory and accountability records must be maintained and readily available for 
inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities or other oversight bodies 
 
 
DESTRUCTION AND RETURN (ALL STUDY AGENTS) 
 
At the end of each treatment, unused supplies of oxaliplatin should be destroyed according to 
institutional policies. 
 
7. TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks associated with study therapies are described in Section 10.4.  No other investigational 
agents or therapies other than those described herein may be administered with the intent to 
treat the participant's malignancy.   
 
7.1 
DOSAGE AND ADMINISTRATION 
 
All systemic chemotherapy and radiation therapy will be administered in accordance with 
institutional standards.  The mFOLFIRINOX (Table 4) and GA (Table 5) regimens described in 
this protocol are provided as a reference only, and the exact dosing and frequency is at the 
discretion of the treating oncologist. Recommended modifications to the mFOLFIRINOX and GA 

 
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dosing are described in Sections 7.2.1 and 7.2.2, respectively.  The exact modifications to these 
treatment regimens are, however, at the discretion of the treating oncologist in accordance with 
intuitional standards.  The actual number of mFOLFIRINOX and/or GA treatment cycles 
administered, along with associated dosing should be recorded for each participant. 
 
 MFOLFIRINOX 
 
Starting on Cycle 1 Day 1, participants will initiate the mFOLFIRINOX as recommended in 
Table 4.  Each course of mFOLFIRINOX is administered as a 14-day cycle.  Participants are 
planned to receive approximately 2 months of mFOLFIRINOX (approximately 4 cycles) before 
disease restaging (Re-stage I).  Absent disease progression or failure to respond to 
mFOLFIRINOX (as described in Section 3.1), participants will proceed to receive an additional 2 
months of mFOLFIRINOX (approximately 4 cycles), for a total of approximately 4 months of 
mFOLFIRINOX (i.e., approximately 8 cycles), after which they will be undergo disease restaging 
(Re-stage II).  A reduction or increase in the total number of planned mFOLFIRINOX treatment 
cycles is permitted at the discretion of the treating physician.  The total number of 
mFOLFIRINOX cycles received must be recorded in the appropriate eCRF. 
 
Table 4. Recommended mFOLFIRINOX Treatment regimen* 
Oxaliplatin 
85 mg /m² 
IV over ~2 hours 
Day 1 
Then, 
Folinic acid  
400 mg /m² 
IV over ~2 hours 
Day 1 
approximately 30 minutes after starting folinic acid, give: 
Irinotecan 
150 mg /m² 
IV over ~90 minutes, concurrently with 
folinic acid 
Day 1 
Then, 
Fluorouracil 
2400 mg /m² 
IV continuous infusion over ~46 hours Start on Day 1 
* The mFOLFIRINOX regimen is be administered per institutional standards. Per the treating physician, the 
individual dose and frequency of one (or more) drug agents comprising the mFOLFIRINOX regimen may be 
reduced or omitted if there is concern over toxicity or other warranting medical concerns. 
 
 GEMCITABINE AND NAB-PACLITAXEL (GA) 
 
Per criteria described in Section 3.1, if at Re-stage I, a switch in treatment from mFOLFIRINOX 
to GA is warranted, participants will start GA in a manner consistent with institutional standards 
(Table 5).  Each GA treatment cycle is 28 days.  Starting on Day 1, participants are planned to 
receive approximately 2 months of GA (approximately 2 cycles), after which they will be 
undergo disease restaging (Restage II).  Treatment should only be initiated if a participant has 
an ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L and other toxicities ≤ grade 2 or as described in 
Section 7.2.2.  Reduced doses should not be escalated.  Recommended GA dose modification 
guidelines to manage toxicities are described in Section 7.2.2.  
 
In general, the switch to GA should occur after Re-stage I; however, treatment with GA may 
occur earlier if, per the discretion of the treating physician, a participant demonstrates toxicity or 
inability to tolerate mFOLFIRINOX without needing to be presented at a TB conference.  In such 
cases, the GA treatment may be extended beyond the planned 2 months of therapy.  The total 
number of GA cycles received must be recorded in the appropriate eCRF. 
 
Table 5. GA Treatment regimen* 
nab-Paclitaxel 
125 mg /m² 
IV 
Days 1, 8, 15 

 
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PI: Charles Lopez MD, PhD 
Do not substitute for or with other paclitaxel formulations. 
Gemcitabine 
1000 mg /m² 
IV 
Days 1, 8, 15 
* The GA regimen is be administered per institutional standards. Per the treating physician, the individual dose and 
frequency of one (or more) drug agents comprising the GA regimen may be reduced or omitted if there is concern 
over toxicity or other warranting medical concerns. 
 
 LOSARTAN 
 
Starting on Cycle 1, losartan may be administered at a starting dose of 25 mg PO QD for the 
first 2 weeks (i.e., Day 1 - 14) of initiating study intervention.  Participants will have blood 
pressure monitored as shown in schedule of events. Participants currently receiving an 
angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) will 
remain eligible for study participation. In such cases, losartan will not be assigned as part of the 
study intervention. These participants will continue to receive their ACE inhibitor or ARB per 
standard-of-care. The ACE inhibitor or ARB type should be recorded as a concomitant 
medication (including dose and frequency). Provided that by Cycle 2 Day 1, participants 
maintain a resting systolic BP >100 mm Hg, the dose of losartan will be increased to 50 mg PO 
QD.  Losartan may be administered continuously throughout their assigned systemic 
chemotherapy as well as any RT that may be administered per the recommendation of the 
multi-disciplinary tumor board.  Losartan will be discontinued at the completion of RT (or earlier 
if the RT is not recommended).  In the event that losartan is not tolerated, the dose may be held 
or reduced as described in Section 7.2.5.  Participants that discontinue losartan during the 
course of the study will remain eligible to continue on-study.  
 
7.2 
DOSING DELAYS AND MODIFICATIONS 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
(i.e., elective surgery, unrelated medical events, vacation, and holidays) not related to study 
therapy.  Participants should be placed back on study therapy within 4 weeks of the scheduled 
interruption unless otherwise discussed with the investigator.  The reason for interruption should 
be documented in the participant's study record. 
 
 RECOMMENDED MFOLFIRINOX TOXICITY MANAGEMENT 
 
All toxicities observed during the course of mFOLFIRINOX treatment regimens will managed 
according to institutional standards.  Supportive care measures are described in Section 7.7.  
The dosing levels described in Table 6 are provided as general recommendations, but any 
changes to the FOLFIRINOX regimen is ultimately at the discretion of the treating physician.  All 
mFOLFIRINOX dose interruptions or modification(s) should be recorded.   
 
Table 6. Recommended mFOLFIRINOX Dose Levels 
Drug agent 
Starting Dose*  
1st Dose reduction  
2nd Dose reduction) 
Irinotecan 
150 mg/m2 
120 mg/m2 
-- 
Oxaliplatin 
85 mg/m2 
60 mg/m2 
-- 
Fluorouracil infusion 
2400 mg/m2 
75% 
25% 
*Lower starting doses for any individual drug agent are at the discretion of the treating physician in 
accordance with institutional standards.  
 
New cycles of mFOLFIRINOX should not be started until platelets ≥ 75 x 109/L and ANC ≥ 1.5 x 
109/L, recovery from diarrhea (to baseline without antidiarrheal [e.g., loperamide] for at least 24 
hours), and other non-hematologic toxicities have recovered to ≤ grade 2.  Doses should be 

 
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PI: Charles Lopez MD, PhD 
adjusted based on the worst preceding toxicity.  
 
The mFOLFIRINOX dose should not be re-escalated if reduced for toxicity, and the regimen 
may be discontinued if toxicity recurs after 2 dose reductions.  Refer to Table 7 for 
recommended management of mFOLFIRINOX toxicities.  
 
Note: Tables 7, 8 and 9. Recommended Dose Modifications for mFOLFIRINOX Toxicities will 
be followed for the first protocol cycle, if SOC chemotherapy is administered prior to enrollment 
 
Table 7. Recommended Dose Modifications for mFOLFIRINOX Toxicities 
Toxicity 
Occurrence 
Irinotecan 
Oxaliplatin 
Flurouracil 
Neutropenia 
Delayed Day 1 treatment 
delayed for ANC <1.5 x 
109/L, OR 
Febrile neutropenia, OR 
grade 4 neutropenia >7 
days 
1st 
Reduce to 1 
dose level 
No change 
- 
2nd 
Reduce to 1 
dose level 
Reduce to 1 
dose level 
- 
Discontinue treatment if no recovery after a 2-week delay, or if there is a 
third occurrence of ANC <1.5 x 109/L on day 1 
For grade 4 neutropenia 
>7 days during treatment, 
OR febrile neutropenia, 
1st 
- 
Reduce to 1 
dose level 
Reduce to 75% 
of original dose 
2nd 
Reduce to 1 
dose level 
- 
Reduce to 75% 
of original dose 
3rd 
Discontinue 
Thrombocytopenia 
Delay in Day 1 treatment 
for platelets < 75 x 109/L  
1st 
- 
Reduce to 1 
dose level 
Reduce to 75% 
of original dose 
2nd 
Reduce to 1 
dose level 
- 
- 
Discontinue treatment if no recovery after a 2-week delay, or if there is a 
third occurrence of platelets < 75 x 109/L 
For grade 3 or 4 
thrombocytopenia during 
treatment 
1st 
- 
Reduce to 1 
dose level 
Reduce to 75% 
of original dose 
2nd  
Reduce to 1 
dose level 
- 
Reduce to 25% 
of original dose 
3rd  
Discontinue treatment 
Diarrhea 
Do not retreat with mFOLFIRINOX until resolution of diarrhea for at least 24 hours without antidiarrheal 
medication 
Diarrhea ≥ grade 3 OR 
Diarrhea with fever and/or 
≥ Grade 3 neutropenia 
1st 
Reduce to 1 
dose level 
- 
- 
2nd 
- 
Reduce to 1 
dose level 
Reduce to 75% 
of original dose 
3rd  
Discontinue treatment 
Mucositis 
Grade 3 or 4 mucositis or 
hand-foot syndrome 
- 
- 
Reduce to 25% 
of original dose 
Neurotoxicity 
persistent grade 3 
paresthesias/dysesthesias, 
OR  
transient grade 2 
symptoms lasting >7 days 
- 
- 
- 
No change 

 
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Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Table 7. Recommended Dose Modifications for mFOLFIRINOX Toxicities 
Toxicity 
Occurrence 
Irinotecan 
Oxaliplatin 
Flurouracil 
Grade 4 or persistent 
grade 3 
paresthesia/dysesthesia 
 
- 
Discontinue 
- 
Other Toxicities 
Any other toxicity ≥grade 2, except anemia and alopecia, can justify dose reduction if medically 
indicated. 
For other non-hematologic toxicities: if grade 2, hold treatment until ≤grade 1; if grade 3 or 4, hold 
treatment until ≤grade 2. 
 
In the event of hepatic or renal impairment, mFOLFIRINOX may be managed according to 
recommendations described in Table 8 and Table 9, respectively.  
 
Table 8. Recommended Dose Modifications for mFOLFIRINOX-related Hepatic Toxicities 
Transaminases 
Bilirubin† 
Irinotecan 
Oxaliplatin 
5FU 
1-1.5 X ULN or Gilbert's 
Consider dose 
reduction 
No change 
No change 
> 3 X ULN* 
>1.5-4 X ULN 
Omit 
No change 
No change 
> 4 X ULN 
Omit 
No change 
Omit 
* or 5 X ULN with liver metastases 
† If bilirubin values increases, consider investigating for reversible causes such as biliary obstruction and 
reevaluate after stent. 
 
Table 9. Recommended Dose Modifications for mFOLFIRINOX-related Renal Impairment 
Creatinine 
Clearance (mL/min) 
Oxaliplatin 
(% previous dose) 
Fluorouracil 
(% previous dose) 
Irinotecan 
(% previous dose) 
>60 
No change 
No change 
No change 
>30-60 
Caution 
No change 
No change 
10-30 
Discontinue 
Consider dose reduction 
Caution 
<10 
Discontinue 
Consider dose reduction 
Caution 
 
 RECOMMENDED GA TOXICITY MANAGEMENT 
 
All toxicities observed during the course of GA treatment regimens will managed according to 
institutional standards.  Supportive care measures are described in Section 7.7.  The dosing 
levels described in Table 10 are provided as general recommendations, but any changes to the 
GA regimen is ultimately at the discretion of the treating physician.  All GA dose interruptions or 
modification(s) should be recorded in the appropriate electronic case report form (eCRF).   
 
Table 10. Recommended GA Dose Levels 
Drug agent 
Starting Dose  
1st Dose reduction  
2nd Dose reduction) 
nab-paclitaxel (mg/m2) 
125 
100 
75 
gemcitabine (mg/m2) 
1000 
800 
600 
 
Participants should be discontinued from study therapy if there is any need for further reductions 
of nab-paclitaxel or gemcitabine that is required beyond the 2 allowable dose reductions shown 
in Table 10.  Refer to Table 11 for recommended management of GA toxicities. 
 
Table 11. Recommended Dose Modifications for GA Toxicities 
Toxicity  
Management 

 
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Version Number: 2.4 
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PI: Charles Lopez MD, PhD 
Table 11. Recommended Dose Modifications for GA Toxicities 
nab-Paclitaxel dose 
Gemcitabine dose 
Grade 3 or 4 febrile neutropenia 
Hold until afebrile and ANC ≥ 1.5 x 109/L, then ↓1 dose level 
Grade 2 or 3 skin toxicity 
Reduce 1 dose level and 
continue; discontinue if 
persists 
Reduce 1 dose level and 
continue; discontinue if persists 
Grade 3 or 4 sensory neuropathy 
Hold until ≤ grade 1, then 
Reduce 1 dose level OR 
consider discontinuing for 
Grade 4. 
No change 
Grade 3 other toxicity, including 
mucositis, diarrhea (except 
nausea/vomiting/alopecia) 
Hold until ≤ grade 1, 
then Reduce 1 dose level 
Hold until ≤ grade 1, 
then Reduce 1 dose level 
Grade 4 other toxicity or any cystoid 
macular edema 
Discontinue 
Discontinue 
Pneumonitis 
Hold and investigate; discontinue if confirmed. 
 
 HEMATOLOGIC DOSE MODIFICATIONS DURING DAYS 8 AND 15 OF CYCLE 
 
Omitted doses during the cycle will not be made up. Note day 15 dose modifications depend on 
day 8 dosing. 
 
Table 12. Recommended Dose Modifications for GA-related Hematological Toxicities 
Day 8 
counts x 109/L 
Day 8 
nab-Paclitaxel and 
Gemcitabine doses 
Day 15 
counts x 109/L 
Day 15 
nab-Paclitaxel and 
Gemcitabine doses 
ANC ≥ 1 and 
platelets ≥ 75 
Day 1 dose 
If Day 8 dose unchanged from Day 1: 
ANC ≥ 1 and platelets ≥ 75 
DAY 1 DOSE 
ANC 0.5-0.99 or platelets 
50-74 
DAY 1 DOSE, add G-CSFa 
ANC < 0.5 or platelets < 50 
OMIT 
ANC 0.5- 0.99 or 
platelets 50-74 
Reduce 1 dose level If Day 8 dose was REDUCED: 
ANC ≥ 1 and platelets ≥ 75 
DAY 1 DOSE, add G-CSFa 
ANC 0.5-0.99 or platelets 
50-74 
DAY 8 DOSE, add G-CSFa 
ANC < 0.5 or platelets < 50 
OMIT 
Day 8  
counts x 109/L 
Day 8 nab-paclitaxel 
and gemcitabine 
doses 
Day 15 counts x 109/L 
Day 15 nab-paclitaxel 
and gemcitabine doses 
ANC < 0.5 or 
platelets < 50 
Omit for Day 8 
If Day 8 dose was OMITTED: 
ANC ≥ 1 and platelets ≥ 75 
Day 1 dose, add G-CSFa 
ANC 0.5-0.99 or platelets 
50-74 
Reduce 1 DOSE LEVEL, add 
G-CSFa 
ANC < 0.5 or platelets < 50 
OMIT 
a If G-CSF is not available, suggest reducing an additional dose level. G-CSF is optional for isolated 
thrombocytopenia. 
 
 HEPATIC IMPAIRMENT 
 
Participants with hepatic impairment may be at increased risk of myelosuppression and should 
be closely monitored. Nab-paclitaxel is not recommended in patients with metastatic pancreatic 
cancer who have moderate to severe hepatic impairment. 
 

 
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PI: Charles Lopez MD, PhD 
Table 13. Recommended Dose Modifications for GA-related Hepatic Toxicities 
Bilirubin 
AST 
Nab-paclitaxel* 
(% previous dose - 
suggested) 
Gemcitabine* 
(% previous dose - 
suggested) 
>1 to ≤ 1.5 x ULN 
and 
≤ 10 x ULN 
100% 
100% 
>1.5 to ≤ 5 x ULN 
and 
≤ 10 x ULN 
Insufficient data; 
discontinue 
Reduce to 75% of original dose 
> 5 x ULN 
or 
> 10 x ULN 
Discontinue 
Discontinue 
*Based on clinical judgment of treating physician – less conservative adjustments may be considered if hepatic 
changes are secondary to disease rather than hepatic cirrhosis or hepatitis.  
 
Table 14. Recommended Dose Modifications for GA-related Renal Toxicities 
Creatinine Clearance 
(mL/min) 
Nab-paclitaxel* 
(% previous dose - suggested) 
Gemcitabine* 
(% previous dose –suggested) 
≥ 30 to < 90 
100% 
100% 
< 30 
Discontinue 
Discontinue 
*Based on clinical judgment of treating physician 
 
 RECOMMENDED LOSARTAN TOXICITY MANAGEMENT 
 
Table 15. Recommended Losartan Dose Levels 
Dose Level (DL) 
Losartan 
DL1Starting Dose  
25 mg PO QD 
DL2 maintenance  
50 mg PO QD  
 
 Cycle 1  
 
Participants will initiate losartan at a dose of 25 mg PO QD (Table 14).  Participants 
experiencing symptoms of hypotension (e.g., lightheaded) and or have systolic BP <100 mm Hg 
during this first 2-weeks (based on any un/scheduled vitals assessment) will have losartan 
treatment interrupted for 7 (± 2) days.  If systolic BP remains <100 mm Hg after 1 week (i.e., by 
Cycle 2 Day 1), losartan should be discontinued.   
 
 Cycle 2+ 
 
Participants experiencing symptoms of hypotension (e.g., lightheaded) and or have an average 
systolic BP <100 mm Hg while receiving losartan at 50 mg PO QD will have losartan treatment 
interrupted for 7 (± 4) days.  Losartan dosing should be managed as follows: 
 
1. If other causes for hypotension are identified (e.g., infection, dehydration), then losartan 
should be interrupted until other cause is resolved.  After which, losartan may be re-initiated 
at 25 mg PO QD, and if after 1 week the systolic BP is sustained >100 mm Hg, then the 
dose may be increased to 50 mg PO QD.  
 
