Conditions: Resected Pancreatic Adenocarcinoma
Keywords: Pancreas Radiation mFOLFIRINOX
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
This trial aims to determine a safe schedule of short-course proton beam radiation therapy with adjuvant mFOLFIRINOX for patients with resected pancreatic adenocarcinoma.

Detailed description:
The investigators hypothesize that resected pancreatic cancer patients will benefit from enhanced local control with the addition of radiation therapy to adjuvant FFX. The recently reported PRODIGE 24 study, demonstrated that 12 cycles of adjuvant FFX without radiation therapy significantly improved survival and time to metastatic failure rates as compared to GEM alone. Excessive distant failures rates using prior adjuvant systemic therapies, may have limited the impact of radiation therapy; therefore, improvements in systemic control can increase the benefit of local control.

In this study, the investigators utilize 5 fraction PRT, delivered over 1 week, during adjuvant FFX (between cycles 6 and 7) to minimize the interruptions in chemotherapy as well as to reduce the length of time from surgical resection to initiating adjuvant radiation therapy. Conventional radiation therapy is typically delivered over 5 weeks and is commonly given after the completion of adjuvant chemotherapy. Conventional radiation therapy cannot be given concurrently with FFX due to the synergistic toxicities. In contrast, PRT significantly reduces the exposure of normal tissues to the effects of radiation therapy and has been safely delivered using a 5 fraction schedule with chemotherapy, as previously discussed.

Chemotherapy will consist of mFOLFIRINOX in 14-day cycles x 12 as used in the PRODIGE 24 study:

* Irinotecan 150 mg/m2 IV day 1
* Oxaliplatin 85 mg/m2 IV day 1
* Leucovorin 400 mg/m2 IV day 1
* 5-fluorouracil 2,400 mg/m2 IV days 1-3 (no bolus)
* Pegfilgrastim 6 mg SC on-body injector day 3 (optional, up to investigator's discretion, can alternatively do day 4 without on-body injector)
* Suggested supportive care medications: fosaprepitant 150 mg IV day 1, dexamethasone 12 mg IV day 1, ondansetron 16 mg IV day 1, dexamethasone 4 mg PO q AM days 2-3, ondansetron 8 mg PO BID days 2-3.
* Dose adjustments will be permitted at the discretion of the treating oncologist based on patients' prior tolerability to FFX
* Proton radiation will consistent of 5 daily doses of 5 GyE total, ideally administered Monday through Friday but can be administered within 7 business days, between cycles 6 and 7

Arms:
arm 1: mFOLFIRINOX + Proton beam radiation

Radiation given on days 8-12 of cycle 6 arm 2: mFOLFIRINOX + Proton beam radiation

Radiation given on days 15-19 of cycle 6

Interventions: intervention 1: mFOLFIRINOX intervention 2: Proton beam radiation
Intervention descriptions: intervention 1: Chemotherapy will consist of mFOLFIRINOX in 14-day cycles x 12 as used in the PRODIGE 24 study:

* Irinotecan 150 mg/m2 IV day 1
* Oxaliplatin 85 mg/m2 IV day 1
* Leucovorin 400 mg/m2 IV day 1
* 5-fluorouracil 2,400 mg/m2 IV days 1-3 (no bolus)
* Pegfilgrastim 6 mg SC on-body injector day 3 (optional, up to investigator's discretion, can alternatively do day 4 without on-body injector)
* Suggested supportive care medications: fosaprepitant 150 mg IV day 1, dexamethasone 12 mg IV day 1, ondansetron 16 mg IV day 1, dexamethasone 4 mg PO q AM days 2-3, ondansetron 8 mg PO BID days 2-3. intervention 2: Proton beam radiation will consist of 5 daily doses of 5 GyE total, ideally administered Monday through Friday but can be administered within 7 business days, between cycles 6 and 7

Protocol document:
Prot_SAP_000.pdf: 
1 
Version 1.0, September 6, 2018 
 
Phase I Study of Proton Therapy in Adjuvant Pancreatic Cancer 
(PROTON-PANC) 
 
Georgetown Protocol #: 
2018-1021 
Clinicaltrials.gov #:   
Pending 
Initial Concept Approval Date: 
Version 1.0, July 18, 2018 
Initial Protocol Version Date: 
Version 1.0, September 6, 2018 
Version 1.1, September 25, 2018 
 
Study Chair:    
Benjamin A. Weinberg, MD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
3800 Reservoir Road, NW 
Washington, DC 20007 
 
 
 
 
Study Radiation Chair:  
Keith Unger, MD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
Washington, DC 
 
 
 
 
 
 
Sub-Investigators:  
John L. Marshall, MD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
Washington, DC 
 