2. Absent an alternative explanation for hypotension, if, after the 1 week interruption, the 
participant’s average systolic BP is >100 mm Hg, then losartan may be re-initiated at 25 mg 
PO QD for 7 days, and if the systolic BP remains above 100 mm Hg after a period 7 (± 2) 
days, then the dose may be increased to 50 mg PO QD.  At the discretion of treating 
physician, and in consultation with the investigator, continuous dosing of losartan may be 
maintained at 25 mg PO QD.  
 

 
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3. Absent an alternative explanation for hypotension, if, after the 1 week interruption, the 
participant experiences sustained lightheadedness or sustained systolic BP <100 mm Hg, 
then losartan should be permanently discontinued. 
 
4. Absent an alternative explanation for hypotension, any participant that requires more than 2 
consecutive dose interruptions for hypotension (average systolic BP is <100 mm Hg), then 
losartan will be permanently discontinued.  
 
Note that any participant discontinuing losartan may still continue to remain on-study.   
 
7.3 
RADIATION THERAPY 
 
After completing approximately 4 months (~8 cycles) of systemic chemotherapy (i.e., 
FOLFIRINOX or GA), participants will have their disease restaged (Re-stage II).  The protocol 
defined algorithm for participants receiving RT is described in Section 3.1.  For participants with 
tumor vessel involvement at baseline, if findings at Re-stage II shows resolution of tumor 
contact with pancreatic vasculature, then participants may receive short-course RT as described 
in Section 7.3.1.1.  Participants with tumor vessel involvement that is persistent at Re-stage II 
evaluation may receive long-course RT with or without a radiosensitizer as described in Section 
7.3.1.2.   
 
Participants with any clinically-relevant condition that would contraindicate RT may, in opinion of 
the treating physician, proceed to undergo surgery (if eligible).  Other deviations from the 
protocol defined algorithm for choice of RT is permitted at the discretion of the treating radiation 
oncologist or recommendation of the multi-disciplinary tumor board.  The reason for not 
following the protocol defined RT algorithm should be recorded.  
 
All RT treatment will be administered between Monday and Friday, and will not occur on 
Saturdays, Sundays or holidays. There should be no more than a 14 day interruption between 
the planned administration of each fraction; however, interruptions longer than this will not be 
considered deviations, and participants may continue to with planned RT if deemed appropriate 
based on the clinical judgement of the treating radiation oncologist.  Interruptions to planned RT 
greater than 14 days should be recorded.  A delayed start to RT beyond after chemotherapy 
beyond 4 weeks is permitted at the discretion of the principal investigator.   
 
 DOSE SPECIFICATIONS 
 
All RT will be carried out in accordance with institutional standards. The choice of external 
radiation therapy (conformal 3-D, intensity modulated radiation therapy [IMRT], volumetric 
modulated arc therapy (VMAT)) is based on the discretion the treating radiation oncologist. 6MV 
or greater photons will be used.  Beam arrangement should be consistent with institutional 
practice.  
 
 Short-course RT dose specifications 
 
The prescribed dose is 30 Gy in 10 fractions of 3 Gy delivered 5 days a week. Treatment plans 
must be normalized such that 95% of the planned tumor volume (PTV) receives 30 Gy and the 
minimum dose (Dmin) to the tumor is 85% of the prescribed dose (25.5 Gy). The maximum dose 
(Dmax) to the PTV must not exceed 110% of this dose (33 Gy).   
 
 Long-course RT dose specifications 
 

 
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Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
At the discretion of the treating radiation oncologist or recommendation of the multidisciplinary 
tumor board, RT will be administered in either 15 fractions (37.5-67.5 Gy) or 25 fractions (45-50 
Gy) over 5 days a week as described in Table 15.  In both regimens, RT may be given 
concurrently with capecitabine (825 mg/m2 PO BID) or 5-FU (225 mgm2/day given as a 
continuous infusion) as described in Section 7.3.4. 
 
Table 16. Long-course RT Dose Prescriptions  
Total Prescribed Dose (Gy) Dose/Fraction (Gy) # of Fractions Schedule 
15 Fraction 
(15#) RT 
regimen 
67.5 
4.5 
15 
Daily 
45 
3 
15 
Daily 
37.5 
2.5 
15 
Daily 
25 Fraction 
(25#) RT 
regimen 
45 
1.8 
25 
Daily 
50 
2 
25 
Daily 
 
For the 15# RT regimen, the target volumes planning goals along with minimum and maximum 
doses to the PTV are described in Table 16 
 
Table 17. Dosimetric Objectives and constraints for 15# RT Regimen 
Target Volumes 
Optimal dose 
Acceptable Variation 
PTV_67.5* 
95% of the PTV must receive 99% of  
prescribed dose 
95% of PTV is covered to ≥ 95%  
Dmax must be ≤ 120% of prescribed 
dose 
Dmax is located within internal target 
volume (ITV) 
PTV_45* 
95% of the PTV must receive 99% of  
prescribed dose 
95% of PTV is covered to ≥ 95% 
Dmax is located within internal target 
volume (ITV) 
 
PTV_37.5* 
95% of the PTV must receive 99% of  
prescribed dose 
95% of PTV is covered to ≥ 95% 
Dmax is located within internal target 
volume (ITV) 
 
* Dmax is located within internal target volume (ITV) 
 
For the 25# RT regimen, the target volumes planning goals along with minimum and maximum 
doses to the PTV are described in Table 15. 
 
Table 18. Dosimetric Objectives and constraints for 25# RT Regimen 
Target Volumes 
Optimal dose 
Acceptable Variation 
PTV_45 
95% of the PTV must receive 97% of  
prescribed dose 
95% of PTV is covered to ≥ 95% 
Dmax must be ≤ 110% of the prescribed 
dose (49.5 Gy) 
Dmax is located within PTV 
Dmin must be ≥ 90% of prescribed dose 
(40.5 Gy) 
 
Dmax is located within internal target 
volume (ITV) 
 
PTV_50 
95% of the PTV must receive 95% of  
95% of PTV is covered to  ≥ 80% 

 
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Table 18. Dosimetric Objectives and constraints for 25# RT Regimen 
Target Volumes 
Optimal dose 
Acceptable Variation 
prescribed dose 
of ITV PRV bowel 
Dmax must be ≤ 120% of the prescribed 
dose (60 Gy) 
 
Dmax is located within internal target 
volume (ITV) 
 
 
 LOCALIZATION, SIMULATION AND PLANNING 
 
All simulation, planning, and treatment is to be performed in accordance with institutional 
standards. 
 
 Treatment Volumes 
 
The gross tumor volume (GTV) will be the primary tumor plus any involved regional lymph 
nodes identifiable on CT/MRI scan. 
 
The clinical target volume (CTV) will be defined as the GTV plus 0.5 cm.  The PTV will be the 
CTV plus 0.5 cm. 
 
The normal structures to be contoured are: left and right kidneys, liver, stomach, duodenum, 
small intestine, spinal cord 
 
 Treatment Planning Simulation 
 
Treatment planning will be based on a helical pancreatic CT per established institutional 
protocol and should include oral contrast to delineate the small bowel.  IV contrast can be 
included, unless contraindicated due to allergy or renal insufficiency, in which case an 
MRI scan of the abdomen or CT without contrast should be performed.   
 
Participants should be simulated (and treated) supine with arms up. Immobilization is strongly 
recommended and management of motion should follow institutional standards, including: 
• 
Breath-hold (with the use of Active Breathing Control [ABC], SDX, or similar devices)  
• 
Self-held breathing with respiratory monitoring (e.g. RPM) as a beam-hold mechanism. 
• 
Fluoroscopic/electromagnetic gating or tracking using implanted fiducial markers 
 
The normal structures to be contoured are: left and right kidneys, liver, stomach, duodenum, 
small intestine, spinal cord. If the duodenum is invaded by the tumor, the normal duodenum 
outside of this region should be contoured as the critical structure. Normal tissue dose-volume 
constraints for each of the 3 RT regimens are described in Table 18. 
 
Table 19. Normal tissue dose-volume constraints 
Regimen 
Structure 
Constraints 
Short-course 30 
Gy (10 Fractions) 
Kidney_L 
Kidney_R 
90% of the volume equivalent to one kidney ≤ 15 Gy; 
V15 ≤ 30% for each kidney  
Liver 
Mean dose ≤ 20 Gy 
Small Bowel 
Dmax to a small point of 0.03 cc must be ≤ 36 Gy. 
Stomach 
Dmax to a small point of 0.03 cc must be ≤ 36 Gy. 
Spinal cord 
Dmax to a small point of 0.03 cc must be ≤ 30 Gy. 
Duodenum 
Dmax to a small point of 0.03 cc must be ≤ 36 Gy 

 
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Table 19. Normal tissue dose-volume constraints 
Regimen 
Structure 
Constraints 
15# RT regimen 
Kidney_L 
Kidney_R 
V18 ≤ 33% for each kidney  
Liver 
Mean dose ≤ 24 Gy 
Large Bowel  
(+3-5 mm) 
Dmax to a small point of 0.03 cc must be ≤ 50 Gy 
Small Bowel 
(+3-5 mm) 
Dmax to a small point of 0.03 cc must be ≤ 40 Gy 
Stomach PRV 
(Stomach +3-5 mm) 
V37.5 Gy ≤ 40 cc; 
Dmax to a small point of 0.03 cc must be ≤ 45 Gy 
Spinal cord 
Dmax to a small point of 0.03 cc must be ≤ 30 Gy 
Duodenum PRV 
(Duodenal segments 
1 and 2 and 3-5 mm 
expansion) 
V37.5 Gy ≤ 40 cc; 
Dmax to a small point of 0.03 cc must be ≤ 45 Gy. 
Spleen 
Mean dose ≤ 6 Gy 
25# RT regimen 
Kidney_L 
Kidney_R 
V20 ≤ 33% for each kidney  
Liver 
Mean dose ≤ 28 Gy 
Small Bowel 
Dmax to a small point of 0.03 cc must be ≤ 58 Gy 
V50 Gy ≤ 10 cc 
V45 Gy ≤ 135 cc 
Stomach  
 
Dmax to a small point of 0.03 cc must be ≤ 60 Gy 
V50 Gy ≤ 5 cc 
V45 Gy ≤ 75 cc 
Spinal cord 
Dmax to a small point of 0.03 cc must be ≤ 30 Gy 
Duodenum PRV 
(Duodenal segments 
1 and 2 and 3-5 mm 
expansion) 
Dmax to a small point of 0.03 cc must be ≤ 60 Gy 
V56 Gy ≤ 5 cc 
V45 Gy ≤ 30 cc 
 
 
 QUALITY ASSURANCE 
 
Per institutional standard of care, the treating radiation oncologist will perform a RT Quality 
Assurance Review of the treatment plans prior to the participant starting their treatment. 
 
 CHEMOTHERAPY DURING RADIATION THERAPY 
 
The 15# and 25# RT regimens are intended to be administered concurrently with 5FU or 
capecitabine consistent with institutional standards.  The choice of 5FU or capecitabine is at the 
discretion of the treating oncologist.  
 
 Capecitabine 
 
Oral capecitabine should be administered at a dose of 830mg/m2 twice daily on the days that 
participants are receiving RT (i.e., Monday-Friday).  Suggested dose modification instructions 
are provided in Section 7.3.4.3. 
 
 Fluorouracil  
 
5FU continuous infusion (200 – 250 mg/m2/day) is given on the first day of radiation and 

 
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continues until completion of the planned 15# or 25# RT regimen.  The continuous infusion is 5 
or 7 days each week, depending on institutional policy.  Suggested dose modification 
instructions are provided in Section 7.3.4.3. 
 
 Recommended dose modifications for fluorouracil (5FU) or capecitabine given 
concurrently with radiation 
 
Hematologic Toxicity should be managed according to institutional standards. Recommended 
dose modification are described in Table 19. 
 
Table 20. Recommended Management of 5FU or Capecitabine Hematologic Toxicity 
Toxicity 
Recommended Dose Modification 
ANC > 1000 and platelets > 75,000 
No dose modification 
ANC 500-999 and/or platelets 50,000-
75,000 
Continue radiation. Hold 5FU or capecitabine until 
ANC > 1000 and platelets > 75,000, then resume at 
permanent 25% dose reduction. 
 
ANC < 500 and/or 
platelets < 50,000 
Hold 5FU or capecitabine and radiation until ANC > 
1000 and platelets >75,000 then resume radiation and 
restart fluorouracil at permanent 25% dose reduction. 
NOTE: Patients who have required two dose reductions and who experience a third episode of ANC < 
1000 and platelets < 75,000 can complete radiation but should not receive additional 5FU 
 
Hematologic Toxicity should be managed according to institutional standards. Recommended 
dose modification are described in Table 20.  Note that participants who experience an AE 
unrelated to study treatment (e.g., deep venous thrombosis, pulmonary embolus or non-
neutropenic infection), do not require dose modifications; rather, 5FU or capecitabine treatment 
may be interrupted and resumed after recovery from these adverse events.  Only toxicities 
related to treatment require dose modifications.   
 
Table 21. Recommended Management of 5FU or Capecitabine Non-hematologic Toxicity 
Toxicity 
Recommended Dose Modification 
Grade 3 or 4 AE, 1st occurrence 
Hold fluorouracil or capecitabine and radiation until 
toxicity has resolved to grade ≤ 2, then resume 
radiation and 5FU with a permanent 25% dose 
reduction. 
Grade 3 or 4 AE, 2nd occurrence 
Hold fluorouracil or capecitabine and radiation until 
toxicity has resolved to grade ≤ 2, then resume 
radiation and fluorouracil with a permanent 25% 
dose reduction. 
Grade 3 or 4 AE, 3rd occurrence 
 
Hold 5FU or capecitabine and radiation until toxicity 
has resolved to grade ≤ 2, then resume radiation 
and fluorouracil with a permanent 25% dose 
reduction. 
Grade 3 or 4 AE, 4th occurrence or Grade 
3 or 4 AE that persists for > 4 weeks 
Discontinue 5FU or capecitabine and radiation 
permanently 
Grade 2 Hand/Foot Syndrome 
Hold capecitabine until resolves to grade ≤ 1, then 
resume at permanent 25% dose reduction 

 
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Table 21. Recommended Management of 5FU or Capecitabine Non-hematologic Toxicity 
Toxicity 
Recommended Dose Modification 
Grade 3 Hand/Foot Syndrome 
Hold capecitabine until resolves to < grade 1, then 
resume at permanent 50% dose reduction 
NOTE: Based on the clinical judgment of the treating physician, radiation may continue when 
5FU/capecitabine is held due to toxicity associated with these drug agents  
 
7.4 
SURGERY 
 
Participants in this study are planned for complete resection based on the recommendation of 
the multidisciplinary tumor board; however, the final decision to for surgical eligibility falls to the 
judgment of the operating surgeon.  Surgical resection of the participant’s pancreatic tumor will 
be performed using standard surgical techniques (e.g., pancreaticoduodenectomy or 
pancreatectomy), and may include exploratory laparotomy to assess further assess 
resectability.  In general: 
(a) Pancreaticoduodenectomy (i.e., Whipple technique) is the recommended surgical 
technique for PDAC localized in the pancreas head and uncinate. This surgical 
technique may include skeletalization of the anterior, lateral, and posterior borders of the 
superior mesenteric artery (SMA) down to the level of the adventitia. 
(b) Distal pancreatectomy with En-bloc splenectomy is recommended for participants with 
adenocarcinoma located in the left pancreas (body or tail),   
 
In general, surgery should take place approximately 1-4 weeks following completion of RT, or 
last chemotherapy administration (if RT is omitted).  Longer delays are permitted, however, if in 
the best interest of participant’s safety.  If surgery is delayed, repeat imaging within 28 days of 
the surgery date may be requested (per standard of care or as clinically indicated) to confirm no 
distant disease precluding surgery with curative intent. 
 
Information regarding the surgery will be recorded including: 
• 
Time to surgery (from completion of RT, or last chemotherapy administration [if RT is 
omitted]),  
• 
Operation performed,  
• 
Requirement for vascular resection and reconstruction, 
• 
Completeness of the resection (R0, R1 or R2), 
• 
Duration of the operation, 
• 
Blood loss, 
• 
Length of stay 
• 
Need for re-admission within 30 days of surgery 
 
7.5 
DISCONTINUATION FROM STUDY INTERVENTION 
 
Participants MUST discontinue investigational products (and non-investigational product at the 
discretion of the investigator) for any of the following reasons: 
 
• 
Participant’s request to stop study treatment.  Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures.  The only exception to this is when a participant specifically withdraws 
consent for any further contact. 
• 
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 

 
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investigator, indicates that continued participation in the study is not in the best interest of 
the participant 
• 
Termination of the study by Sponsor-Investigator 
• 
Loss of ability to freely provide consent through imprisonment, or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness.  
• 
Disease progression in the absence of clinical benefit as determined by the Investigator. 
• 
Specific study drug discontinuation criteria described in Sections 7.2.1 and 7.2.2. 
• 
Noncompliance of the participant with protocol-mandated procedures based on the 
judgment of the Sponsor-Investigator. 
• 
Participant becomes pregnant. 
 
If a participant has not progressed following discontinuation of study drug(s), every effort should 
be made to continue to obtain radiographic tumor assessments until documented progression or 
until the participant has started alternate cancer therapy. 
 
All participants who discontinue study treatment should comply with protocol-specified follow-up 
procedures as outlined in Section 8.11.  The only exception to this requirement is when a 
participant withdraws consent for all study procedures including post-treatment study follow-up 
or loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness). 
 
If study treatment is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records and entered on 
the appropriate CRF. 
 
7.6 
TREATMENT PERIOD AND MAINTENANCE 
 
The trial intends to direct the standard of care treatment of participants to receive 
mFOLFIRINOX and/or GA (approximately 4 months), after which participants may continue 
directly to surgery, or proceed to receive short-course (approximately 1 to 3 weeks) or long-
course (approximately 4 to 8 weeks) RT that is consistent with the neoadjuvant treatment of 
resectable/borderline-resectable pancreatic cancer. These treatment decisions may be guided 
by an institutionally established multi-disciplinary tumor board if warranted. The multi-
disciplinary tumor board’s discussion of each participant’s medical case may be held in-person, 
or conducted electronically (e.g., teleconferencing, email).  At the completion of standard of care 
RT, eligible participants will proceed to undergo surgical resection (if eligible).  After surgical 
resection, all study participants will no longer be on protocol-directed therapy and will proceed to 
the end-of-treatment visit and follow-up (Section 8.7).  Participants that discontinue study 
treatment and/or do not undergo surgical resection will similarly proceed to the end-of-treatment 
visit and follow-up (Section 8.7). 
 