 
Michael J. Pishvaian, MD, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
Washington, DC 
 
 
Sunnie X. Kim, MD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
Washington, DC 
 
 
Aiwu Ruth He, MD, PhD  
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
Washington, DC 


2 
Version 1.0, September 6, 2018 
 
 
Louis M. Weiner, MD    
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
Washington, DC 
 
 
 
Biostatistician:  
Hongkun Wang, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
Washington, DC 
 
Funding Sources: 
Ruesch Center for the Cure of Gastrointestinal Cancers 
 
 
 


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Version 1.0, September 6, 2018 
TABLE OF CONTENTS                                      PAGE 
 
Table of Contents                                                   3 
Figures and Tables                                                  5 
Glossary of Abbreviations and Definition of Terms                            6 
Study Synopsis                                                     8 
1.0 Background and Justification                                       13 
1.1 Pancreatic Ductal Adenocarcinoma                                13 
1.2 Adjuvant Chemotherapy                                       13 
1.3 Adjuvant Chemoradiation                                       13 
1.4 Proton Therapy and Targeted Radiation Therapy for PDAC                13 
1.5 Fluorouracil and Leucovorin                                     14 
1.6 Oxaliplatin                                                 14 
1.7 Irinotecan                                                 15 
1.8 mFOLFIRINOX Regimen                                       15 
2.0 Study Objectives                                                16 
2.1 Primary Objective                                            16 
2.2 Exploratory Objectives                                         16 
2.3 Primary Endpoint                                            16 
     2.4 Exploratory Endpoints                                         16 
     2.5 Indication                                                 16 
3.0 Subject Population                                               17 
3.1 Subject Population, Number of Subjects and Feasibility                   17 
3.2 Inclusion Criteria                                            17 
3.3 Exclusion Criteria                                            18 
3.4 Prior and Concomitant Therapy                                   19 
4.0 Trial Design and Detailed Study Procedures                             20 
4.1 Treatment Plan Overview                                       20 
 
4.2 Detailed Study Plan                                          21 
 
4.3 Patient Study Number Assignment and Sample Labeling                  23 
 
4.4 Detailed Patient Assessments                                    23 
5.0 Dosages and Dispensation of Drugs                                   31 
 
5.1 mFOLFIRINOX Administration                                   31 
 
5.2 Packaging, Labeling, Storage, and Handling of Chemotherapy              31 
6.0 Safety Variables and Toxicity Assessment                              32 
 
6.1 Adverse Event Assessments                                    32 
 
6.2 Study Monitoring                                            32 
 
6.3 Adverse Events and Toxicity Definitions                             33 
6.4 Adverse Events Collection Period                                 34 
6.5 Adverse Events Reporting                                        34 
6.6 Pregnancy                                                35 
6.7 Toxicity Management and Dose Adjustments                         35 
6.8 Prohibited Concomitant Medications                               36 
7.0 Efficacy Assessment                                             37 
7.1 Efficacy Variables                                            37 
     7.2 RECIST v1.1 Criteria for Tumor Response                           37 
     7.3 Evaluation of Best Overall Response                               37 
     7.4 Definition of Disease Recurrence                                 38 
8.0 Statistical Considerations                                          39 
      8.1 Primary Objective                                           39 
      8.2 Exploratory Objectives                                        39 
      8.3 Primary Endpoint                                           39 
      8.4 Exploratory Endpoints                                        39 


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      8.5 Study Design and Sample Size Calculation                          39 
      8.6 Analysis Plan for Exploratory Objectives                            40 
      8.7 Safety Assessments                                         40 
9.0 Ethical Considerations                                            41 
      9.1 Institutional Review Board (IRB)                                 42 
      9.2 Ethical Conduct of the Study                                    42 
      9.3 Subject Information and Consent                                 42 
      9.4 Ethical Consideration for Enrollment                              42 
      9.5 Protection of Patient Confidentiality                               42 
Appendices 
Appendix A – References                                             42 
 
 


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Version 1.0, September 6, 2018 
FIGURES, TABLES, AND ABBREVIATIONS                        PAGE  
Figures  
Figure 1: Study Schema                                            11, 21 
Figure 2: Chemical Structure of Fluorouracil                                  14 
Figure 3: Chemical Structure of Oxaliplatin                                   15 
 
Tables 
Table 1: ECOG Performance Status                                        8 
Table 2: Study Activities (Dose Level 1)                                     26 
Table 3: Study Activities (Dose Level 2)                                     27 
Table 4: Study Activities Checklist                                        28 
Table 5: Drug Administration                                            31 
Table 6: Dose Levels for Modifications for mFOLFIRINOX (Recommended)             35 
Table 7: Dose Modifications for mFOLFIRINOX (Recommended)                    35 
Table 8: Dose Limiting Toxiticies                                         36 
 