7.7 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Supportive measures for optimal medical care are to be given throughout the study as indicated 
by the treating physician’s assessment of the participant’s medical need and institutional and 
general medical guidelines for the care of participants receiving treatment for their PDAC.  
Medications required to treat AEs, manage cancer symptoms or concurrent diseases, or provide 

 
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supportive care are allowed in general.  These may include anti-emetics, analgesics, anti-
pyretics, anti-diarrheals, pancreatic enzyme supplements, appetite stimulants, antacids, H2-
blockers, proton pump inhibitors, anxiolytics, anti-depressants, sleep aids, and other common 
medicines as needed.  The participant must be told to notify the investigational site about any 
new medications begun after the start of the study treatment.  All medications (other than 
investigational products) and significant non-drug therapies (including vitamins, herbal 
medications, physical therapy and blood transfusions) administered during the study must be 
listed on the case report form (CRF). Expected supportive care apart of institutional pathways to 
address common reactions to treatment (e.g. atropine for acute cholinergic syndrome listed in 
the Beacon plan under PRN Medications”). Many of the agents associated with supportive care 
in this context are therefore part of the Beacon plan. These medications are reviewed before 
every chemotherapy administration. Source documentation is from the signed treatment Beacon 
plan; the conmed log is not updated again with the same information. 
 
 CLINICALLY SIGNIFICANT DEHYDRATION 
 
Intravenous fluids to maintain hydration during chemotherapy should be managed per 
institutional standard of care.  
 
 GASTROINTESTINAL  
 
Anti-emetics, anti-diarrheal agents, and acid suppressive therapies (e.g., antacids, H2 blockers, 
and proton pump inhibitors) may be prescribed per institutional guidelines.  
 
Study participants may receive anti-emetic therapy as needed during their treatment which may 
include ondansetron, prochlorperazine, haloperidol and lorazepam.  Participants may be 
premedicated for nausea and vomiting according to institutional standards.  The use of anti-
diarrheals will be administered per investigator’s discretion according to institutional standards.  
First line agents such as loperamide and tincture of opium, and/or octreotide can be utilized. 
 
 ACUTE CHOLINERGIC SYNDROME 
 
Irinotecan is associated with acute cholinergic syndrome (e.g., early diarrhea), and may be 
treated with atropine sulfate (e.g., 250 µg s.c.), unless clinically contraindicated.  Atropine may 
be administered prior to irinotecan, if indicated. 
 
 INFECTION PROPHYLAXIS 
 
The use, and choice, of prophylactic antibacterial, antifungal, and antiviral agents is 
recommended according to institutional guidelines.  Use of anti-infective agents as prophylaxis 
and treatment must be documented on the CRFs.   
 
 TREATMENT OF FEVER AND NEUTROPENIA 
 
Neutropenic fever (defined as ANC < 1000 cells/µL and known to be falling and temperature 
≥38.0°C) will be treated per institution guidelines.   
 
 GROWTH FACTOR SUPPORT 
 
Use of growth factor support to prevent neutropenia should be used as clinically indicated or at 
the treating physician’s discretion, in accordance with institutional guidelines. The choice of 

 
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growth factor is at the investigator's discretion.  Likewise, the use of an erythropoiesis-
stimulating agent is at the discretion of the treating physician.   
 
 BLOOD PRODUCTS  
 
All blood products are to be irradiated and leukocyte-reduced according to institution guidelines. 
Additionally, cytomegalovirus (CMV)-negative participants should receive CMV-negative blood 
products according to institution guidelines.  Use of transfusion support must be documented on 
the case report forms. 
 
 DYSARTHRIA 
 
Dysarthria (marble mouth) associated with irinotecan may be treated with diphenhydramine (50 
mg IV) as needed, until symptoms resolve. Diphenhydramine premedication may be given 
before initiating subsequent cycles of irinotecan.  
 
 CONTRACEPTION 
 
The study agents may cause embryo-fetal harm.  Furthermore, it is not known if these agents 
have transient adverse effects on the composition of sperm.  FOCBP and male participants 
must agree to use effective methods of contraception as described in Appendix B.   
 
 USE IN PREGNANCY 
 
If a participant inadvertently becomes pregnant while on treatment with study agents, the 
participant will immediately discontinue study therapy.  The site will contact the participant at 
least monthly and document the participant’s status until the pregnancy has been completed or 
terminated.  The site will report the outcome of the pregnancy to Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  The 
pregnancy will be recorded on the CRF and reported by the Investigator to the IRB.  If a male 
participant impregnates his female partner, the pregnancy will be recorded on the CRF and 
reported by the Investigator to the IRB. Refer to Section 10.6. 
 
 USE IN NURSING WOMEN 
 
It is unknown whether study agents or their metabolites are excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, participants who are breast-feeding are not eligible for 
enrollment.  Participants must not breast-feed while receiving protocol therapy and for 30 days 
following the last dose of protocol therapy.  
 
7.8 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
No other concomitant therapies or investigational therapies are allowed during the study. Use of 
alternative medications (herbal or botanical for anticancer purposes) is not permitted during the 
study.  
 
To prevent unwanted hepatic or gastro-intestinal toxicities while on study, participants are not 
permitted, unless at the discretion of the investigator, new over-the-counter drugs, as well as 
herbal and dietary supplements.   

 
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 5-FU 
 
• 
Initiation of 5-FU treatment regimen in patients stabilized on warfarin therapy is associated 
with marked elevations of prothrombin time and INR.  
• 
Concurrent administration of 5-FU and phenytoin may result in increased serum levels of 
phenytoin.  
• 
May increase the effects of warfarin and other anticoagulants.  
 
5-FU should be administered in conjunction with medications that may affect dihydroprimidine 
dehydrogenase activity. 
 
 OXALIPLATIN 
 
• 
May increase the effects of warfarin and other anticoagulants. 
• 
Nephrotoxic agents may increase toxicity. 
• 
Cold temperatures or cold objects can precipitate or exacerbate symptoms of acute 
peripheral neuropathy. 
o Concomitant use of ice for mucositis prophylaxis during infusion should be avoided as 
cold temperature can exacerbate acute neurological symptoms. 
 
QT prolongation and ventricular arrhythmias (including fatal Torsade de Pointes) – avoid drugs 
known to prolong the QT interval (e.g., Class Ia and III anti-arrhythmics). 
 
 IRINOTECAN 
 
• 
Irinotecan is a major substrate of cytochrome P450 CYP2B6 and CYP3A4. Risk of drug 
interactions causing decreased concentrations of irinotecan with CYP3A inducers. Risk of 
drug interactions causing increased concentrations of irinotecan with CYP3A inhibitors.  
o Avoid concomitant use of CYP3A4-inducing (e.g., rifampicin, carbamazepine, 
Phenobarbital, phenytoin) or inhibiting (e.g., ketoconazole, clarithromycin, indinavir, 
nefazodone, atazanavir, gemfibrozil) drugs. 
o Participants should also be counselled on the consumption of grapefruit, starfruit, Seville 
oranges juices or products. 
o Concomitant use of St John’s Wort is contraindicated. 
 
Prochlorperazine anti-emetic should be avoided on the same day as irinotecan treatment due to 
an increased risk of akathisia. Prochlorperazine may be taken as part of take-home regimen. 
 
 NAB-PACLITAXEL 
 
No drug interaction studies have been conducted with nab-paclitaxel, but are likely to be similar 
to those reported for paclitaxel, which is metabolized by CYP2C8 and CYP3A4. Caution is 
recommended for concomitant use of nab-paclitaxel with CYP2C8 and CYP3A4 inhibitors, 
substrates, or inducers.  
 
 CAPECITABINE 
 
Black-box warning: Participants receiving concomitant capecitabine and oral coumarin-
derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin 

 
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time) monitored frequently in order to adjust the anticoagulant dose accordingly.  A clinically 
important capecitabine-warfarin drug interaction was demonstrated in a clinical pharmacology 
trial.  Altered coagulation parameters and/or bleeding, including death, have been reported in 
patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as 
warfarin or phenprocoumon.  
 
 LOSARTAN  
 
• 
Co-administration of losartan with other drugs that raise serum potassium levels may result 
in hyperkalemia, and serum potassium in such participants should be monitored 
accordingly. 
• 
Increases in serum lithium concentrations and lithium toxicity have been reported during 
concomitant administration of lithium with angiotensin II receptor antagonists.  Serum lithium 
in such participants should be monitored accordingly. 
• 
Co-administration of NSAIDs (including selective COX-2 inhibitors) with angiotensin II 
receptor antagonists such as losartan may result in deterioration of renal function, including 
possible acute renal failure.  These effects are usually reversible, and renal function should 
be monitored periodically in participants receiving losartan and NSAID therapy. 
 
7.9 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 
• 
No concomitant therapy or investigational anti-cancer therapy is allowed during the study. 
Use of alternative medications (herbal or botanical for anticancer purposes) is not permitted 
during the study. Concomitant participation in other trials investigating supportive care 
interventions (e.g., cancer-related cachexia) is permitted per PI discretion. 
• 
Nab-paclitaxel is not recommended for use in patients with a history of interstitial lung 
disease, multiple allergies, progressive dyspnea or unproductive cough (cases of serious 
pneumonitis were reported in those treated with combination nab-paclitaxel and 
gemcitabine). 
• 
Participant is pregnant or breastfeeding. 
• 
Hypersensitivity to capecitabine or any of its components, or to 5FU 
• 
Capecitabine is contraindicated in those with severe renal impairment (i.e., CrCl < 30 
ml/min). 
• 
Dual blockade of the Renin-Angiotensin System with angiotensin receptor blockers, ACE 
inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, 
hyperkalemia, and changes in renal function (including acute renal failure) compared to 
monotherapy.  Do not co-administer aliskiren with losartan in participants with diabetes. 
 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management may be removed from the trial.  Participants 
may receive other medications that the investigator deems to be medically necessary. 
 
8. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE  
 
8.1 
STUDY-SPECIFIC PROCEDURES 
 
The timing and frequency for all study procedures is described in Schedule of Events (Section 

 
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8.11). A telehealth visit may be performed in lieu of an office visit, per PI discretion and 
institutional standards. 
 
 MEDICAL HISTORY  
 
A medical history will be obtained by the investigator or qualified designee. In addition to 
collecting information on demographics, the 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 participant’s PDAC will be recorded separately and 
not listed as medical history. 
 
 DISEASE ASSESSMENT 
 
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s PDAC. 
 
 MEDICATION HISTORY  
 
A complete medication history will be acquired concurrent with medical history.  
 
 PHYSICAL EXAMINATION  
 
Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant or advanced Registered Nurse Practitioner as local law permits 
and per institutional standards.  The physical examination to be conducted will include an 
evaluation of: general appearance; head, ears, eyes, nose, and throat; neck; skin; 
cardiovascular system; respiratory system; gastrointestinal system; lymphatic system, 
musculoskeletal system, and nervous system. All other physical exams after baseline will 
include an evaluation of any AEs, or any previously reported symptoms, or prior physical 
examination findings.  All physical examinations will also include: 
 
 Vital signs  
 
Vitals to be collected include BP, HR, temperature, and oxygen saturation by pulse oximetry.  
As part of screening, vitals should be obtained within 28 days prior to first dose of study agent.  
On day of planned treatment, vitals at baseline, should be collected prior to treatment start. 
Thereafter as indicated in schedule in Section 8.11.   
 
Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History CRF.  Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event CRF.  
 
 Height and weight  
 
Height and weight will be collected within 45 days of C1D1.  Thereafter, only weight is required. 
 
 Performance status  
 
Performance status will be determined as per assessment schedule in Section 8.11.  Refer to 
Appendix A for performance criteria. 
 

 
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 RADIOGRAPHIC OR OTHER IMAGING ASSESSMENTS  
 
Radiographic imaging for disease assessment will follow standard of care and be performed 
according to institutional guidelines.  Tumor imaging (e.g., computed tomography [CT], 
magnetic resonance imaging [MRI], or other imaging modalities such as fluorodeoxyglucose 
(18F)-positron emission tomography [PET], ultrasound) should be performed as clinically 
indicated.  Results of imaging performed while participants are enrolled in this study should be 
recorded in CRF.  
 
Initial tumor imaging must be performed within a 28-day window during screening. Scans 
performed as part of routine clinical management are acceptable for use as the screening scan 
if they are of diagnostic quality, meet the requirements specified in the imaging manual, and 
performed within a 28-day window during screening.  Initial tumor imaging may be performed up 
to 45 days prior to C1D1, at the discretion of the Principle Investigator.  After completing on-
study therapy, results of subsequent imaging assessments may be captured as part of study 
follow-up.  
 
 ELECTROCARDIOGRAM (ECG)  
 
A standard 12-lead ECG should be performed only as clinically indicated. 
 
 ADVERSE EVENT EVALUATION  
 
Toxicities and adverse experiences will be assessed at each visit using the NCI CTCAE 5.0. 
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
performance status, hematology, chemistry, coagulation, urinalysis, thyroid function, and 
pregnancy, as well as collecting of AEs at every visit. 
 
Adverse events will be monitored from the time the participant signs the study Consent Form.  
Participants will be instructed to report all AEs during the study and will be assessed for the 
occurrence of AEs throughout the study, through to end of treatment visit.  All AEs (serious and 
non-serious) must be recorded on the source documents and CRFs regardless of the 
assumption of a causal relationship with the study drug.  
 
Abnormal laboratory values will only be recorded as an AE if determined to be clinically 
significant by the investigator. 
 
For details on AE collection and reporting, refer to Section 10. 
 
 ASSESSMENT OF STUDY AGENT ADHERENCE 
 
Participants that self-administer oral study agents (e.g., losartan) will check in with the 
investigator at each visit.  Participants will receive instruction on how to administer study drug 
from a physician, clinical research nurse, or other designated, qualified healthcare provider.   
 
8.2 
LABORATORY PROCEDURES AND EVALUATIONS 
 
Refer to Section 8.11 for a schedule of all laboratory test and procedures. 
 
 HEMATOLOGY 
 

 
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Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Hematologic profiling will be collected per institutional standards, and should include evaluation 
of hematocrit, hemoglobin, platelets, white blood cells with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), and absolute lymphocyte count. 
 
 BIOCHEMISTRY  
 
Blood chemistry will be collected per institutional standards and should include the following:  
 
• Albumin 
• Alkaline phosphataseA 
• Alanine aminotransferaseA 
• Aspartate aminotransferaseA 
• Calcium 
• Chloride 
• Creatinine 
• Glucose 
• Total bilirubinA 
• Total protein 
• Total CO2  
 
• Potassium 
• Sodium  
• Urea or blood urea 
nitrogen, depending on 
local practice 
 
A Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If 
total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome) then fractionate into direct and 
indirect bilirubin. 
 
 URINALYSIS  
 
Urinalysis to be performed only as clinically indicated. If performed results should be collected in 
CRF.  
 
 COAGULATION PANEL 
 
Coagulation assays to be performed only as clinically indicated (e.g., INR, prothrombin time, 
and PTT).  If performed results should be collected in CRF. 
 
 PREGNANCY TEST  
 
A serum (β-HCG) or urine pregnancy test is required during screening for all persons of 
childbearing potential.  The pregnancy test is required within 72 hours of initiating protocol 
therapy.  If the urine pregnancy test is positive, a serum pregnancy test must be performed per 
institutional standards.   
 
 TUMOR MARKERS  
 
CA 19-9 and/or CEA will be collected per institutional standards and/or per investigator 
discretion 
 
8.3 
EXPLORATORY STUDIES 
 
 BIOLOGICAL SAMPLE COLLECTION  
 
Tissue is collected for this study will be used to support one or more of the exploratory studies 
described in Appendix C.  In general, biopsy samples may (depending on tissue availability) be 
used for further profiling of cellular and molecular tumor characteristics based on emerging data.   
 

 
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Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 Pretreatment Biospecimen Collection  
 
Participants will be consented to have pretreatment tissue biopsy provided that the biopsy (e.g., 
EUS-guided FNA) is planned per standard of care, for cytologic or histologic proof pancreatic 
ductal carcinoma during screening. Similarly, if during screening a staging laparoscopy is 
planned per standard of care, then participants will be asked to consent to the collection of 
tumor tissue for research. Six core biopsies are recommended, but additional cores may be 
collected if deemed feasible by the provider. If during screening, no standard-of-care tissue 
biopsy is planned, then no additional research-only procedure will be mandated and participants 
will remain eligible for trial participation. In such cases, participants will be consented for the 
requisition of archival tissue blocks (if possible) or a recommended minimum of twenty (20) 
FFPE unstained slides, and one (1) Hematoxylin and Eosin (H&E) slide.  
 
 
Cores preserved in 10% neutral-buffered formalin will be delivered to the Oregon Pancreatic 
Tumor Registry (OPTR).  Additional cores for optional exploratory research analytics may be 
preserved in additional formats and distributed directly to research laboratories at OHSU 
(Appendix C).  At a minimum, samples should be labeled with the following information: 
o Participant Study ID 
o Date of collection 
 
Shipping of Specimens 
 
Freshly isolated samples should be transported in a closed container from clinic to OHSU 
research laboratories for processing as described above.  
 
Wong Laboratory 
Knight Cancer Research Building, Room 3000 
2720 S. Moody Avenue 
Portland, OR 97201 
Tel: 503 494-8953│Email: wongme@ohsu.edu  
 
Tumor tissue is to be shipped/couriered for processing to the following address: 
 
OPTR Study Coordinator 
OHSU, CLSB 4N079 
2730 SW Moody Ave 
Portland, OR 97201-5042 
Phone: (503) 494-8988 │Fax: (503) 346-8281│optr@ohsu.edu 
 
 Excess tumor collection at time of planned surgery (only for participants with resectable 
or borderline resectable disease undergoing planned surgery) 
 
Participants with disease that is amenable to surgical intervention will undergo planned surgical 
resection of PDAC lesions.  As part of consenting to study participation, either core surgical 
biopsies or tumor pieces will be collected from the pancreas.  Core biopsies will be separated 
into two tubes, with half of the sample processed fresh for preservation of viable cells, and the 
other half fixed in FFPE. Tumor pieces will also be split, with a portion frozen or preserved in 
FFPE, and a portion used for generating primary cultures.  Specific core preservation formats 
may change to support exploratory research analytics (Appendix C).  Samples should be 
labeled and couriered as described above.  