 
                         
 
 


6 
Version 1.0, September 6, 2018 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
5-FU        5-fluorouracil 
AE         Adverse event 
ALP        Alkaline phosphatase 
ALT         Alanine aminotransferase 
ANC        Absolute neutrophil count 
AST        Aspartate aminotransferase 
β-hCG       β-human chorionic gonadotropin 
BTC        Biliary tract cancer 
BUN        Blood urea nitrogen 
CBC        Complete blood count 
CI          Confidence interval 
CNS        Central nervous system 
CR         Complete response 
CRF        Case report form 
CT         Computed tomography 
CYP        Cytochrome P450 
DLT        Dose-limiting toxicity 
DNA        Deoxyribonucleic acid 
DSMC       Data and safety monitoring review committee 
ECOG       Eastern Cooperative Oncology Group 
ECG        Electrocardiogram 
FDA        US Food and Drug Administration 
FdUMP      5-Fluoro-2′-deoxyuridine 5′-monophosphate 
FOLFIRI     Leucovorin, fluorouracil, and irinotecan 
FOLFIRINOX  Leucovorin, fluorouracil, irinotecan, and oxaliplatin (FFX) 
FOLFOX     Leucovorin, fluorouracil, and oxaliplatin 
FUTP       5-fluorouridine 5'-triphosphate 
GEM        Gemcitabine 
GGT        Gamma-glutamyl transpeptidase 
HIV         Human immunodeficiency virus 
HR         Hazard ratio 
IFL         Irinotecan, fluorouracil (bolus), and leucovorin 
IHC         Immunohistochemistry 
IND         Investigational new drug 
INR         International normalized ratio 
IV          Intravenously 
LCCC       Lombardi Comprehensive Cancer Center 
LD         Longest diameter 
LFT         Liver profile 
LLN         Lower limit of normal 
LV         Leucovorin 
MRI         Magnetic resonance imaging 
mOS        Median overall survival 
mPFS       Median progression-free survival 
NGS        Next-generation Sequencing 
ORR        Overall response rate 
OS         Overall survival 
PCR        Polymerase chain reaction 
PD         Progression of disease 
PI          Principal investigator 
PK         Pharmacokinetics 


7 
Version 1.0, September 6, 2018 
PO         By mouth 
PR         Partial response 
PRT        Proton Radiation Therapy 
PS         Performance Status 
PT         Prothrombin time 
PTT        Partial thromboplastin time 
QD         Once daily 
RECIST      Response Evaluation Criteria in Solid Tumors 
RFS        Recurrence-free survival 
RNA        Ribonucleic acid 
RP2D       Recommended Phase II Dose 
RR         Response rate 
SAE        Significant adverse event 
SD         Stable disease 
TS         Thymidylate synthase 
UGT1A1     UDP glucuronosyltransferase family 1 member A1 
ULN        Upper limit of normal 
 
 


8 
Version 1.0, September 6, 2018 
STUDY SYNOPSIS 
Title 
Phase I Study of Proton Therapy in Adjuvant Pancreatic Cancer (PROTON-PANC) 
Short Title 
Proton Therapy in Adjuvant Pancreatic Cancer 
 
Protocol  
Number 
2018-1021 
 
Clinicaltrials.g
ov number: 
pending 
Phase 
Phase I 
 
Investigational 
Agents 
1) Proton Beam Therapy 
 
Indication 
Resected adenocarcinoma of the pancreatic head 
 
Concept and 
Scientific 
Rationale 
Pancreatic Cancer 
In 2018, it is estimated that 55,440 new cases of pancreatic ductal 
adenocarcinoma (PDAC) will be diagnosed and 44,330 people will die of PDAC in 
the United States.1 Importantly, PDAC incidence is increasing and is estimated to 
overtake colorectal cancer as the 2nd-leading cause of cancer-related death in the 
United States by 2030.2 Most patients with PDAC have either metastatic or 
unresectable locally advanced disease at the time of diagnosis and are unable to 
have a potentially curative surgical resection. For the 10-20% of patients who are 
able to undergo a surgical resection, outcomes are still relatively poor. The optimal 
treatment strategy for resectable pancreatic cancer remains under investigation. 
Subsets of patients with resectable disease appear to benefit from neoadjuvant 
therapy; however, many patients with resectable disease will receive upfront 
surgery. Although distant recurrence predominates after resection, up to 30% of 
patients have only local disease as the first site of recurrence.3,4  
 