 
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Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
 BLOOD COLLECTION FOR RESEARCH 
 
Peripheral blood for research purposes will be drawn from participants scheduled to have 
venipuncture for routine clinical purposes.  The timing for blood collections is described in 
Section 8.11, Schedule of Events; however, at the discretion of the investigator, the frequency 
blood collections may be reduced or omitted from each study participant. If after blood 
collection, the treatment is held, per institutional standards and as long as treatment is resumed 
within two weeks, a subsequent research blood draw will not be collected at the treatment’s 
reattempt. Research blood will be processed for evaluation in the biological experiments 
described in Appendix C or may be stored as part of a bio-repository for future related studies.  
 
i) Collection and Handling of Specimens 
 
Up to 40 mL of blood will be collected into the appropriate blood collection tubes as directed by 
the PI or the study team. 
 
ii) Shipping of Specimen 
 
All whole blood collection tubes must be labeled with the minimum following information: 
o Participant Study ID 
o Date of collection 
 
Specific handling and shipping instructions will be provided by the PI or study team based on 
method of sample collection. All samples must be shipped on day of collection to: 
 
OPTR Study Coordinator 
OHSU, CLSB 4N079 
2730 SW Moody Ave 
Portland, OR 97201-5042 
Phone: (503) 494-8988 │Fax: (503) 346-8281│optr@ohsu.edu 
 
8.4 
SCREENING ASSESSMENTS 
 
A screening (consultation) visit may occur as part of standard of care.  If a participant is eligible 
for the study after review of key inclusion/exclusion criteria, additional screening visits will be 
scheduled while staff members are requesting insurance authorization to participate in a clinical 
trial.  The following will be reviewed at screening visit:  
i) Clinical history and physical exam (per standard of care), and  
ii) informed consent obtained and documented 
 
Toxicities which occur prior to the start of treatment will not be subject to analysis.  Consent 
must be obtained before initiation of any clinical screening procedure that is performed solely for 
the purpose of determining eligibility for this research study.  Evaluations performed as part of 
routine care before informed consent can be utilized as screening evaluations if done within the 
defined time period. 
 
8.5 
BASELINE ASSESSMENTS 
 
Baseline assessments should occur prior to start of window treatment with study therapy on Day 

 
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Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
1. Participants will be evaluated for medical history, physical examination, vital signs, 
performance status, concomitant medications, blood sampling for hematology and laboratory 
tests, and pretreatment biopsy, as well as any other specific assessments listed in Section 8.11, 
Schedule of Events (Table 21). 
 
8.6 
ASSESSMENTS DURING TREATMENT 
 
Specific on-study assessments are listed in the Section 8.11, Schedule of Events (Table 21, 
Table 22).  Under certain circumstances (e.g., clinic holiday, inclement weather) scheduled 
visits may be delayed by additional 7 days from the intended study visit.  
 
8.7 
EARLY TERMINATION VISIT 
 
Participants that discontinue study treatment early, undergo surgery, and do not withdraw from 
the study, should be evaluated for surgical margin status (e.g., R0, R1).  The EOT visit should 
coincide with any planned post-surgical visit per institutional standards.  EOT assessments are 
listed in, Section 8.11, Schedule of Events (Table 24).  If a participant does not reach EOT or 
terminates participation early due to transition to hospice or death, an EOT visit will not be 
conducted. 
 
8.8 
END OF TREATMENT VISIT 
 
A single end of treatment visit should be conducted as clinically indicated and following 
institutional standards. Preferably, the end of treatment visit should occur prior to the initiation of 
any other off-protocol interventional therapy.  This planned end of treatment visit should 
coincide with the standard of care post-surgical follow-up visit or any follow-up visit with a 
surgery, medical and/or radiation oncologist that is consistent with institutional standards. The 
assessments for this end of treatment visit are listed in Section 8.11, Schedule of Events (Table 
24). 
 
8.9 
FOLLOW-UP 
 
After the end of treatment visit, participants will be followed every 3 months (± 1 month) for the 
first 6 months, then every 6 months (± 1 month) for up to 2 years from the start of study 
treatment per institutional standards. Any variation in follow up visits will not be considered 
deviations, as long as institutional standards are maintained.  This information may be updated 
periodically via electronic health records, or follow-up contact may be made with the participant 
(e.g., by phone) or their treating physician to that end.  Participants removed from protocol 
therapy for unacceptable AE(s) will be followed until resolution or stabilization of the AE.  The 
assessments for this follow-up visit are listed in Section 8.11, Schedule of Events (Table 24). 
 
Follow up assessments, including physical exams, hematology, biochemistry, and research 
blood samples will be performed and/or collected only when convenient and feasible for the 
patient, per institutional standards. Any physical exam, lab work, and/or research blood not 
performed/collected, will not be considered a deviation, as long as institutional standards are 
maintained. 
 
8.10 
UNSCHEDULED VISITS 
 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed (e.g., laboratory or clinical assessments) should be recorded in (e)CRF.

 
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Version Number: 2.4 
Version Date: 20 September 2023 
PI: Charles Lopez MD, PhD 
8.11 
SCHEDULE OF EVENTS 
 
Table 22. Study Assessments for mFOLFIRINOX Regimen 
Visit Days 
(± 7 Days [D])* 
Screening** 
mFOLFIRINOX Treatment CyclesΔ 
Re-stage II 
Cycle 1§ Cycle 2 Cycle 3 Cycle 4 Re-stage I Cycle 5 Cycle 6 Cycle 7 Cycle 8 
 
D -45 to D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
mFOLFIRINOX 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Losartan 
 
Continuous Daily Administration (refer to Section 7.1.3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medicationsA 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Physical ExaminationB 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
HematologyC 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
BiochemistryD 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
CA19-9 E 
X 
 
X 
 
X 
 
 
X 
 
X 
 
CEA E 
X 
 
X 
 
X 
 
 
X 
 
X 
 
ECG 
**only as clinically indicated** 
Urinalysis 
**only as clinically indicated** 
Pregnancy test F 
X 
 
 
 
 
 
 
 
 
 
 
AE assessment G 
 
**continually assessed** 
Radiographic imaging H 
X 
 
 
 
 
X 
 
 
 
 
X 
Research Tumor tissuesI 
X 
 
 
 
 
 
 
 
 
 
 
Research blood samples J 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
* Study visits may be performed ±7 days of the planned 
** Screening may occur up to 45 days from initiating study treatment.   
§ Baseline visit should be conduct on Cycle 1 Day 1 prior to initiating study therapy, but may occur up to 7 days earlier. 
Δ FOLFIRINOX treatment cycles are 14 days. The FOLFIRINOX treatment cycle is the default schedule. If systemic chemotherapy is switched from 
FOLFIRINOX to GA, then the study schedule and subsequent visits are to be adjusted according to the GA treatment schedule in Table 22. 
A For concomitant medications – enter new medications at baseline and those started during the trial through to the EOT visit. 
B All physical exams will include assessing weight, vital signs (including blood pressure), and ECOG performance status. Height will be obtained at screening 
only. 
C Hematology profiling per institutional standards, including: hematocrit, hemoglobin, platelets, white blood cells with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), and absolute lymphocyte count. For Baseline/Screening, blood should be collected and profiled within 28 days of 
treatment start. 

 
73 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
D Biochemistry tests should be collected per institutional standards, including: comprehensive metabolic panel (Na, K, Cl, CO2, BUN, Creatinine, Ca, Glucose, 
Albumin, Alkaline Phosphatase, total Bilirubin, AST, total Protein, ALT), amylase, and lactate dehydrogenase. Refer to Section 8.2.2. For Baseline/Screening, 
blood chemistry should be collected and profiled within 28 days of treatment start. 
E If screening CA19-9 or CEA falls outside of screening window, it is allowed per investigator discretion as long as a C1D1 CA19-9 is drawn. 
F For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Pregnancy tests (serum and/or urine 
tests) should be repeated, if required, per institutional guidelines. 
G AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness.  Record grade 3 and 4 AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs occurring up until 30 days after the last 
dose of trial treatment, or until resolution/stabilization of treatment-related toxicities. 
H  Radiographic imaging will be performed as clinically indicated and follow institutional standards. Initial tumor imaging at screening will be performed within the 
28-day window during screening. Initial tumor imaging may be performed up to 45 days prior to C1D1, at the discretion of the Principle Investigator.  If surgery is 
delayed, repeat imaging within 28 days of the surgery date may be requested (per standard of care or as clinically indicated) to confirm no distant disease 
precluding surgery with curative intent. Additional imaging may be performed if clinically indicated.  
I   Tissue biopsies are not mandatory, and should be optionally performed if a biopsy is performed per standard of care. Likewise, if staging laparoscopy is 
clinically indicated per standard of care, pre-treatment tissue may be collected at this time.  Excess tumor tissue may be collected at the time of surgery. 
J  Research blood draws should be collected at same time as standard of care evaluations, including any pre- and/or post-surgical blood draws required per 
standard of care. Per discretion of the investigator, the frequency blood collections may be reduced or omitted from each study participant. If after blood 
collection, the treatment is held, per institutional standards and as long as treatment is resumed within two weeks, a subsequent research blood draw will not be 
collected at the treatment’s reattempt 
 
Table 23. Study Assessment for GA Regimen 
Visit Days 
(± 7 Days [D])* 
GA Treatment CyclesΔ 
 
Re-stage II 
Cycle 1 
Cycle 2 
D1 
D8 
D15 
D1 
D8 
D15 
Gemcitabine 
X 
X 
X 
X 
X 
X 
 
Nab-Paclitaxel 
X 
X 
X 
X 
X 
X 
 
Losartan 
Continuous Daily Administration (refer to Section 7.1.3) 
Prior/concomitant medicationsA 
X 
 
 
X 
 
 
 
Physical ExaminationB 
X 
 
 
X 
 
 
 
HematologyC 
X 
X 
X 
X 
X 
X 
 
BiochemistryD 
X 
X 
X 
X 
X 
X 
 
CA19-9 E 
X 
 
 
X 
 
 
 
CEA E 
X 
 
 
X 
 
 
 
ECG 
**only as clinically indicated** 
Urinalysis 
**only as clinically indicated** 
AE assessment F  
**continually assessed** 

 
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NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Radiographic imaging G  
 
 
 
 
 
 
X 
Research blood samplesH 
X 
 
X 
X 
 
X 
 
Δ GA treatment cycles are 28 days. 
A For concomitant medications – enter new medications at baseline and those started during the trial through to the EOT visit. 
B All physical exams will include assessing weight, vital signs (including blood pressure), and ECOG performance status. Height will be obtained within 45 days 
of C1D1 . 
C Hematology profiling per institutional standards, including: hematocrit, hemoglobin, platelets, white blood cells with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), and absolute lymphocyte count. Should be collected pre-dose on Day 1; however prior results within 14 days of initiating 
on-study therapy are acceptable. Pre- and/or post-surgical hematology after completing window treatment may occur as clinically indicated. 
D Biochemistry tests should be collected per institutional standards, including: comprehensive metabolic panel (Na, K, Cl, CO2, BUN, Creatinine, Ca, Glucose, 
Albumin, Alkaline Phosphatase, total Bilirubin, AST, total Protein, ALT).. Refer to Section 8.2.2 
E If screening CA19-9 or CEA falls outside of screening window, it is allowed per investigator discretion as long as a C1D1 CA19-9 is drawn. 
 F AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness.  Record grade 3 and 4 AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs occurring up until 30 days after the last 
dose of trial treatment, or until resolution/stabilization of treatment-related toxicities. 
 G Radiographic imaging will be performed as clinically indicated and follow institutional standards. Initial tumor imaging at screening will be performed within 45 
days prior to the first dose of trial treatment.  If surgery is delayed, repeat imaging within 28 days of the surgery date may be requested (per standard of care or 
as clinically indicated) to confirm no distant disease precluding surgery with curative intent. Additional imaging may be performed if clinically indicated.  
H Research blood draws should be collected at same time as standard of care evaluations, including any pre- and/or post-surgical blood draws required per 
standard of care. Per discretion of the investigator, the frequency blood collections may be reduced or omitted from each study participant. If after blood 
collection, the treatment is held, per institutional standards and as long as treatment is resumed within two weeks, a subsequent research blood draw will not be 
collected at the treatment’s reattempt 
 
Table 24. Study Assessments for RT Regimens 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
RT Daily Fractions† 1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
Short-course RT X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 Fraction RT X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
25 Fraction RT X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Losartan 
Continuous Daily Administration (refer to Section 7.1.3) 
Prior/concomitant medicationsA 
X weekly 
X weekly 
X weekly 
X weekly 
X weekly 
Physical ExaminationB 
X weekly 
X weekly 
X weekly 
X weekly 
X weekly 
HematologyC 
X weekly 
X weekly 
X weekly 
X weekly 
X weekly 
BiochemistryD 
X weekly 
X weekly 
X weekly 
X weekly 
X weekly 
CA19-9 & CEA 
**only as clinically indicated** 
AE assessmentE 
X weekly 
X weekly 
X weekly 
X weekly 
X weekly 
Research blood samplesF 
 
Every 2 weeks 
 

 
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NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
† The specific considerations for a participant to receive RT, either short-course or long-course (i.e., 15 of 25 fractions), is described in Section 3.1.  
A For concomitant medications – enter new medications at baseline and those started during the trial through to the EOT visit. 
B All physical exams will include assessing weight, vital signs, and ECOG performance status. Height should be obtained at screening only. Physical 
examination may be omitted during short-course RT, per institutional standards 
C Hematology profiling per institutional standards, including: hematocrit, hemoglobin, platelets, white blood cells with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), and absolute lymphocyte count. Should be collected pre-dose on Day 1; however prior results within 14 days of initiating 
on-study therapy are acceptable. Pre- and/or post-surgical hematology after completing window treatment may occur as clinically indicated. Hematology labs 
may be omitted during short-course RT, per institutional standards. 
D Biochemistry tests should be collected per institutional standards, including: comprehensive metabolic panel (Na, K, Cl, CO2, BUN, Creatinine, Ca, Glucose, 
Albumin, Alkaline Phosphatase, total Bilirubin, AST, total Protein, ALT). Refer to Section 8.2.2. Biochemistry labs may be omitted during short-course RT, per 
institutional standards 
E AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness.  Record grade 3 and 4 AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs occurring up until 30 days after the last 
dose of trial treatment, or until resolution/stabilization of treatment-related toxicities. 
F Research blood draws should be collected at same time as standard of care evaluations, including any pre- and/or post-surgical blood draws required per 
standard of care. Per discretion of the investigator, the frequency blood collections may be reduced or omitted from each study participant. 
 
Table 25. Surgery, End of treatment (EOT), and Follow-up Assessments 
 
Surgery§ 
End of treatment (EOT)‡ 
Follow-up† 
Margin Status 
X 
 
 
Physical ExaminationA 
 
X 
X 
HematologyB 
 
X 
X 
BiochemistryC 
 
X 
X 
AE assessmentD 
 
X 
 
Clavien-Dindo Classification 
 
X 
 
Research Tumor tissueE 
X 
 
 
Research blood samplesF 
X 
X 
X 
Radiographic imagingG 
X 
X 
XH 
§ Surgery should be performed at least 1-4 weeks following the last dose of study treatment. In the unlikely event that a participant does not undergo surgery, 
these individuals may consent to an optional post-treatment biopsy (i.e., 1-4 weeks following the last dose of study treatment).   
‡ An EOT should be conducted as clinically indicated and following institutional standards. Assessments listed under EOT do not need to occur on the same 
date and can instead be performed as clinically indicated and following institutional standards.   
† Participants will be followed according to planned standard of care visits every 3 months (± 1 month) for the first 6 months. Thereafter, participants will be 
followed once every 6 months (±1 month) for up to 2 years from start of treatment.  
A All physical exams will include assessing weight, vital signs, and ECOG performance status. Height should be obtained at screening only. Physical exams, will 
be performed only when convenient and feasible for the patient, per institutional standards. 
B Hematology profiling per institutional standards, including: hematocrit, hemoglobin, platelets, white blood cells with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), and absolute lymphocyte count. Hematology collected only when convenient and feasible for the patient, per institutional 
standards. 
C Serum chemistry tests should be collected per institutional standards, including: comprehensive metabolic panel (Na, K, Cl, CO2, BUN, Creatinine, Ca, 
Glucose, Albumin, Alkaline Phosphatase, total Bilirubin, AST, total Protein, ALT). Refer to Section 8.2.2. Biochemistry collected only when convenient and 

 
76 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Table 25. Surgery, End of treatment (EOT), and Follow-up Assessments 
 
Surgery§ 
End of treatment (EOT)‡ 
Follow-up† 
Margin Status 
X 
 
 
feasible for the patient, per institutional standards. 
D AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness.  Record grade 3 and 4 AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs occurring up until 30 days after the last 
dose of trial treatment, or until resolution/stabilization of treatment-related toxicities. 
E Tissue biopsies are not mandatory, and should be optionally performed if a biopsy is performed per standard of care. Likewise, if staging laparoscopy is 
clinically indicated per standard of care, pre-treatment tissue may be collected at this time.  Excess tumor tissue may be collected at the time of surgery. 
F Research blood draws should be collected at same time as standard of care evaluations, including any pre- and/or post-surgical blood draws required per 
standard of care. Per discretion of the investigator, the frequency blood collections may be reduced or omitted from each study participant. Research blood 
samples will be collected only when convenient and feasible for the patient, per institutional standards. 
G Radiographic imaging will be performed only as clinically indicated and follow institutional standards. The results of imaging performed per standard of care, 
for the purpose of assessing disease response or status, should be recorded.   
H Radiographic imaging will be performed at End of Study will coincide with standard of care imaging for participants without clinical evidence of progression to 
confirm participant is progression-free. If after blood collection, the treatment is held, per institutional standards and as long as treatment is resumed within two 
weeks, a subsequent research blood draw will not be collected at the treatment’s reattempt. 
 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
9. EFFICACY MEASURES 
 
9.1 
MARGIN STATUS 
 
All participants that undergo surgical resection (per standard surgical techniques [e.g., 
pancreaticoduodenectomy or distal pancreatectomy]) will have a comprehensive pathological 
review of the resected tumor specimen based on according to the American Joint Committee on 
Cancer [AJCC] staging system (8th edition).49  Margin status will be classified as R0 or R1 as 
follows: 
• 
R0 margin status is defined as the absence of any tumor cells within 1 mm from the 
resection margin.50  Also referred to as pathological complete response (pCR). 
• 
R1 margin status is defined as cases either: 
o R1<1 mm - cases with a tumor-free margin <1 mm from the resection margin 
o R1 direct - tumor cells directly at the margin 
 
9.2 
IMAGING RESPONSE 
 
All assessments of imaging response to standard of care systemic chemotherapy (e.g., 
FOFIRINOX or GA) at Re-staging I and II, respectively, will be abstracted from the radiologist’s 
clinical report.  Disease progression (recurrence or relapse) will be based on radiologist’s 
assessment in clinical records noting an increase lesion size or occurrence of new lesion(s). 
 
9.3 
PROGRESSION-FREE SURVIVAL (PFS) 
 
PFS is defined as the time from start of systemic chemotherapy to the first of either recurrence 
or relapse (anywhere in the body) or death at time of last follow-up at 24-months from start of 
study treatment.  Participants who are lost to follow up, or are still alive at last follow-up will be 
censored at the time of last assessment. 
 
9.4 
DISEASE-FREE SURVIVAL (DFS) 
 
DFS is defined as the time from surgical resection to the date of recurrence or relapse 
(anywhere in the body) or death at time of last follow-up at 24-months from start of study 
treatment. Participants who are lost to follow up, or are still alive at last follow-up will be 
censored at the time of last assessment. 
 
9.5 
OVERALL SURVIVAL (OS) 
 
OS is defined as the time from start of systemic chemotherapy to death (from any cause) at time 
of last follow-up at 24-months from start of study treatment.  Participants who are lost to follow 
up, or are still alive at last follow-up will be censored at the date of last contact. 
 
9.6 
SURGICAL COMPLICATIONS 
 
Surgical complications will be based on the Clavien-Dindo classification per PI and/or treating 
oncologist in the review of the surgical discharge summary and daily progress notes in the 
patient’s medical records shown in Table 21.  Complications will be captured up to 30 days from 
date of surgery. 
 
Table 26. Classification of Surgical Complications 
Grade 
Definition 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Grade I 
Any deviation from the normal post-operative course without the need for 
pharmacological treatment or surgical, endoscopic, and radiological interventions.  
 
Allowed therapeutic regimens are: drugs such as antiemetics, antipyretics, analgesics, 
diuretics, electrolytes, and physiotherapy. This grade also includes wound infections 
opened at the bedside. 
Grade II 
Requiring pharmacological treatment with drugs other that such allowed for grade I 
complications.  
Blood transfusions and total parenteral nutrition are also needed. 
Grade III 
Requiring surgical, endoscopic, or radiological intervention.  
Grade IIIa 
Intervention not under general anesthesia 
Grade IIIb 
Intervention under general anesthesia 
Grade IV 
Life-threatening complications (including CNS complications)* requiring IC/ICU 
management. 
Grade IVa 
Single organ dysfunction (including dialysis) 
Grade IVa 
Multi-organ dysfunction. 
Grade V 
Death of a patient 
Suffix “d” 
If the patient suffers from a complication at the time of discharge, the suffix “d” (for 
“disability”) is added to the respective grade of complication. This label indicates the 
need for a follow-up to fully evaluate the complication. 
*Brain hemorrhage, ischemic stroke, subarachnoid bleeding, but excluding transient ischemic attacks.  
CNS, central nervous system; IC, immediate care; ICU, intensive care unit. 
Adapted from Dindo et al.48  
  
 
10. SAFETY 
 
10.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
The Investigator is responsible for monitoring the safety of participants who have enrolled in the 
study. Safety assessments will be based on medical review of adverse events and the results of 
safety evaluations at specified time points as described in Section 8.11, Schedule of Events.  
 
10.2 
DEFINITIONS 
 
 ADVERSE EVENT (AE) 
 
An adverse event is defined as any undesirable physical, psychological or behavioral effect 
experienced by a participant during their participation in an investigational study, in conjunction 
with the use of the investigational product, whether considered intervention-related (21 CFR 
312.32 (a)). In general, this includes signs or symptoms experienced by the participant from the 
time of signing the informed consent to completion of the study.  
 
AEs may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the participant and/or 
observed by the Investigator or medical staff.  
• 
Clinically significant laboratory abnormalities.  
• 
A significant worsening of the participant’s condition from study entry.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment that resolve but then recur after treatment.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment which increase in frequency, intensity, or a change in quality after 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
treatment.  
 
 SERIOUS ADVERSE EVENT (SAE) 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
Investigator or Sponsor-investigator, it results in any of the following outcomes: 
  
• 
Death,  
• 
A life-threatening adverse event,  
• 
In-patient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• 
A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and/or participant may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include: 
 
• 
Allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
• 
Blood dyscrasias or convulsions that do not result in in-patient hospitalization, or 
• 
The development of drug dependency or drug abuse.  
 
 UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers UPs involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
2. Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
This study will use the OHRP definition of UP. 
 
 SEVERITY OF EVENT 
 
The Investigator will grade the severity of each AE using, when applicable, the current version 
of the CTCAE v5.0. In the event of an AE for which no grading scale exists, the Investigator will 
classify the AE as defined below:  
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL  

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL.  
Grade 4: Life-threatening consequences; urgent intervention indicated.  
Grade 5: Death related to AE.  
Note: a semi-colon indicates ‘or’ within the description of the grade. 
 
 ASSESSMENT OF CAUSALITY RELATIONSHIP TO STUDY INTERVENTION 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below: 
 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out.  
Potentially Related: There is some evidence to suggest a causal relationship  
Unrelated: The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely 
related to another etiology.  
 
10.3 
EXPECTEDNESS 
 
The Investigator will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study agent. 
 
10.4 
ADVERSE EVENT LISTS  
 
Neoadjuvant administration of mFOLFIRINOX or GA, with or without RT, and surgery is the 
standard of care approach to treating patients with resectable/borderline resectable PDAC.  
Both FOLFIRINOX and GA treatment regimens are widely used and have well-established 
safety profiles.9-17,19 
 
 ADVERSE EVENT LIST FOR MFOLFIRINOX 
 
Refer to the respective package inserts for 5-FU, irinotecan, and oxaliplatin.  AEs associated 
with each drug agent are summarized in Table 22. 
 
Table 27. Common and Severe AEs for drug agents comprising mFOLFIRINOX regimen 
Irinotecan – Common AEs 
System 
AE (grade, frequency (%)) 
Dermatologic 
• 
Alopecia (43.1% to 60% ) 
Endocrine 
metabolic 
• 
Weight decreased (30% ) 
Gastrointestinal 
• 
Abdominal pain (all grade, 17.2% to 67.7%; grade 3 and 4, 2.1% to 14%),  
• 
Constipation (all grade, 30% to 43.9%; grade 3 and 4, 0.4% to 10%),  
• 
Diarrhea, All grade (early-onset, 43% to 51%; late-onset, 72.4% to 88%),  
• 
Loss of appetite (all grade, 34.2% to 55%; grade 3 and 4, 2.1% to 7.2%),  
• 
Nausea (all grade, 66.9% to 86%; grade 3 and 4, 2.1% to 17%),  
• 
Vomiting (all grade, 44.8% to 67%; grade 3 and 4, 3.5% to 14%) 
Hematologic 
• 
Anemia (all grade, 60% to 97.2%),  
• 
Drug-induced eosinophilia, leukopenia (all grade 63% to 96.9%),  

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
• 
Neutropenia (all grade 54% to 96.9%),  
• 
Thrombocytopenia (all grade, 32.6% to 96%) 
Hepatic 
• 
Increased bilirubin level (19.1% to 87.6%) 
Neurologic 
• 
Asthenia (all grade, 57.9% to 76%; grade 3 and 4, 9% to 19.5%), 
• 
Dizziness (15% to 23.1%),  
• 
Parasympathomimetic adverse reaction (28.3%) 
Respiratory 
• 
Cough (17% to 26.7%),  
• 
Dyspnea (9.7% to 27.6%) 
Irinotecan – Serious AEs 
Cardiovascular 
• 
Disorder of cardiovascular system 
Gastrointestinal 
• 
Diarrhea, Grade 3 and 4 (4.9% to 31% ),  
• 
Gastrointestinal perforation 
Hematologic 
• 
Anemia (grade 3 and 4, 2.1% to 8.4%),  
• 
Febrile neutropenia (adults, 2% to 7.1%),  
• 
Hemorrhage (1% to 5%),  
• 
Infectious disease, Neutropenic (1% to 2.2%),  
• 
Leukopenia (grade 3 and 4, 17.4% to 37.8%),  
• 
Neutropenia (grade 3 or 4, adults, 26% to 53.8%),  
• 
Thrombocytopenia (grade 3 and 4, up to 4%),  
• 
Thromboembolic disorder (5.4% to 11.7%) 
Immunologic 
Hypersensitivity reaction 
Respiratory 
Interstitial lung disease 
Oxaliplatin – Common AEs 
System 
AE (grade, frequency (%)) 
Gastrointestinal 
• Abdominal pain (Monotherapy, 31%; combination therapy, up to 39%), 
Constipation (Combination therapy, up to 32% ),  
• Diarrhea (Monotherapy, 46%; combination therapy, up to 76%),  
• Loss of appetite (Monotherapy, 20%; combination therapy, up to 35%), 
• Nausea (Monotherapy, 64%; combination therapy, 64% to 83%),  
• Stomatitis (Monotherapy, 14%; combination therapy, up to 42%),  
• Vomiting (Monotherapy, 37%; combination therapy, 40% to 64%) 
Hematologic 
• Anemia (all grades, monotherapy, 64%; combination therapy, 25% to 81%), 
Granulocytopenic disorder (grade 3 and 4 (39% to 45%),  
• Leukopenia, (all grades, monotherapy, 13%; combination therapy, up to 
85%), Neutropenia, (all grades, Monotherapy, 7%; combination therapy, 71% 
to 81%),  
• Thrombocytopenia (all grades Monotherapy, 30%; combination therapy, 44% 
to 77%) 
Hepatic 
• Abnormal alkaline phosphatase (Combination therapy, 14% to 16%), 
ALT/SGPT level abnormal (Monotherapy, 36%; combination therapy, 5% to 
31%),  
• AST/SGOT level abnormal (Monotherapy, 54%; combination therapy, 11% to 
47%) 
Musculoskeletal 
• 
Backache (Monotherapy, 11%; combination therapy, 19%) 
Neurologic 
• 
Paresthesia (62% to 77% ) 
Respiratory 
• 
Cough (Monotherapy, 11%; combination therapy, up to 35% ) 
Other 
• 
Fatigue (Monotherapy, 61%; combination therapy, up to 70% ),  
• 
Fever (Monotherapy, 25%; combination therapy, 29% ) 
Oxaliplatin – Serious AEs 
Cardiovascular 
• 
Edema (Monotherapy, 5%; combination therapy, up to 15%),  
• 
Prolonged QT interval, Torsades de pointes 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Endocrine 
• 
Metabolic acidosis 
Gastrointestinal 
• 
Bowel obstruction,  
• 
Colitis (including clostridium difficile)  
• 
diarrhea,  
• 
acute pancreatitis 
Hematologic 
 
• 
Anemia (grade 3 or 4, Monotherapy, 1%; combination therapy, 1% to 3%), 
• 
Febrile neutropenia (Combination therapy, up to 12% ),  
• 
Hemolytic anemia, Immuno-allergic, Leukopenia, (grade 3 or 4, 
Combination therapy, 13% to 24%),  
• 
Neutropenia (grade 3 or 4, Combination therapy, 36% to 53%),  
• 
Thrombocytopenia (grade 3 or 4, Monotherapy, 3%; combination therapy, 
2% to 5% ),  
• 
Thrombocytopenia, Immuno-allergic 
Hepatic 
• 
Increased liver function test (Combination therapy, 57%),  
• 
Veno-occlusive disease of the liver 
Immunologic 
• 
Anaphylaxis, hypersensitivity reaction (Monotherapy, grade 3 or 4, 1% to 
3%; combination therapy, all grades, 6% to 12%),  
• 
Infusion reaction 
Musculoskeletal 
• 
Rhabdomyolysis 
Neurologic 
• 
Dysesthesia, Pharyngolaryngeal (1% to 38%),  
• 
Neuropathy, Acute or persistent (Overall neuropathy, 69% to 92%; acute 
neuropathy, 56%; persistent neuropathy, 21% to 60%),  
• 
Posterior reversible encephalopathy syndrome (less than 0.1%) 
Ophthalmic 
• 
Transient visual loss 
Otic 
• 
Hearing loss 
Renal 
• 
Hemolytic uremic syndrome,  
• 
Interstitial nephritis, acute 
Respiratory 
• 
Dyspnea (Monotherapy, 13%; combination therapy, up to 20% ), 
• 
Pneumonitis (Severe),  
• 
Pulmonary fibrosis (Less than 1% 
)                                                                                                                          
Other 
• 
Angioedema,  
• 
Sepsis 
5-FU – Common AEs 
Dermatologic 
Allergic contact dermatitis, Crust on skin, Hand-foot syndrome due to cytotoxic 
therapy, Pruritus, Scar, Sensation of burning of skin, Sore skin, Ulcer of skin or 
mucosa 
Gastrointestinal 
Diarrhea, Inflammatory disease of mucous membrane 
Hematologic 
Leukocytosis 
5-FU – Serious AEs 
Cardiovascular 
Angina pectoris, Cardiotoxicity, Nonspecific ST-T abnormality on 
electrocardiogram 
Gastrointestinal  
Gastrointestinal ulcer 
Hematologic 
Myelosuppression, Anemia, leukopenia, thrombocytopenia 
Neurologic  
Hyperammonemic encephalopathy, Neurotoxicity 
 
 ADVERSE EVENT LIST FOR GA 
 
Refer to the respective package inserts of nab-paclitaxel and gemcitabine.  AEs associated with 
each drug agent are summarized in Table 28. 
 
Table 28. Common and Severe AEs for drug agents comprising GA regimen 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
GEMCITABINE 
ORGAN SITE 
SIDE EFFECT* (%) 
Cardiovascular 
Arrhythmia (rare) 
Arterial thromboembolism (rare) 
Heart failure (rare) 
Hypertension (<2%) 
Dermatological 
Alopecia (14%) 
Rash (25%) (may be severe) 
Gastrointestinal 
Constipation (8%) 
Diarrhea (12%) 
Mucositis (8%) 
Nausea, vomiting (64%) (severe 18%) 
General 
Edema (20%) 
Fatigue (40%) (in combination with paclitaxel) 
Flu-like symptoms (37%) 
Other (radiosensitizer) 
Hematological 
Hemolytic uremic syndrome (<1%) 
Myelosuppression ± infection, bleeding (25%) (severe) 
Hepatobiliary 
Elevated LFTs (68%) (10% severe) 
Hypersensitivity 
Hypersensitivity (rare) 
Infection 
Infection (9%) (severe 1%) 
Injection site 
Injection site reaction (4%) 
Musculoskeletal 
Musculoskeletal pain (16%) 
Nervous System 
Peripheral neuropathy (3%) 
PRES (rare) 
Somnolence (9%) 
Renal 
Creatinine increased (7%) 
Proteinuria (36%) 
Respiratory 
Adult respiratory distress syndrome (ARDS) (rare) 
Dyspnea (8%) 
Pneumonitis (rare) 
Vascular 
Capillary leak syndrome (rare) 
Gangrene (rare) 
Vasculitis (rare) 
Nab-Paclitaxel 
ORGAN SITE 
SIDE EFFECT* (%) 
Cardiovascular 
Arterial thromboembolism (<1%) 
Atrioventricular block (rare) 
Bradycardia (<1%) 
Cardiotoxicity (<10%) (prior cardiac history or cardiotoxins) 
ECG changes (35%) 
Hypotension (5%) 
Venous thromboembolism (rare) 
Dermatological 
Alopecia (90%) 
Nail disorder (1%) 
Other - Scleroderma-like skin changes (rare) 
Photosensitivity (rare) 
Rash, pruritus (9%) (may be severe) 
Gastrointestinal 
Anorexia (very common) 
Constipation (very common) 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Dehydration (<10%) 
Diarrhea (27%) (may be severe) 
Esophagitis (rare) 
GI obstruction (<1%) 
GI perforation (<1%) 
Mucositis (7%) 
Nausea, vomiting (30%) 
General 
Edema (10%) 
Fatigue (47%) (8% severe) 
Hematological 
Hemolytic uremic syndrome (rare) 
Myelosuppression ± infection, bleeding (80%) (9% severe) 
Thrombotic thrombocytopenic purpura (TTP; rare) 
Hepatobiliary 
Elevated LFTs (39%) (rarely severe) 
Pancreatitis (<1%) 
Hypersensitivity 
Hypersensitivity (4%) (rarely severe) 
Injection site 
Injection site reaction (1%) (including extravasation and radiation recall; 
rarely may be severe) 
Metabolic / 
Endocrine 
Tumor lysis syndrome (rare) 
Musculoskeletal 
Musculoskeletal pain (44%) (8% severe) 
Nervous System 
Autonomic neuropathy (rare) 
Cognitive disturbance (rare) 
Cranial neuropathy (rare) 
Dizziness (rare) 
Mood changes (rare) 
Sensory neuropathy (71%) (10% severe ) 
Ophthalmic 
Conjunctivitis (rare) 
Eye disorders (13%) (1% severe including keratitis and blurred vision) 
Optic neuritis (rare) 
Other - Cystoid macular edema (rare) 
Watering eyes (rare) 
Renal 
Creatinine increased (11%) 
Renal failure (<10%) (acute) 
Respiratory 
Cough, dyspnea (12%) 
Other - Lung Fibrosis (rare) 
Pneumonitis (rare) 
Pneumothorax (rare) 
Rare - refers to events with incidence < 1% 
 
 ADVERSE EVENTS LIST FOR LOSARTAN 
 
The safety profile of losartan is well-established.  AEs associated with losartan are summarized 
below.  Refer to package insert for additional information. 
 
Treatment with losartan potassium was well-tolerated with an overall incidence of adverse 
events similar to that of placebo. In controlled clinical trials, discontinuation of therapy for 
adverse events occurred in 2.3% of patients treated with losartan potassium and 3.7% of 
patients given placebo.  In 4 clinical trials involving over 1000 patients on various doses (10 to 
150 mg) of losartan potassium and over 300 patients given placebo, the adverse events that 
occurred in 2% of patients treated with losartan potassium and more commonly than placebo 
were: dizziness (3% vs. 2%), upper respiratory infection (8% vs. 7%), nasal congestion (2% vs. 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
1%), and back pain (2% vs. 1%).  Less common adverse reactions also reported are 
summarized in Table 29.  
 
Table 29. Less Common AEs for losartan* 
Blood and lymphatic system 
disorders 
Anemia 
Psychiatric disorders 
Depression 
Nervous system disorders  
Somnolence, headache, sleep disorders, paresthesia, 
migraine. 
Ear and labyrinth disorders  
Vertigo, tinnitus. 
Cardiac disorders 
Palpitations, syncope, atrial fibrillation, CVA. 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnea. 
Gastrointestinal disorders 
Abdominal pain, constipation, nausea, vomiting. 
Skin and subcutaneous tissue 
disorders 
Urticaria, pruritus, rash, photosensitivity. Musculoskeletal 
and connective tissue disorders: Myalgia, arthralgia. 
Reproductive system and breast 
disorders 
Impotence. 
General disorders and 
administration site conditions 
Edema. 
*The definition (i.e., frequency) of less common AEs for losartan is not defined in package insert 
 
10.5 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an UP, AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, upon review by a study 
monitor, or during an audit. All AEs including local and systemic reactions not meeting the 
criteria for SAEs will be captured on the appropriate CRF.  Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, seriousness, expectedness, 
relationship to study product (assessed only by those with the training and authority to make a 
diagnosis), and date of resolution/stabilization of the event. All AEs occurring while on study 
must be documented appropriately regardless of relationship. All AEs will be followed through to 
the end of treatment visit. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE after the participant 
provides informed consent.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent need only 
be documented one time, or until there is a change in the grade, at which point the new grade 
will be documented one time. 
 