Adjuvant Chemotherapy 
While the role of adjuvant chemoradiation is debated, systemic chemotherapy is 
the standard adjuvant therapy. Adjuvant chemotherapy options have historically 
involved either single-agent gemcitabine (GEM) or 5-fluorouracil (5-FU) with 
leucovorin (LV). Both agents had similar median overall survival (mOS) when 
compared head-to-head in the ESPAC-3 trial (23.6 months with GEM and 23.0 
months with 5-FU, P = 0.39), with GEM favored due to a better toxicity profile.5 The 
ESPAC-4 trial changed the adjuvant treatment paradigm, demonstrating that GEM 
plus capecitabine (CAPE, oral 5-FU) had a longer mOS than GEM alone (28.0 vs. 
25.5 months, P = 0.032).6 The PRODIGE 24 trial revolutionized the standard of 
care for fit patients, demonstrating that mFOLFIRINOX (FFX: LV, 5-FU, irinotecan, 
and oxaliplatin) was superior to GEM in terms of mOS (54.4 vs. 35.0 months, P = 
0.003).7 Thus, FFX is the new standard adjuvant regimen for fit patients. There is 
also an ongoing trial of GEM/nab-paclitaxel vs. GEM as an adjuvant treatment 
option.8 
 
Adjuvant Chemoradiation 
Chemoradiation typically consists of 5-FU or CAPE administered concurrently with 
radiation. The ESPAC-1 study suggested that patients who received 
chemoradiation had inferior mOS (13.9 months) compared to patients who 
received chemotherapy alone (21.6 months), chemoradiation followed by 
chemotherapy (19.9 months), or observation alone (16.9 months), although the 


9 
Version 1.0, September 6, 2018 
study was not adequately powered to compare the 4 arms independently.9 These 
results suggest that upfront administration of adjuvant systemic chemotherapy is 
paramount over other treatment modalities. The results of the RTOG 0848 trial will 
hopefully elucidate the role of adjuvant chemoradiation timed at the end of 
adjuvant chemotherapy.10 In the RTOG 0848 trial, patients with no evidence of 
disease recurrence after 5 cycles of adjuvant GEM are randomized to 1 more cycle 
of GEM or chemoradiation with 5-FU or CAPE. 
 
Proton Therapy and Targeted Radiation Therapy  for Pancreatic Cancer 
Proton-based radiotherapy (PRT) is an exciting novel treatment option for the 
treatment of PDAC. Conventional radiation therapy techniques typically require 25 
to 28 fractions delivered over 5 to 6 weeks. However, because of the precision of 
proton therapy, it is feasible to complete treatment using a short course of only 5 
sessions. Prior work has shown that concomitant CAPE and PRT is associated 
with a low rate of gastrointestinal toxicity.11 In a phase I/II study, Hong and 
colleagues demonstrated the safety of short-course proton-based chemoradiation 
with CAPE in the neoadjuvant setting for patients with resectable PDAC.12 The 
recommended phase II dose was 5 daily doses of 5 GyE. The MGH group 
attempted to deliver the same 5 fraction treatment using IMRT, however the 
toxicities were unacceptable.13 For resected PDAC, photon-based stereotactic 
body radiation therapy delivered in 5 fractions (33 Gy) can be safely integrated 
with FFX chemotherapy in the adjuvant setting.14 Nichols and colleagues 
compared treatment plans using protons to conventional photon intensity-
modulation radiotherapy (IMRT) and found that proton-based postoperative 
chemoradiation decreases off-target small bowel and stomach exposure.15 Thus, 
proton-based chemoradiation should cause fewer acute and long-term toxicities 
than conventional photon-based IMRT. Additionally, we hypothesize that delivery 
of radiation therapy earlier after resection (as opposed to following the completion 
of adjuvant chemotherapy) will increase its effectiveness while not disrupting 
adjuvant chemotherapy.  Therefore, we propose a phaseI study to assess the 
safety and feasibility of short-course PRT with adjuvant FFX. 
 
Study Duration 
12 months 
 
Study Centers 
1) Lombardi 
Comprehensive 
Cancer 
Center, 
Georgetown 
University, 
Washington, DC 
Objectives 
Primary Objective:  
To determine the recommended phase II dose and schedule (RP2D) of short-
course PRT integrated within adjuvant FFX (radiation 12 days following 
chemotherapy or 5 days following chemotherapy). The co-primary objectives are to 
demonstrate the safety and feasibility of short-course PRT within systemic 
adjuvant chemotherapy with FFX, including the number of cycles received and 
relative chemotherapy dose-intensity. 
 
Exploratory Objectives: 
 
To determine the median recurrence-free survival (mRFS) and median overall 
survival (mOS) in patients treated with adjuvant FFX and proton radiation.  
 