At each study visit, the Investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization, as 
determined by the treating provider in accordance with institutional standards.  
 
The Investigator will record all reportable events with start dates occurring any time after the 
participant provides informed consent through the end of treatment visit.  AEs will be evaluated 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
using the current version of the CTCAE v5.0.    Any SAE that occurs after treatment with 
alternative therapy will be reported only if the Investigator or current treating physician has 
assessed the SAE as related to the study treatment.  
  
10.6 
REPORTING PROCEDURES 
 
 OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS 
 
Unanticipated Problems and AEs will be reported to OHSU IRB according to the policies, 
procedures and guidelines posted on the OHSU IRB web site. 
 
Events that must be reported by the Investigator to the IRB are detailed in the OHSU IRB 
Investigator Guidance: Prompt Reporting Requirements (HRP-801).  Events that meet the 
criteria for OHSU RNI must be reported to the IRB within 5 days of learning of the event.  At a 
minimum, events requiring reporting to the IRB include: 
• 
Any new or increased risk related to the research, including AEs or IND safety reports 
that require a change to the protocol or consent,  
• 
New FDA black box warning,  
• 
Publications identifying new risks,  
• 
Data Safety Monitoring Board/Committee letters recommending changes or discussing 
new risks 
• 
Unanticipated adverse device effect 
• 
Unauthorized disclosure of confidential participant information 
 
 MEDWATCH REPORTING  
 
The Investigator is required to report some events to the FDA through the Mandatory MedWatch 
reporting program, even if the trial involves a commercially available agent.  Events to be 
reported include any UPs (i.e., not listed in the package insert) and any SAEs with a suspected 
association to 5-FU, irinotecan, oxaloplatin, gemcitabine, nab-paclitaxel, or losartan. 
 
Adverse events that occur during clinical studies are to be reported to FDA as specified per 
applicable investigational new drug/biologic regulations using FDA Form 3500 (MedWatch 
Voluntary Reporting form, available here).  A copy of the MedWatch form and supporting 
materials will be kept on file in the study regulatory binder.  
 
 REPORTING OF PREGNANCY 
 
To ensure participant safety, each pregnancy in a participant on study treatment must be 
reported within 24 hours of learning of its occurrence.  The pregnancy should be followed to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or any pregnancy- or 
childbirth-related and/or newborn complications. 
 
The pregnancy should be recorded and reported by the Investigator to the IRB.  Pregnancy 
follow-up should be reported using the same form.  Any SAE experienced during pregnancy 
must also be reported. 
  
If while on study treatment a participant’s sexual partner becomes pregnant, the pregnancy and 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
pregnancy outcomes must also be reported as described above.  Consent to report information 
regarding the pregnancy should be obtained from the pregnant individual. 
 
10.7 
STUDY STOPPING RULES 
 
The overall study will be paused, and appropriate authorities (e.g., IRB, Knight Data and Safety 
Monitoring Committee) notified if the following events occur: 
• 
Life-threatening grade 4 toxicity attributable to protocol therapy that is unmanageable, or 
unexpected. 
• 
Death suspected to be related to study treatment. 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 
STATISTICAL HYPOTHESIS 
 
This is an open-label, non-randomized, phase II trial to assess the efficacy of an adaptive 
treatment strategy that allows for early switching of neoadjuvant systemic chemotherapy in 
patients with resectable and borderline resectable pancreatic cancer, or patients with locally-
advanced, unresectable pancreatic cancer (LAPC). 
 
11.2 
SAMPLE SIZE DETERMINIATION 
 
Murphy et al20 reported on a single arm phase II trial in which 48 patients (27 male, 21 female) 
with newly diagnosed BRPC were given eight cycles of neoadjuvant FOLFIRINOX as well as 
short-course or long-course chemoradiation.  In this study, the R0 resection was achieved in 31 
of 48 patients (65%).  However, reported R0 rates across other studies can vary widely (26% to 
87%). 14,16,17,51  Moreover, the impact of providing an early switch to GA in the neoadjuvant 
setting after failing FOLFIRNOX has only been evaluated in a small retrospective cohort study 
of 25 patients, of which 11 proceeded to undergo surgical resection, of which 9 (81.8%) had an 
R0 resection.43  Without an adequate historical benchmark, the study will estimate the precision 
of the proportion of R0 in order to assess the clinical utility of allowing for early switching of 
neoadjuvant therapies.  Based on the literature, and assuming that the proportion of R0 is 60%, 
a sample size of 32 patients will allow us to estimate the proportion with an exact 95% CI (0.41, 
0.76); that is, a width of 0.35 for the 95% CI.  Given that the major purpose of this study is to 
provide a good estimate for the proportion of R0 to be used as a benchmark for future studies, 
we deemed the width of the 95% CI as adequate.  Assuming that 80% of enrolled participants 
will finish systemic chemotherapy (FOLFIRINOX or GA) and undergo surgery (20% loss), a total 
of 40 participants with resectable or BRPC will be enrolled towards the primary endpoint.  
 
An additional 20 participants with LAPC will be enrolled as part of an exploratory cohort to 
estimate the proportion of individuals that achieve an R0 resection. A prior clinical study has 
suggested that neoadjuvant FOLFIRINOX with losartan followed by individualized CRT in 
patients with LAPC is associated with an R0 resection rate of 61%. The impact of providing an 
early switch to GA in the neoadjuvant setting after failing FOLFIRNOX has not been sufficiently 
explored in patients with LAPC. This exploratory cohort will be used as a benchmark for future 
studies. 
 
11.3 
POPULATIONS FOR ANALYSES  
 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
   COHORTS AND SUBGROUPS 
 
Resectable and BRPC participants (n = 40) and LAPC participants (n = 20) will be analyzed as 
two separate disease cohorts.  
Subgroup analysis will be performed for those receiving NeoOPTIMZE adaptive therapy 
followed by radiation therapy, where indicated (treatment subset).   
 SAFETY ANALYSIS SET 
 
The safety analysis set includes all enrolled participants who received at least 1 dose of 
systemic chemotherapy (FOLFIRINOX or GA).  All safety analyses will be conducted using the 
safety population.  Analysis for demographics, baseline characteristics, disease history, on-
study treatment summaries and participant disposition will also be conducted using this safety 
population.   
 
The surgery safety analysis set is a sub-set of the safety analysis set that includes all 
participants who undergo surgical resection of their pancreatic cancer (per institutional 
standard).  
 
 EFFICACY ANALYSIS SET 
 
The efficacy analysis set includes all participants enrolled in the study who received at least 1 
dose of systemic chemotherapy (FOLFIRINOX or GA) and had at least 1 post-baseline disease 
assessment.   
 
 
11.4 
DESCRIPTION OF STATISTICAL METHODS 
 
 DESCRIPTIVE STATISTICS 
 
Descriptive statistics will be used to summarize disposition, demographics, baseline 
characteristics, baseline disease characteristics, study drug administration, and safety 
outcomes.  Descriptive summaries of discrete data will present the sample size and the 
incidence as frequency and percentage.  Descriptive summaries of continuous data will present 
the sample size, group mean, standard deviation, median, and range.  Confidence intervals (CI) 
may be included as appropriate. The analyses will be stratified by disease cohort (Resectable or 
BRPC patients vs. LAPC patients).  
 
 
Baseline Descriptive Statistics 
 
Summaries of demographics, baseline characteristics, and baseline disease characteristics will 
be presented for participants using the safety analysis set to include the following: 
 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Demographics: 
Baseline Disease characteristics: 
• Sex (Male, Female) 
• Disease stage at study entry 
• Age (continuous) 
• Mutational status (if reported) 
• Ethnicity 
 
• Race 
 
Baseline Characteristics: 
 
• Height (cm) 
 
• Weight (kg) 
 
• ECOG performance status 
 
 
 
On-study Treatment Summaries 
 
Overall exposure to study drugs (FOLFIRINOX and/or GA) and RT, the numbers of participants 
completing each cycle, and the dose intensity will be summarized using descriptive statistics.  
 
 ANALYSIS OF PRIMARY ENDPOINT 
 
Using the surgery analysis set, the proportion of resectable or BRPC participants with R0 
resection will be estimated with exact 95% CI.  
 
 ANALYSIS OF THE SECONDARY ENDPOINTS  
 
Using the efficacy analysis set for resectable and BRPC participants, the estimated distribution 
of the PFS, and OS will be plotted using Kaplan Meier curves and reported with median survival 
and 95% confidence intervals (if available) for the full population and for the treatment subset 
(NeoOPTIMIZE plus RT). DFS will be analyzed similarly using the surgery analysis set and 
using surgical patients in the treatment subset (NeoOPTIMIZE plus RT).When feasible, sub-
group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX ± RT [i.e., short- 
or long-course, or both RT modalities combined]) will be performed for PFS, DFS, and OS.  
 
The incidence of grade ≥3 toxicities will be determined using the safety analysis set for all 
participants (both disease cohorts).  The exact 95% confidence interval will be reported with the 
point estimate of toxicity rate. 
 
Peri- and post-operative complications occurring within 30 days following surgery will be 
categorized per the Clavien-Dindo classification system.  Using the surgery analysis set for 
resectable and BRPC participants, the proportion of participants with peri- and post-operative 
complications occurring within 30 days following surgery, and the proportion of 30-day post-
operative mortality will be estimated and reported with two-sided exact 95% confidence 
intervals.  If necessary, the proportion of 30-day post-operative mortality may be estimated from 
the Kaplan Meier method. 
 
 ANALYSIS OF THE EXPLORATORY ENDPOINTS  
 
Using the safety analysis set, the levels of CA19-9 will descriptively reported (across all 
participants).  
 
Using the surgery analysis set, the proportion of LAPC participants with R0 resection will be 
estimated with exact 95% CI.  

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
When adequate data are available, PFS, DFS and OS for LAPC patients will be analyzed as 
described above using the LAPC efficacy set, and the LAPC treatment subset (NeoOPTIMZE 
plus RT).Surgical complications and 30-day post-operative mortality will be estimated as above 
using the LAPC surgical set, when there are sufficient numbers of participants undergoing 
resection.  Results will be qualitatively described when statistical measures are not feasible. 
 
 SAFETY ANALYSES 
 
Adverse events will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA 
Version 21.1) preferred term and system organ class and a preferred term.  The severity of the 
AE will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0 criteria.  Descriptive statistics using the safety analysis 
set will be used to report on all on-study grade ≥ 3 AEs per CTCAE v5.0.  Grade 3-4 laboratory 
abnormalities will be summarized using worst grade NCI CTCAE v 5.0 criteria. 
 
11.5 
HANDLING OF MISSING DATA 
 
Missing data will not be imputed.  Whenever possible, the analysis will be conducted using all 
available data.  Missing data will be reported in the descriptive summary, and it will be noted if 
participants were excluded from the analysis due to missing data. 
 
12. CLINICAL MONITORING 
 
12.1 
OHSU KNIGHT COMPREHENSIVE CANCER CENTER DATA & SAFETY 
MONITORING PLAN 
 
All clinical trials at the Knight are required to have a Data and Safety Monitoring Plan (DSMP). 
This study is under the oversight of the Knight Comprehensive Cancer Center’s DSMC as 
described in the Knight institutional DSMP.  The Knight DSMP outlines the elements required to 
ensure the safety of clinical trial participants, the accuracy and integrity of the data, and the 
appropriate modification of cancer-related clinical trials for which significant benefits or risks 
have been discovered or when the clinical trial cannot be successfully concluded. The Knight 
DSMP also describes the methods and procedures for ensuring adequate, risk-based oversight 
of cancer-related research at OHSU. 
 
As described in the Knight DSMP, regardless of a trial’s risk level and any specific Knight 
oversight in place, the Investigator is singularly responsible for overseeing every aspect of the 
design, conduct, and final analysis of his/her investigation.  The Knight DSMC reviews and 
monitors data for this study.  The DSMC comprises clinical and research specialists who have 
experience in oncology and who have no direct relationship with the study.  The DSMC will 
address any issue that raises questions about data integrity or trial participant safety with the 
Investigator and study team.  Should any major concern arise, the Knight DSMC may also 
recommend corrective action, and determine whether to suspend or terminate the study. 
 
The Knight DSMC initially reviews each protocol to determine the risk profile of the trial design. 
This assessment establishes trial reporting requirements commensurate with the risk, and also 
directs the scope and frequency of Quality Assurance audits.  The DSMC may adapt report and 
audit requirements at any time, if indicated, (refer to Knight DSMP for additional details on 
reporting and audit frequency).  The Investigator will submit trial-specific data reports for the 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
DSMC to assess toxicity and safety data; the report must provide the DSMC with such 
information as: up-to-date participant accrual; current dose level information; DLT information;  
unexpected AEs that have been reported; AEs and SAEs reported by category; AEs of special 
or clinical interest; summary of any death on study; summary of all deaths occurring within 30 
days of intervention; deviations from the approved protocol that have been reported; eligibility 
exceptions; any inspection, audit, or monitor report; publications and/or developments that may 
affect scientific validity, participant safety or the ethics of the trial, and a summary of trial status. 
The study team will provide other information (e.g. scans, laboratory values) upon request. 
 
12.2 
CLINICAL DATA & SAFETY MONITORING 
 
The OHSU Investigator is ultimately, singularly responsible for overseeing every aspect of the 
investigation, including design, governing conduct at all participating sites, and final analysis of 
study data.  
 
If monitoring is required, per the Knight DSMP, then monitoring visits will be performed during 
the study to ensure that the rights and well-being of human participants are protected, that the 
reported trial data are accurate, and that the conduct of the trial is in compliance with the 
protocol, GCP, and applicable regulatory requirements.  In this case, details of monitoring 
activities, including designation of assigned monitoring entities, scope of monitoring visits, 
timing, frequency, duration of visits, and visit reporting, will be included in a separate TSMP. 
 
If monitoring is required, per the Knight DSMP, then the Investigator agrees that the monitor will 
be permitted to conduct monitoring visits at appropriate intervals.  The Investigator agrees to 
provide all relevant information and documentation as requested by the monitor, including 
access to all original study documents and source data (electronic medical records and/or 
source documents, if necessary).  The monitor will conduct source data review and verification 
as outlined in the TSMP and, following each visit, will generate a report summarizing the visit 
findings. 
 
In the absence of a formal monitoring plan, the Investigator may work with their study team to 
conduct and document internal monitoring of the study to verify protection of human 
participants, quality of data, and/or ongoing compliance with the protocol and applicable 
regulatory requirements. 
 
If at any time Investigator noncompliance is discovered at OHSU or any participating site (if 
applicable), the Sponsor-Investigator shall promptly either secure compliance or end the 
participation of the participating study site. 
 
Independent audits will be conducted by the Knight DSMC to verify that the rights and well-
being of human participants are protected, that the reported trial data are accurate, that the 
conduct of the trial is in compliance with the protocol and applicable regulatory requirements, 
and that evidence of ongoing investigator oversight is present. 
 
12.3 
QUALITY ASSURANCE & QUALITY CONTROL 
 
The investigational site will provide direct access to all trial related source data/documents, and 
reports for the purpose of monitoring by the monitor and/or sponsor, and auditing by the Knight 
DSMC and/or regulatory authorities.  
 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
All clinical trials at the Knight Cancer Institute are required to have a Data and Safety Monitoring 
Plan.  All clinical work conducted under this protocol is subject to ICH GCP guidelines.  This 
includes inspection of study-related records by the lead site, sponsor, its designee, or health 
authority representatives at any time. 
 
QA audit activities will occur as detailed in the Knight institutional DSMP.  All discrepancies, 
queries, deviations, observations, and findings of non-compliance will be compiled into a final 
audit report.  The PI must review and assess each finding, and generate a response to the audit 
report that incorporates a Corrective and Preventative Action (CAPA) plan.  The CAPA must 
analyze root cause(s) of noncompliance to determine the appropriate changes to correct and 
resolve issues, and prevent recurrence. 
 
Quality Control (QC) activities will occur to monitor and ensure the safety of study participants 
and the validity and integrity of data.  Monitoring will be a continuous, ongoing and multifaceted 
process.  This includes review by the Knight DSMC and IRBs, as well as internal data quality 
control, review and evaluation.  Site monitoring visits are central to this process, and will include 
reporting to appropriate individuals with oversight responsibilities. 
 
The Sponsor-investigator, or study monitor, will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
 
 
13. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
13.1 
SOURCE DATA/DOCUMENTS 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. The Investigator will maintain adequate case 
histories of study participants, including accurate CRFs, electronic (e)CRFs and relevant 
electronic data capture (EDC) system (if applicable), and all relevant source documentation. 
 
 PARTICIPANT & DATA CONFIDENTIALITY 
 
The information obtained during the conduct of this clinical study is confidential, and unless 
otherwise noted, disclosure to third parties is prohibited. Information contained within this study 
will be maintained in accordance with applicable laws protecting participant privacy, including 
the provisions of the Health Insurance Portability and Accountability Act (HIPAA). 
 
Participant confidentiality is strictly held in trust by the participating Investigator(s) and study 
team. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or manufacturer supplying study product may inspect all documents and records required to be 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
maintained by the Investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records.  
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and institutional regulations. Study 
participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored within the Knight Comprehensive Cancer Center per OHSU’s 
Information Security Directives. Individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by clinical sites and by Knight Comprehensive Cancer Center research staff will be 
secured and password protected per OHSU’s Information Security Directives. At the end of the 
study, or after the appropriate period of record retention stated in Section 13.1.4, all study 
databases will be de-identified and archived within the Knight Comprehensive Cancer Center. 
 
 DATA COLLECTION & STORAGE: PRIVACY, CONFIDENTIALITY & SECURITY  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. Standard institutional practices will be followed as 
described in the OHSU’s Information Security Directives to maintain the confidentiality and 
security of data collected in this study. Study staff will be trained with regard to these 
procedures. 
 
Loss of participant confidentiality is a risk of participation.  Efforts will be made to keep study 
participant identities confidential except as required by law.  Participants’ samples will be 
identified by code only. Specifically, each consenting participant will be assigned a unique 
coded identifier consisting of numbers.  This identifier will be associated with the participant 
throughout the duration of their participation in the trial.  The coded identifier will also be used to 
identify any participant specific samples. 
 
Basic accrual tracking information (demographic, consent, visit information) will be captured in 
OHSU’s electronic clinical information research system (eCRIS), hosted on OHSU secure 
servers and managed by OHSU’s information technology group at their data center in downtown 
Portland, Oregon.  Any additional printed documents containing participant identifiers, such as 
those from the medical record to confirm eligibility, will be filed in binders and kept in a locked, 
secure location. 
 