Number of 
Subjects 
A minimum of 2 and a maximum of 12 evaluable patients 


10 
Version 1.0, September 6, 2018 
 
Diagnosis and 
Main Inclusion 
and Exclusion 
Criteria 
Key Inclusion Criteria 
 
Pathologically-confirmed pancreatic adenocarcinoma of the pancreatic head 
 
Undergone pancreaticoduodenectomy with curative intent 
 
Completed 2 cycles of adjuvant chemotherapy composed of 5-fluorouracil, 
leucovorin, oxaliplatin, and irinotecan 
 
Complete resection (R0) or resection with microscopic positive magins (R1) 
 
Adequate healing post-operatively 
 
Adequate hepatic, renal, and bone marrow function 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1 
 
Prior neoadjuvant chemotherapy is alllowed 
 
Key Exclusion Criteria 
 
Ampullary adenocarcinoma 
 
Woman who are pregnant or breastfeeding 
 
Macroscopic positive margins (R2) or evidence of residual local or metastatic 
disease 
 
Resection not including pancreaticoduodenectomy 
 
Known allergy or intolerance to leucovorin, 5-fluorouracil, oxaliplatin, or 
irinotecan 
 
Prior radiation to the upper abdomen 
 
Inability to swallow pills or bowel obstruction 
 
Any invasive cancer in the previous 3 years requiring chemotherapy or 
radiation or anticancer therapy following surgery 
 
Insurance unwilling to pre-authorize PRT, FFX, and pegfilgrastim 
 
Clinically significant liver disease 
o Patients with resolved hepatitis B infection are eligible if HBsAg testing 
is negative 
o Patients with resolved hepatitis C infection are eligible if viral RNA PCR 
is negative 
 
Uncontrolled HIV infection (CD4 count must be at least 200 and viral load 
undetectable on a stable antiretroviral regimen) 
 
Major surgery within 4 weeks prior to enrollment 
 
Study Design 
 
We hypothesize that resected pancreatic cancer patients will benefit from 
enhanced local control with the addition of radiation therapy to adjuvant  FFX. The 
recently reported PRODIGE 24 study, demonstrated that 12 cycles of adjuvant  
FFX without radiation therapy significantly improved survival and time to metastatic 
failure rates as compared to GEM alone.  Excessive distant failures rates using 
prior adjuvant systemic therapies, may have limited the impact of radiation therapy; 
therefore, improvements in systemic control can increase the benefit of local 
control.  
 
 
 
 
 
 
 
 
 


11 
Version 1.0, September 6, 2018 
Figure 1. Study Schema  
 
 
DL = dose level, FFX = mFOLFIRINOX, G = pegfilgrastim on-body injector 
(optional), P = proton radiation (5 GyE). 
 
In this study, we utilize 5 fraction PRT, delivered over 1 week, during adjuvant FFX 
(between cycles 6 and 7) to minimize the interruptions in chemotherapy as well as 
to reduce the length of time from surgical resection to initiating adjuvant radiation 
therapy. Conventional radiation therapy is typically delivered over 5 weeks and is 
commonly given after the completion of adjuvant chemotherapy. Conventional 
radiation therapy cannot be given concurrently with FFX due to the synergistic 
toxicities. In contrast, PRT significantly reduces the exposure of normal tissues to 
the effects of radiation therapy and has been safely delivered using a 5 fraction 
schedule with chemotherapy, as previously discussed. 
 
Chemotherapy will consist of mFOLFIRINOX in 14-day cycles x 12 as used in the 
PRODIGE 24 study:  
 
Irinotecan 150 mg/m2 IV day 1 
 
Oxaliplatin 85 mg/m2 IV day 1 
 
Leucovorin 400 mg/m2 IV day 1 
 
5-fluorouracil 2,400 mg/m2 IV days 1-3 (no bolus) 
 
Pegfilgrastim 6 mg SC on-body injector day 3 (optional, up to investigator’s 
discretion, can alternatively do day 4 without on-body injector) 
 
Suggested supportive care medications: fosaprepitant 150 mg IV day 1, 
dexamethasone 12 mg IV day 1, ondansetron 16 mg IV day 1, 
dexamethasone 4 mg PO q AM days 2-3, ondansetron 8 mg PO BID days 
2-3. 
 