Study outcome data will be captured in electronic case report forms (eCRFs) using an electronic 
data capture (EDC) system that is approved by OHSU’s office of Information Privacy and 
Security.  To preserve confidentiality, PHI in the EDC system will be limited to just birth date and 
visit dates.  The web-accessible EDC system is password protected and encrypted with role-
based security, and administered by designated informatics staff within OHSU or Knight 
Comprehensive Cancer Center.  All users of the database are assigned a unique ID, username, 
and password and must complete training appropriate to their role before they are authorized to 
enter, access, and store data in the database.  
 
Where applicable, data from correlative studies may be entered into the EDC system by study 
personnel.  All other electronic data extracts will be stored only on local study site computers 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
and restricted drives, which are limited to only study investigators and staff with authorization to 
access the data.  Quality assurance will be conducted as outlined in Section 12.3, Quality 
Assurance & Quality Control. 
 
 FUTURE USE OF STORED SPECIMENS AND DATA 
 
Each participant who signs consent will be assigned a unique coded identifier consisting of 
numbers.  This identifier will be associated with the participant throughout the duration of their 
participation in the trial.  The coded identifier will be used to identify any participant specific 
samples.  Blood and tissue samples that are collected for the purposes of this protocol will be 
stored until they can be analyzed and will then be destroyed unless the participant consents to 
participation in the Oregon Pancreas Tumor Registry (OPTR).  If the participant agrees, any 
remaining samples (tumor) may be stored in the OPTR (IRB# 3609) indefinitely and further 
analyzed to address scientific questions and/or development of biological tests related to 
pancreatic cancer. 
 
 MAINTENANCE OF RECORDS 
 
Records and documents pertaining to the conduct of this study, source documents, consent 
forms, laboratory test results and medication inventory records, must be retained by the 
Investigator for a period of 2 years until after the investigation is discontinued.  It is the 
responsibility of the sponsor to inform the Investigator when these documents no longer need to 
be retained. 
 
If the Investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed upon designee, such as another institution or another investigator at 
OHSU.  Records must be maintained according to institutional or FDA requirements.  
 
13.2 
PUBLICATION AND DATA SHARING POLICY 
 
This study will adhere to the requirements set forth by the ICMJE and FDAAA that requires all 
clinical trials to be registered in a public trials registry (e.g., ClinicalTrials.gov) prior to participant 
enrollment.  Authors included in the publication of findings from this trial must have participated 
in the work and take public responsibility for appropriate portions of the content.   
 
 DATA SHARING POLICY FOR GENOME-WIDE ASSOCIATION STUDIES (GWAS) 
 
Dissemination of any genetic (genotypic and phenotypic) will be consistent with the permissions 
and limitations delineated on the study consent signed by study participants.  Any genetic data 
shared publically will be completely de-identified.  Documentation that describes how the 
institutions have considered the interests of the research participants, such as privacy and 
confidentiality is required.  
 
 DATA SHARING WITH EXPLORATORY OBSERVATIONAL STUDIES 
 
Associated clinical data will be shared with investigators of the ongoing, OHSU, prospective 
observational study entitled “The Use of Dynamic Contrast Enhanced Magnetic Resonance 
Imaging (DCE MRI) in the Management of Pancreatic Cancer“ (IRB#9694) study if they are 
consented to IRB#9694. Note that participation in IRB#9694 is not required for participation in 
this trial.   

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
13.3 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed.  Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  Conflicts of interest, for all study group members, should be 
disclosed and managed according to OHSU’s established policies and procedures. 
Refer to link: https://o2.ohsu.edu/integrity-department/conflict-of-interest/index.cfm 
 
14. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
14.1 
ETHICAL STANDARD 
 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, 21 CFR 213 (if applicable), and/or the ICH E6. 
 
14.2 
INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
 
14.3 
INFORMED CONSENT 
 
Written informed consent will be obtained from all participants in this trial, as stated in the 
Informed Consent section of 21 CFR Part 50.  Documentation of the consent process and a 
copy of the signed consent shall be maintained in the participant’s medical record.  
 
 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families 
as appropriate. Consent forms will be IRB-approved and the participant will be asked to read 
and review the document. The Investigator will explain the research study to the participant and 
answer any questions that may arise. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks/benefits of the 
study, alternatives to participation, and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the participants for their records. The rights and welfare of the 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
 
14.4 
PROTOCOL REVIEW 
 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Comprehensive Cancer Center’s Clinical Research Review Committee 
(CRRC) and the appropriate IRB prior to any participant being consented on this study.   
 
14.5 
CHANGES TO PROTOCOL  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment submitted by the Investigator and approved by the CRRC and IRB, before the 
revision or amendment may be implemented.  The only circumstance in which the amendment 
may be initiated without regulatory approval is for a change necessary to eliminate an apparent 
and immediate hazard to the participant.  In that event, the Investigator must notify the IRB (and 
sponsor/FDA if under an IND/IDE) within 5 business days after the implementation.  
 
If Sponsor-investigator holds an IND application for this study, the FDA must also be notified of 
changes to the protocol per 21 CFR 312. 
 
15. REFERENCES 
 
1. 
Siegel, R.L., Miller, K.D. & Jemal, A. Cancer statistics, 2017. CA: A Cancer Journal for 
Clinicians 67, 7-30 (2017). 
2. 
Howlader, N., et al. SEER Cancer Statistics Review, 1975-2016,. in SEER Cancer stats 
April 2019 (2019). 
3. 
Rahib, L., et al. Projecting cancer incidence and deaths to 2030: the unexpected burden 
of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74, 2913-2921 
(2014). 
4. 
Griffin, J.F., Poruk, K.E. & Wolfgang, C.L. Pancreatic cancer surgery: past, present, and 
future. Chinese Journal of Cancer Research 27, 332-348 (2015). 
5. 
Mayo, S.C., et al. Management of patients with pancreatic adenocarcinoma: national 
trends in patient selection, operative management, and use of adjuvant therapy. J Am 
Coll Surg 214, 33-45 (2012). 
6. 
Merkow, R.P., et al. Postoperative complications reduce adjuvant chemotherapy use in 
resectable pancreatic cancer. Annals of surgery 260, 372-377 (2014). 
7. 
Neoptolemos, J.P., et al. Comparison of adjuvant gemcitabine and capecitabine with 
gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a 
multicentre, open-label, randomised, phase 3 trial. The Lancet 389, 1011-1024 (2017). 
8. 
Oettle, H., et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes 
among patients with resected pancreatic cancer: the CONKO-001 randomized trial. 
Jama 310, 1473-1481 (2013). 
9. 
Goldstein, D., et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: 
long-term survival from a phase III trial. J Natl Cancer Inst 107(2015). 
10. 
Von Hoff, D.D., et al. Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. The New England journal of medicine 369, 1691-1703 (2013). 
11. 
Conroy, T., et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. 
New England Journal of Medicine 364, 1817-1825 (2011). 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
12. 
Sahora, K., et al. NeoGemOx: Gemcitabine and oxaliplatin as neoadjuvant treatment for 
locally advanced, nonmetastasized pancreatic cancer. Surgery 149, 311-320 (2011). 
13. 
Sahora, K., et al. NeoGemTax: Gemcitabine and Docetaxel as Neoadjuvant Treatment 
for Locally Advanced Nonmetastasized Pancreatic Cancer. World Journal of Surgery 35, 
1580-1589 (2011). 
14. 
Jang, J.Y., et al. Oncological Benefits of Neoadjuvant Chemoradiation With Gemcitabine 
Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer: A 
Prospective, Randomized, Open-label, Multicenter Phase 2/3 Trial. Annals of surgery 
268, 215-222 (2018). 
15. 
Saif, M.W., Syrigos, K.N. & Katirtzoglou, N.A. S-1: a promising new oral fluoropyrimidine 
derivative. Expert Opinion on Investigational Drugs 18, 335-348 (2009). 
16. 
Hosein, P.J., et al. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or 
borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer 12, 
199 (2012). 
17. 
Blazer, M.A., et al. Tolerability and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in 
patients with borderline-resectable pancreatic cancer (BRPC) and locally advanced 
unresectable pancreatic cancer (LAURPC). Journal of Clinical Oncology 32, 275-275 
(2014). 
18. 
Sohal, D., et al. SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) 
with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic 
ductal adenocarcinoma (PDA). J Clin Oncol 38(2020). 
19. 
Versteijne, E., et al. Preoperative Chemoradiotherapy Potentially Improves Outcome for 
(Borderline) Resectable Pancreatic Cancer: Preliminary Results of the Dutch 
Randomized Phase III PREOPANC Trial. International Journal of Radiation 
Oncology*Biology*Physics 102, 1606-1607 (2018). 
20. 
Murphy, J.E., et al. Total Neoadjuvant Therapy With FOLFIRINOX Followed by 
Individualized Chemoradiotherapy for Borderline Resectable Pancreatic 
Adenocarcinoma: A Phase 2 Clinical Trial. JAMA oncology 4, 963-969 (2018). 
21. 
Cannon, A., et al. Desmoplasia in pancreatic ductal adenocarcinoma: insight into 
pathological function and therapeutic potential. Genes Cancer 9, 78-86 (2018). 
22. 
Padera, T.P., et al. Cancer cells compress intratumour vessels. Nature 427, 695-695 
(2004). 
23. 
George, A.J., Thomas, W.G. & Hannan, R.D. The renin–angiotensin system and cancer: 
old dog, new tricks. Nature Reviews Cancer 10, 745-759 (2010). 
24. 
Pinter, M. & Jain, R.K. Targeting the renin-angiotensin system to improve cancer 
treatment: Implications for immunotherapy. Science Translational Medicine 9, eaan5616 
(2017). 
25. 
Liu, J., et al. TGF-β blockade improves the distribution and efficacy of therapeutics in 
breast carcinoma by normalizing the tumor stroma. Proceedings of the National 
Academy of Sciences 109, 16618-16623 (2012). 
26. 
Provenzano, Paolo P., et al. Enzymatic Targeting of the Stroma Ablates Physical 
Barriers to Treatment of Pancreatic Ductal Adenocarcinoma. Cancer Cell 21, 418-429 
(2012). 
27. 
Chauhan, V.P., et al. Angiotensin inhibition enhances drug delivery and potentiates 
chemotherapy by decompressing tumour blood vessels. Nature communications 4, 2516 
(2013). 
28. 
Diop-Frimpong, B., Chauhan, V.P., Krane, S., Boucher, Y. & Jain, R.K. Losartan inhibits 
collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in 
tumors. Proceedings of the National Academy of Sciences 108, 2909-2914 (2011). 
29. 
Murphy, J.E., et al. Total Neoadjuvant Therapy With FOLFIRINOX in Combination With 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A 
Phase 2 Clinical Trial. JAMA oncology 5, 1020-1027 (2019). 
30. 
Yu, I.S. & Cheung, W.Y. A Contemporary Review of the Treatment Landscape and the 
Role of Predictive and Prognostic Biomarkers in Pancreatic Adenocarcinoma. Canadian 
Journal of Gastroenterology and Hepatology 2018, 10 (2018). 
31. 
Insert, O.P. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208558s010lbl.pdf. (2019). 
32. 
Berardi, R., et al. Prognostic factors in pancreatic cancer: The role of perineural, 
vascular and lymphatic invasion and of Ca 19-9. J Gastroint Dig Syst 3, 2 (2013). 
33. 
Ferrone, C.R., et al. Perioperative CA19-9 Levels Can Predict Stage and Survival in 
Patients With Resectable Pancreatic Adenocarcinoma. Journal of Clinical Oncology 24, 
2897-2902 (2006). 
34. 
Hartwig, W., et al. CA19-9 in potentially resectable pancreatic cancer: perspective to 
adjust surgical and perioperative therapy. Annals of surgical oncology 20, 2188-2196 
(2013). 
35. 
Wong, D., et al. Serum CA19-9 decline compared to radiographic response as a 
surrogate for clinical outcomes in patients with metastatic pancreatic cancer receiving 
chemotherapy. Pancreas 37, 269-274 (2008). 
36. 
Tsai, S., et al. Importance of Normalization of CA19-9 Levels Following Neoadjuvant 
Therapy in Patients With Localized Pancreatic Cancer. Annals of surgery (2018). 
37. 
Brand, R.E., et al. Serum Biomarker Panels for the Detection of Pancreatic Cancer. 
Clinical Cancer Research 17, 805-816 (2011). 
38. 
Chawla, A. & Ferrone, C.R. Neoadjuvant Therapy for Resectable Pancreatic Cancer: An 
Evolving Paradigm Shift. Frontiers in Oncology 9(2019). 
39. 
Hu, Q., et al. Network meta-analysis comparing neoadjuvant chemoradiation, 
neoadjuvant chemotherapy and upfront surgery in patients with resectable, borderline 
resectable, and locally advanced pancreatic ductal adenocarcinoma. Radiation oncology 
(London, England) 14, 120-120 (2019). 
40. 
Silvestris, N., et al. Neoadjuvant multimodal treatment of pancreatic ductal 
adenocarcinoma. Crit Rev Oncol Hematol 98, 309-324 (2016). 
41. 
Sohal, D., et al. SWOG S1505: Initial findings on eligibility and neoadjuvant 
chemotherapy experience with mfolfirinox versus gemcitabine/nab-paclitaxel for 
resectable pancreatic adenocarcinoma [Abstract 414]. Journal of Clinical Oncology 
34(2019). 
42. 
Ettrich, T.J., et al. Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus 
gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a 
prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group. 
BMC cancer 18, 1298-1298 (2018). 
43. 
Vreeland, T.J., et al. Benefit of Gemcitabine/Nab-Paclitaxel Rescue of Patients With 
Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma After Early 
Failure of FOLFIRINOX. Pancreas 48, 837-843 (2019). 
44. 
Katz, M.H.G., et al. Preoperative modified FOLFIRINOX treatment followed by 
capecitabine-based chemoradiation for borderline resectable pancreatic cancer alliance 
for clinical trials in oncology trial A021101. JAMA Surgery 151(2016). 
45. 
Petrelli, F., et al. FOLFIRINOX-Based Neoadjuvant Therapy in Borderline Resectable or 
Unresectable Pancreatic Cancer: A Meta-Analytical Review of Published Studies. 
Pancreas 44(2015). 
46. 
Suker, M., et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic 
review and patient-level meta-analysis. The Lancet Oncology 17, 801-810 (2016). 
47. 
Gemenetzis, G., et al. Survival in Locally Advanced Pancreatic Cancer After 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Neoadjuvant Therapy and Surgical Resection. Annals of surgery 270(2019). 
48. 
Dindo, D., Demartines, N. & Clavien, P.A. Classification of surgical complications: a new 
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 
240, 205-213 (2004). 
49. 
Amin, M.B., et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build 
a bridge from a population-based to a more "personalized" approach to cancer staging. 
CA: a cancer journal for clinicians 67, 93-99 (2017). 
50. 
Strobel, O., et al. Pancreatic Cancer Surgery: The New R-status Counts. Annals of 
surgery 265(2017). 
51. 
Gillen, S., Schuster, T., Meyer Zum Büschenfelde, C., Friess, H. & Kleeff, J. 
Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-
analysis of response and resection percentages. PLoS Med 7, e1000267 (2010). 
52. 
Tsujikawa, T., et al. Quantitative multiplex immunohistochemistry reveals myeloid-
inflamed tumor-immune complexity associated with poor prognosis. Cell reports 19, 203-
217 (2017). 
53. 
Lin, J.R., Fallahi‐Sichani, M., Chen, J.Y. & Sorger, P.K. Cyclic Immunofluorescence 
(CycIF), A Highly Multiplexed Method for Single‐cell Imaging. Current protocols in 
chemical biology, 251-264 (2016). 
54. 
Lin, J.-R., Fallahi-Sichani, M. & Sorger, P.K. Highly multiplexed imaging of single cells 
using a high-throughput cyclic immunofluorescence method. Nature communications 6, 
8390 (2015). 
55. 
Bodenmiller, B. Multiplexed epitope-based tissue imaging for discovery and healthcare 
applications. Cell systems 2, 225-238 (2016). 
56. 
Dewhirst, M.W. & Secomb, T.W. Transport of drugs from blood vessels to tumour tissue. 
Nature Reviews Cancer 17, 738 (2017). 
57. 
Swartz, M.A. & Lund, A.W. Lymphatic and interstitial flow in the tumour 
microenvironment: linking mechanobiology with immunity. Nature Reviews Cancer 12, 
210 (2012). 
58. 
Wilson, W.R. & Hay, M.P. Targeting hypoxia in cancer therapy. Nature Reviews Cancer 
11, 393 (2011). 
59. 
Fridman, W.H., Pagès, F., Sautès-Fridman, C. & Galon, J. The immune contexture in 
human tumours: impact on clinical outcome. Nature Reviews Cancer 12, nrc3245 
(2012). 
60. 
Yao, S., Fan, L.Y.-N. & Lam, E.W.-F. The FOXO3-FOXM1 axis: A key cancer drug 
target and a modulator of cancer drug resistance. in Seminars in cancer biology 
(Elsevier, 2017). 
61. 
Baylin, S.B. & Jones, P.A. A decade of exploring the cancer epigenome—biological and 
translational implications. Nature Reviews Cancer 11, 726 (2011). 
62. 
Tsujikawa, T., et al. Quantitative Multiplex Immunohistochemistry Reveals Myeloid-
Inflamed Tumor-Immune Complexity Associated with Poor Prognosis. Cell Reports 19, 
203-217 (2017). 
 
 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
APPENDIX A: PERFORMANCE STATUS 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
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. 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
APPENDIX B: CONTRACEPTION 
 
Females of childbearing potential who are sexually active with a non-sterilized male partner or 
partners of male participant must use 2 highly effective method of contraception.  These include: 
levonorgestrel-releasing intrauterine system (e.g., Mirena®), copper intrauterine device, and 
hormonal methods. Appropriate hormonal contraceptives include:  Etonogestrel-releasing 
implants (e.g. Implanon® or Norplant®), ethinylestradiol/etonogestrel-releasing intravaginal 
devices (e.g. NuvaRing®), medroxyprogesterone injection (e.g., Depo-Provera®), normal and 
low dose combined oral contraceptive pill, norelgestromin/ethinylestradiol-releasing transdermal 
system (e.g. Ortho Evra®), progesterone based oral contraceptive pill using desogestrel (NB, 
Cerazette® is currently the only highly effective progesterone-based)  
 
Non-sterilized male participants, or partners of female participant, must use male condom plus 
spermicide throughout this period.  Cessation of birth control after this point should be 
discussed with a responsible physician.  Abstaining from sexual activity for the total duration of 
the drug treatment and the drug washout period is an acceptable practice for both female and 
male participants; however, periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of birth control. Female participant should also refrain from 
breastfeeding throughout this period. 
 