Dose adjustments will be permitted at the discretion of the treating 
oncologist based on patients’ prior tolerability to FFX 


12 
Version 1.0, September 6, 2018 
 
Proton radiation will consistent of 5 daily doses of 5 GyE total, ideally 
administered Monday through Friday but can be administered within 7 
business days, between cycles 6 and 7  
Statistical 
Design,  
Feasibility, and 
Trial Duration 
This study will use a 3+3 dose-escalation design to determine the safety and 
feasibility of combining 5 fraction adjuvant PRT with FFX. While there is limited 
literature on the combination of short course PRT and FFX, there are analogous 
experiences using 5 fraction SBRT or IMRT following FFX in routine clinical 
practice. The ongoing Alliance 021501 trial of preoperative chemotherapy vs. 
chemotherapy plus radiation (IMRT using 5 Gy X 5 or SBRT 6.6 X 5) in borderline 
resectable pancreatic cancer mandates that radiation starts 5 days or more 
following the last dose of FFX.16 Additionally, at LCCC we routinely combine 5 
fraction SBRT after a 10-14 day interval from FFX.17 Thus dose level 1 uses a 12 
day interval and dose level 2 uses a 5 day interval. Our proposed trial in the 
postoperative setting aims to integrate PRT between cycles of adjuvant FFX using 
different gaps in time between chemotherapy and radiation, which will serve as 
basis for future trial designs. 
 
No competing adjuvant PDAC trials exist at LCCC. Approximately 30 new patients 
with resected PDAC are seen annually at LCCC. We hypothesize that 24 patients 
will be eligible annually and 50% of these patients will enroll in the trial (12 
evaluable patients maximum). 
 
 
 


13 
Version 1.0, September 6, 2018 
1.0 BACKGROUND AND JUSTIFICATION      
 
1.1 Pancreatic Ductal Adenocarcinoma (PDAC) 
 
In 2018, it is estimated that 55,440 new cases of pancreatic ductal adenocarcinoma (PDAC) will 
be diagnosed and 44,330 people will die of PDAC in the United States.1 Importantly, PDAC 
incidence is increasing and is estimated to overtake colorectal cancer as the 2nd-leading cause 
of cancer-related death in the United States by 2030.2 Most patients with PDAC have either 
metastatic or unresectable locally advanced disease at the time of diagnosis and are unable to 
have a potentially curative surgical resection. For the 10-20% of patients who are able to 
undergo a surgical resection, outcomes are still relatively poor. The optimal treatment strategy 
for resectable pancreatic cancer remains under investigation. Subsets of patients with 
resectable disease appear to benefit from neoadjuvant therapy; however, many patients with 
resectable disease will receive upfront surgery. Although distant recurrence predominates after 
resection, up to 30% of patients have only local disease as the first site of recurrence. 
 
1.2 Adjuvant Chemotherapy 
 
While the role of adjuvant chemoradiation is debated, systemic chemotherapy is the standard 
adjuvant therapy. Adjuvant chemotherapy options have historically involved either single-agent 
gemcitabine (GEM) or 5-fluorouracil (5-FU) with leucovorin (LV). Both agents had similar 
median overall survival (mOS) when compared head-to-head in the ESPAC-3 trial (23.6 months 
with GEM and 23.0 months with 5-FU, P = 0.39), with GEM favored due to a better toxicity 
profile.5 The ESPAC-4 trial changed the adjuvant treatment paradigm, demonstrating that GEM 
plus capecitabine (CAPE, oral 5-FU) had a longer mOS than GEM alone (28.0 vs. 25.5 months, 
P = 0.032). 6 The PRODIGE 24 trial revolutionized the standard of care for fit patients, 
demonstrating that mFOLFIRINOX (FFX: LV, 5-FU, irinotecan, and oxaliplatin) was superior to 
GEM in terms of mOS (54.4 vs. 35.0 months, P = 0.003).7 Thus, FFX is the new standard 
adjuvant regimen for fit patients. There is also an ongoing trial of GEM/nab-paclitaxel vs. GEM 
as an adjuvant treatment option.8 
 
1.3 Adjuvant Chemoradiation 
 
Chemoradiation typically consists of 5-FU or CAPE administered concurrently with radiation. 
The ESPAC-1 study suggested that patients who received chemoradiation had inferior mOS 
(13.9 months) compared to patients who received chemotherapy alone (21.6 months), 
chemoradiation followed by chemotherapy (19.9 months), or observation alone (16.9 months), 
although the study was not adequately powered to compare the 4 arms independently.9 These 
results suggest that upfront administration of adjuvant systemic chemotherapy is paramount 
over other treatment modalities. The results of the RTOG 0848 trial will hopefully elucidate the 
role of adjuvant chemoradiation timed at the end of adjuvant chemotherapy.10 In the RTOG 
0848 trial, patients with no evidence of disease recurrence after 5 cycles of adjuvant GEM are 
randomized to 1 more cycle of GEM or chemoradiation with 5-FU or CAPE. 
 
1.4 Proton Therapy and Targeted Radiation Therapy for Pancreatic Cancer 
 
Proton-based radiotherapy (PRT) is an exciting novel treatment option for the treatment of 
PDAC. Conventional radiation therapy techniques typically require 25 to 28 fractions delivered 
over 5 to 6 weeks. However, because of the precision of proton therapy, it is feasible to 
complete treatment using a short course of only 5 sessions. Prior work has shown that 
concomitant CAPE and PRT is associated with a low rate of gastrointestinal toxicity.11 In a 
phase I/II study, Hong and colleagues demonstrated the safety of short-course proton-based 


14 
Version 1.0, September 6, 2018 
chemoradiation with CAPE in the neoadjuvant setting for patients with resectable PDAC.12 The 
recommended phase II dose was 5 daily doses of 5 GyE. The MGH group attempted to deliver 
the same 5 fraction treatment using IMRT, however the toxicities were unacceptable.13.For 
resected PDAC, photon-based stereotactic body radiation therapy delivered in 5 fractions (33 
Gy) can be safely integrated with FFX chemotherapy in the adjuvant setting.14 Nichols and 
colleagues compared treatment plans using protons to conventional photon intensity-modulation 
radiotherapy (IMRT) and found that proton-based postoperative chemoradiation decreases off-
target small bowel and stomach exposure.15 Thus, proton-based chemoradiation should cause 
fewer acute and long-term toxicities than conventional photon-based IMRT. Additionally, we 
hypothesize that delivery of radiation therapy earlier after resection (as opposed to following the 
completion of adjuvant chemotherapy) will increase its effectiveness while not disrupting 
adjuvant chemotherapy.  Although selected patients with borderline resectable and locally 
advanced PDAC undergo neoadjuvant therapy, the majority of patients with resectable disease 
in the US still receive surgery upfront. Therefore, we propose a phase I study to assess the 
safety and feasibility of short-course PRT with adjuvant FFX. 
 
1.5 Fluorouracil and Leucovorin 
Fluorouracil (5-FU) has been the backbone of chemotherapy regimens for gastrointestinal 
malignancies dating back to the 1950s. 5-FU is FDA-approved for use in colorectal, breast, 
gastric, and PDAC.18 
 
Figure 2. Chemical Structure of Fluorouracil 
 
 
 
 
5-FU is a nucleoside metabolic inhibitor that is converted to FdUMP which inhibits thymidylate 
synthase (TS), disrupting DNA synthesis. Leucovorin (folinic acid) stabilizes the ternary complex 
of FdUMP, TS, and tetrahydrofolate, further potentiating TS inhibition.19 The 5-FU metabolite 
FUTP is incorporated into RNA, and another, FdUTP, is incorporated into DNA, further 
disrupting RNA and DNA synthesis resulting in cell death in rapidly dividing cells. 
 
5-FU must be permanently discontinued in patients with early onset or unusually severe toxicity 
which may indicate complete or near absence of dipyrimidine dehydrogenase (DPD) activity. 
Fluorouracil carries a risk of cardiotoxicity, hyperammonemic encephalopathy, neurologic 
toxicity, diarrhea, palmar-plantar erythrodyesthesia  (hand-foot syndrome), myelosuppression, 
mucositis, increased risk of INR with warfarin, and embryofetal toxicity. 
 
1.6 Oxaliplatin 
 
Oxaliplatin is a platinum-based chemotherapy agent that induces inter- and intra-strand DNA 
crosslinking, halting DNA synthesis. It is FDA-approved20 in combination with infusional 5-FU 
and LV for the management of adjuvant stage III colon cancer based on the MOSAIC trial,21 and 
for the treatment of advanced colorectal cancer. 22 Oxaliplatin carries risks of allergic reactions, 
neuropathy, pulmonary toxicity, hepatotoxicity, and cytopenias.20  
 
Figure 3. Chemical Structure of Oxaliplatin 


15 
Version 1.0, September 6, 2018 
 
 
 
1.7 Irinotecan 
 
The active metabolite of irinotecan (SN-38) is a potent topoisomerase I inhibitor that induces 
DNA damage and cell death (see section 1.7.1.2). Irinotecan is FDA-approved for the first-line 
treatment of metastatic colorectal cancer (mCRC) and for treatment of mCRC following 
progression on or recurrence following 5-FU-based therapy.23 Saltz and colleagues 
demonstrated that the addition of irinotecan 125 mg/m2 IV in combination with 5-FU 425 mg/m2 
IV bolus and LV 20 mg/m2 given weekly for 4 weeks every 6 weeks (IFL regimen) was superior 
to 5-FU and LV at the same doses given daily days 1-5 every 4 weeks in patient with mCRC.24 
André and colleagues also demonstrated the efficacy of bolus 5-FU 400 mg/m2 IV, LV 400 
mg/m2 IV, irinotecan 180 mg/m2 IV, and infusional 5-FU 2400 mg/m2 IV over 46 hours every 2 
weeks (FOLFIRI regimen).25 Fuchs and colleagues later showed that irinotecan, LV, and 
infusional 5-FU (FOLFIRI) was superior to irinotecan, LV, and bolus 5-FU (IFL), both with and 
without bevacizumab.26 FOLFIRI is an established regimen for mCRC in the first- or second-line 
settings.27 
 