 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
APPENDIX C: EXPLORATORY RESEARCH 
 
The following describes exploratory research assays that may be conducted in an effort to 
better understand the tumor biology of pancreatic cancer.  The ability to conduct any of the 
assays described herein is limited to sample availability.  Any excess samples may be stored for 
future research.  
 
A-1. 
EXOSOME PROFILING 
 
Exosomes are vesicles secreted from living cells. In cancer, these exosomes are responsible for 
intercellular communication that can facilitate tumor promoting enterprises such as immune 
evasion, angiogenesis, and metastases. The extent to which PDAC-derived exosomes are 
involved in promoting tumor progression and treatment resistance remains unknown.  
 
i) 
Methods of Assessment  
 
Exosomes will be recovered from blood plasma samples using commercial kits (e.g., Total 
Exosome Isolation Reagent [ThermoFisher]) and established methods. Various molecular 
assays (e.g., ELISA, Mass Spectroscopy, RNA Seq) will be used to quantitative analyze the 
proteomics, transcriptomics and metabolomics of the exosomes.  
 
ii) 
Outcome Measure 
 
Quantitative analysis of proteomics, transcriptomics and metabolomics of the PDAC-derived 
exosomes as it relates to clinical outcomes.  
 
A-2. 
MUTATIONAL GENE PROFILING  
 
Mutations and aberrant gene expression within tumor biopsy samples may be identified using 
the GeneTrails® Comprehensive Solid Tumor Panel, a custom gene assay that is processed 
and analyzed within OHSU’s KDL.  A portion of tumor tissue collected from surgical resection 
will be used for these studies.  The tumor tissue collected will be preserved in FFPE for 
subsequent DNA extraction.   The custom assay provides information on clinically informative 
alterations on profiled genes.  Alterations may include single nucleotide substitutions, insertions, 
deletions, and gains or losses in gene copy number. Up to 50 alterations may be reported for 
any sample, although most will have less than 10.  The panel has a lower limit of detection of 
~3-5% mutant allele.  
 
i) 
Methods of Assessment  
 
A portion of the tumor biopsy specimens (FFPE) will be processed and analyzed within OHSU’s 
KDL according to established institutional standards.  
 
ii) 
Outcome Measure 
 
Characterization of genetic alterations based on custom gene panel.  
 
A-3. 
MICROSATELLITE INSTABILITY  
 
Possible microsatellite instability (MSI) may be assessed within OHSU’s KDL using polymerase 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
chain reaction (PCR) per institutional standards.  A portion of tumor tissue collected from 
surgical resection will be used for these studies.  Peripheral blood will be collected and may also 
be used as a matched control.  The tumor tissue collected may be preserved in FFPE for 
subsequent DNA extraction.  Possible MSI will be evaluated using PCR to co-amplify 5 
mononucleotide markers (BAT-25, BAT-26, NR-21, NR-24, MONO-27), and 2 pentanucleotide 
markers (Penta C and Penta D).  The mononucleotide markers are used for MSI determination 
and the pentanucleotide markers are used to confirm identity match in the tumor tissue and 
matched control blood in each participant.  Samples with instability in two or more of these 
mononucleotide markers are designated MSI-High (MSI-H), whereas those with one unstable 
marker are designated MSI-Low (MSI-L).  Samples with no detectable alterations are MSI-
stable (MSS). 
 
i) 
Methods of Assessment  
 
A portion of the tumor biopsy specimens (FFPE) will be processed and analyzed within OHSU’s 
KDL according to established institutional standards.  
 
ii) 
Outcome Measure 
 
Characterization of MSI profile.   
 
A-4. 
MULTIPLEX IMMUNOHISTOCHEMISTRY AND CYCLIC IMMUNOFLUORESCENCE  
 
Multiplex Immunohistochemistry (mIHC) and cyclic Immunofluorescence (cycIF) will be used to 
facilitate an examination of the tumor intrinsic and extrinsic mechanisms that may change during 
treatment and reduce therapeutic response.  In this study mIHC and cycIF, with a panel of >100 
validated antibodies will allow analysis of the molecular characteristics and organization of 
tumor cells and the microenvironments in which they live.  The rationale for use mIHC is that it 
is easily implemented on conventional autostainers and so can be widely propagated 
particularly in CLIA environments.  Likewise, cycIF enables very high dimension analysis on 
single FFPE sections using conventional reagents and existing instruments to generate high 
quality image data from a wide range of sample types. 
 
Both mIHC52 and cycIF53,54 technologies provide the ability to comprehensively assess the 
functional states of cells within tissues at several levels. These assays are intended to provide 
three levels of information55: (a) expression levels of epitopes that report on cell types and 
biological processes, (b) identity and organization of specific cell types, and (c) functional state 
of each cell type in environmental context thereby allowing assessment of the biological and 
clinical consequences of cell-environment interaction.  The latter information is statistically 
powerful since it allows each tissue section to be analyzed as a set of millions of individual cell-
microenvironment interactions.  Further, these assays allow assessment of subcellular 
localization which plays a critical role in the functionality of multiple proteins.  We have validated 
panels of antibodies (Table 25) that enable assessment of several aspects of biology that may 
alter therapeutic sensitivity including aspects of (a) angiogenesis and lymphangiogenesis56-58, 
(b) immune composition and activity52,59, (c) differentiation state54, (d) cell proliferation53,60, and 
(e) and extracellular matrix composition.54,61  Additional antibodies may be selected as more 
information becomes available.  
 
Table 30. Summary protein panel for evaluation by mIHC and cycIF 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
Lymphoid panel  
PD-1, CD3, RORgt, CD56, CD8, Tbet, GATA3, FoxP3, PD-L1, CD20, CD45 
Myeloid panel, 
Tryptase, CD68, CSF1R, DC-SIGN, CD66b, CD83, CD163, MHCII, PD-L1, 
CD3/20/56, CD45, Tim3 
T cell functional panel 
CD45, CD3, CD4, CD8, IDO, Tbet, CD68, PD-1, Eomes, Ki67, Granzyme B, 
IL-10 
Lymphatic vessels  
LYVE1, podoplanin, VEGFR3, PROX1 
Hematogenous 
vessels  
CD34, CD31, MECA79 
Pericytes  
aSMA, PDGFRb, NG2, Desmin 
Endothelial cell 
activation &adhesion 
P/E Selectin, ICAM-1, VCAM-1, FasL, VEGFR1, VEGFR2, EDN1 
Fibroblasts  
aSMA, CD140a, vimentin, FAP 
Epithelial 
differentiation 
CK5, CK7, CK8, CK14, CK17, CK19; actin, GFAP, MAP2, vinculin, TUBB3, 
pAURK, E-cadherin, N-cadherin, EpCAM, chromogranin A, CD44, Insulin 
Cell status 
HER2, EGFR, pEGFR (Tyr1068), MET, NGFR, ER, PgR, AR, PgR, Ki67, 
PCNA, CDK4, CycD1, CycA2, MCM6, pHistone H3, cleaved PARP, S6RP, 
pS6RP), RB, pRB, POL2A, p21, p27, pSRC, Bax, cCasp3, pCHK2, Bcl2, 
Survivin, gH2ax, cJun, FOXOA1, NFATc1, FOXA2, NF B, pSTAT3, cMYC, 
E2F1, pTyr, S100A4, HSP90b, KAP1.TIF1b, LAMP2, TPCN2, AKT, pAKT, 
pmTOR, pERK, TP53, pATM, 14-3-3, pNDRG1, CoxIV, Tubulin, LaminA/C, 
LaminB1, Fibrillian, NUP98, -catenin 
Extracellular matrix  
Collagen IV, laminin (pan), collagen 1 (pan) 
 
A.4.1. 
Multiplex Immunohistochemistry 
 
i) 
Method of Assessment 
 
A portion of both tumor biopsy and resection specimens (FFPE) will be used for multiplex 
immuno-histochemistry (IHC) profiling as previously reported.62   
 
ii) 
Outcome Measure 
 
Multiplex IHC will be used to quantitatively assess the immune cell complexity (i.e., variations in 
lymphoid and myeloid lineages) and functional status of T cells within tumors of participants 
receiving treatment. Biomarkers markers to be evaluated include (but not limited to) those listed 
in Table 25.  
 
A.4.2. 
Cyclic Immunofluorescence imaging (cycIF)  
 
i) 
Method of Assessment 
 
CycIF analysis will be performed on a single 4-5 µm thick FFPE section cut from core that is in 
as-close proximity to the sections used for mIHC.  The cycIF process is iterative, involving four 
sequential steps: (a) Staining with fluorophore-conjugated antibodies against different protein 
antigens.  We currently use antibodies conjugated to Alexa 488, 555, and 647. (b) Staining with 
Hoechst 33342 to mark nuclei. (c) Four-channel imaging at low and high magnification (10X, 
20X, and 40X objectives). (d) Fluorophore oxidation using hydrogen peroxide, high pH, and UV 
light, followed by a wash step.  A core set of antibodies (Table 25) will be used to interrogate 
samples.  
 
ii) 
Outcome Measures 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
Develop multi-color cycIF imaging to enable spatial mapping of proteins to define the immune, 
microenvironmental, differentiation and proliferation status in treatment responsive and 
treatment resistant FFPE pancreas.  
 
A-5. 
WHOLE EXOME AND TRANSCRIPTOME SEQUENCING 
 
CLIA Whole Exome Sequencing using a hybrid-capture library and run on Illumina sequencing 
instrumentation will be performed on matched tumor/normal pairs derived from tumor surgical 
resection specimens and peripheral blood, respectively.  Non-CLIA Whole Transcriptome 
Sequencing using the Illumina TruSeq RNA Access kit (or other whole transcriptome library 
preparation) and run on Illumina sequencing instrumentation will be performed on RNA from 
both tumor biopsy and surgical resection specimens.  
 
i) 
Methods of Assessments 
 
This study will evaluate the longitudinal DNA and RNA sequencing data being generated from 
participant’s tissue collected during this clinical trial. This will include assessment of clonal 
selection and acquisition of new mutations driving resistance; identification of deregulated 
transcriptional networks induced after acquisition of resistance; and an integration of the data 
from across the two modalities. 
 
ii) 
Outcome measures 
 
Genomic alterations and transcriptional pathways associated with therapeutic resistance in each 
participant. 
 
A-6. 
HIGH RESOLUTION STRUCTURAL ANALYSIS 
 
A portion of the tumors will be examined using high resolution electron microscopy.  This 
research will support goals of understanding structural heterogeneity and responses to therapy. 
 
i)      Methods of Assessments 
 
Tumor tissues will be placed in EM fixative (2.5% glutaraldehyde + 2% paraformaldehyde) prior 
to resin embedding and imaging with scanning beam EM 
 
ii)      Outcome measures 
 
Assessment of subcellular structures and cellular contacts pre- and post-therapy. 
 
A-7. 
LIVE CELL PROPAGATION AND GROWTH INHIBITION 
 
Propagated patient-derived cell models will be screened against multiple therapeutic strategies 
to learn about sensitivity as well as innate and adaptive resistance to therapeutics.     
 
i)       Methods of Assessments 
 
Primary cells will be isolated and grown as necessary under short term growth conditions to 
provide enough cells to support the assay, which involves exposure to a panel of 30-400 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
different small molecule therapeutics. Effects on growth will be measured after 48-96 hours of 
exposure. Where feasible, long-term propagation of tumor-derived cells may also be attempted.  
 
ii) 
Outcome measures 
 
Cellular resistance or sensitivity to standard of care or targeted therapies will be quantified 
through multiple metrics. 
 
A-8. 
FUSION GENE PROFILING 
 
i) 
Method of Assessment 
 
The potential for fusion genes within tumor biopsy samples will be assessed using the 
GeneTrails® Solid Tumor Fusion Gene panel (or an equivalent CLIA validated gene fusion 
assay), a custom assay that is processed and analyzed within OHSU’s KDL.  A portion of tumor 
tissue derived from core needle biopsy collected will be used for these studies.  The biopsied 
tumor tissue collected may be FFPE for subsequent RNA extraction.  
 
ii) 
Outcome Measure 
 
Fusion genes* to be screened include: 
AKT3 
ALK 
BRAF 
EGFR 
EGFR vIII 
ERBB4 
ERG 
FGFR1 
FGFR2 
FGFR3 
MET 
NOTCH1 
NOTCH2 
NRG1 
NTRK1 
NTRK2 
NTRK3 
NUTM1 
PDGFRA 
RAF1 
RET 
ROS1 
 
 
Additional genes may be added as more information becomes available. 
 
This test is designed to detect fusions involving the genes listed above, and is agnostic with 
respect to fusion partners.  All of the driver genes are known to play a role in cancer growth, and 
most of them are actionable with one or more targeted therapies.  Submitted samples are 
examined microscopically and genomic RNA is extracted and purified from dissected, tumor-rich 
areas.  Sequencing libraries are prepared from cDNA using an amplicon-based methodology 
and are sequenced by massively parallel sequencing on an Illumina NextSeq500.  The gene 
fusions can be detected to the range of approximately 1-5% of input cells. 
 
A-9. 
CELL FREE TUMOR DNA (CFDNA) 
 
Assessing cfDNA facilitate determining mechanisms of resistance to the on-study therapeutic 
regimen by identifying genetic changes in tumors as they evolve.  The notion that resistant 
tumors are often distinct clones that separated lineages from those that are identified at the 
beginning of therapy. 
 
i) 
Methods of Assessments 
 
Whole exome sequencing of ctDNA collected after disease progression. These studies will 
compare mutations identified before treatment with those present after treatment to identify 
genetic selection. Additional measure may include the number of genetic lesions shared 
between primary and resistant tumors. 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
 
ii) 
Outcome measures 
 
cfDNA levels from serial blood samples for each participant. 
 
A-10. CIRCULATING TUMOR DNA 
 
i) 
Method of Assessment  
 
Circulating tumor DNA may be isolated from peripheral blood and used to assess genomic 
alterations and tumor heterogeneity. DNA from peripheral blood cells and cell free DNA may be 
isolated and subjected to whole exome sequencing using a hybrid-capture library and run on 
Illumina sequencing instrumentation.  
 
ii) 
Outcome Measures 
 
Genetic alterations present in circulating tumor DNA may be compared to results from CLIA 
whole exome sequencing to estimate the genetic heterogeneity of a patient’s disease. 
 
A-11. REVERSE PHASE PROTEIN ARRAYS (RPPA) 
 
Serial proteomic characterization of basal protein expression and modification levels will enable 
enhanced insight into the genomic evolution and therapeutic response of metastatic lesions. 
 
i) 
Methods of Assessments 
 
Reverse Phase Protein Arrays (RPPA) will require at least 10 mg of frozen tumor tissue to be 
lysed and protein will be extracted. Diluted lysates will be printed on nitrocellulose-coated slides 
and probed with approximately 300 validated primary antibodies followed by detection with 
Biotinylated secondary antibodies. Signal amplification will be achieved using the Vectastain 
Elite ABC kit from Vector Lab. The slides will be scanned, analyzed, and quantified to generate 
spot intensity values and estimate relative protein levels. 
 
ii) 
Outcome Measures 
 
RPPA data will be used to integrate the consequence of genetic aberrations in tumor biopsy 
samples, to validate therapeutic targets, and to demonstrate on‐ and off‐target activity of drugs. 
 
A-12. CIRCULATING TUMOR CELL (CTC) PROFILING 
 
Circulating tumor cells (i.e. CTCs and circulating hybrid cells, CHCs) may be isolated from 
peripheral blood and analyzed for proliferative and apoptotic index to monitor the extent of 
tumor cell death.  
 
i) 
Method of Assessment  
 
Peripheral blood for hematology and serum biochemistry should be collected per institutional 
guidelines.  In most cases, blood samples for research purposes will be drawn from participants 
scheduled to have venipuncture for routine clinical purposes.  In some cases, when this is not 
possible, a research only blood draw will be undertaken.  Peripheral blood mononuclear cells 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
may be assessed for CHC and CTC numbers and phenotype. 
 
ii) 
Outcome Measures 
 
Apoptotic, proliferative and dormant cells may be quantified and correlated with tumor metrics to 
determine the extent to which tumor cells in the peripheral blood serve as a sensor for treatment 
response. Other markers of biological interest, including cell signaling status, may be assessed 
by immunofluorescence or DNA/RNA sequencing in these cells. 
 
A-13. DIELECTROPHORESIS (DEP) CHIP 
 
Dielectrophoretic lab-on-a-chip devices will be tested for its ability to effectively separate PDAC 
cells as a novel platform for liquid biopsies.  
 
i) 
Method of Assessment  
 
In these experiments, peripheral blood collected for research will be assayed using custom 
DEP-CHIPS to evaluate device performance and their ability to isolate CTCs, cfDNA, as well as 
cell free constituents such as tumor-associated RNA, exosomes, and enzyme. 
 
ii) 
Outcome Measures 
 
Depending on sample availability and type of DEP-CHIP assays, the concentration of ell free 
DNA, RNA, exosome and enzyme biomarkers will quantified.  Additional studies will further 
evaluate the validity of this device as a biomarker platform by comparing the isolated genes and 
proteins with corresponding clinical outcomes data.  
 
A-14. PATIENT-DERIVED XENOGRAFT (PDX) MODELS 
 
Mouse models of patient tumors may be generated to study tumor biology and response to 
therapy. 
 
i) 
Method of Assessment 
 
Fresh tumor tissue obtained from patients in this this trial with pancreatic ductal carcinoma 
(PDAC) will be implanted into mice to propagate the tumors. All mouse work will be performed 
under IACUC-approved protocol(s).  Tumor tissues will either be implanted fresh or may be 
processed and stored at -80oC as viable tissue for implantation at a later time.  Successfully 
growing tumors will be removed and analyzed by similar metrics as described above (gene 
profiling, multiplex immunohistochemistry, and cyclic immunofluorescence) to compare to the 
parent tumor. These models may be used to understand the basic biology of PDAC or to 
explore the efficacy of novel targeted therapies. Once established, the tumors will be expanded 
in mice to generate a collection of PDAC PDX models. We will use these established models 
as pre- clinical models of PDAC tumors to test the efficacy of various chemotherapeutic agents 
on human tumors.  Models established from tumors that do not respond to therapy may be 
used to understand resistance mechanisms. 
 
ii) 
Outcome measures 
 
We will evaluate feasibility of generating patient-derived mouse models using either the pre- or 

 
 
NeoOPTIMIZE: Early Switching of Neoadjuvant FOLFIRINOX or GA for resectable/borderline PDAC 
Protocol Number (eIRB#): STUDY00021614 
Version Number: 2.4 
Version Date:20 September 2023 
PI: Charles Lopez MD, PhD 
post-drug treatment tumor tissues. We will compare the tumor cell and microenvironment 
composition, structural features, genetic alterations, and protein expression of the PDX tumor 
to the original patient tumor.