1.8 mFOLFIRINOX Regimen 
 
The PRODIGE 4 ACCORD 11 trial established FFX (non-modified: LV 400 mg/m2, 5-FU 400 
mg/m2 bolus, 5-FU 2400 mg/m2 infusion, irinotecan 180 mg/m2, and oxaliplatin 85 mg/m2, every 
2 weeks) as a standard-of-care for patients with advanced PDAC.28 Patients were randomized 
1:1 to FFX or GEM. Patients who received FFX had superior mOS (11.1 vs. 6.8 months; HR 
0.57, 95% CI 0.45-0.73; P < 0.001) at the expense of more grade 3 or higher toxicities 
(neutropenia 46% vs. 21%, febrile neutropenia 5% vs. 1%, diarrhea 13% vs. 2%, sensory 
neuropathy 9% vs. 0%), although there was a quality of life benefit from FFX. 
 
The PRODIGE 24 trial revolutionized the standard of care for fit patients in the adjuvant setting, 
demonstrating that FFX was superior to GEM in terms of mOS (54.4 vs. 35.0 months, P = 
0.003).7 Thus, FFX is the new standard adjuvant regimen for fit patients. In this trial, FFX was 
modified for tolerability: irinotecan was dropped to 150 mg/m2 and no bolus 5-FU was included.  
 
 
 
 
 
 
 
2.0 STUDY OBJECTIVES 
 
2.1 Primary Objective: 
To determine the recommended phase II dose and schedule (RP2D) of short-course PRT 
integrated within adjuvant FFX (radiation 12 days following chemotherapy or 5 days following 
chemotherapy) for resected PDAC. The co-primary objectives are to demonstrate the safety and 


16 
Version 1.0, September 6, 2018 
feasibility of short short-course proton radiation within systemic adjuvant chemotherapy with 
FFX, including the number of cycles received and relative chemotherapy dose-intensity. 
 
2.2 Exploratory Objectives: 
 
To determine, in patients with resected PDAC undergoing PRT integrated within adjuvant FFX: 
 
2.2.1 Median recurrence-free survival (mPFS) 
 
2.2.2 Median overall survival (mOS)  
 
2.3 Primary Endpoint: 
 
The primary endpoint is to determine the RP2D between the 2 proposed schedules. Using a 
3+3 dose-escalation schema, 2-12 patients will be required to determine the RP2D. 
Co-primary endpoints: 
 
2.3.1 Safety: adverse event data will be collected and presented as descriptive statistics using 
the CTCAE version 5.0. 
 
2.3.2 Feasibility: we will track the success rate in screening patients, completion of proton 
beam planning, completion of proton beam treatment, and completion of adjuvant 
therapy (including number of cycles completed and relative dose intensity). 
 
2.4 Exploratory Endpoints: 
 
2.4.1 Recurrence-free survival (RFS), defined as time from surgery until evidence of disease 
recurrence. 
 
2.4.2 Overall survival (OS), defined as time from surgery until death from any cause or last 
follow-up. 
 
2.5 Indication: 
 
Patients with resected adenocarcinoma of the pancreatic head undergoing adjuvant FFX 
 
 
 
 
 
 
 
 
 
 


17 
Version 1.0, September 6, 2018 
3.0 SUBJECT POPULATION 
3.1 Subject Population, Number of Subjects and Feasibility 
 
3.1.1 Subject Population 
Patients with resected pancreatic adenocarcinoma arising from the pancreatic head who have 
undergone pancreaticoduodenectomy with curative intent and are undergoing adjuvant FFX 
chemotherapy. 
 
3.1.2 Number of Subjects 
2-12 patients 
 
3.1.3 Feasibility 
No competing adjuvant PDAC trials exist at LCCC. Approximately 30 new patients with resected 
PDAC are seen annually at LCCC. We hypothesize that 24 patients will be eligible annually and 
50% of these patients will enroll in the trial (12 evaluable patients maximum). 
 
3.2 Inclusion Criteria 
 
3.2.1 Undergone pancreaticoduodenectomy with curative intent 
 
3.2.2 Pathologically-confirmed 
pancreatic 
adenocarcinoma 
of 
the 
pancreatic 
head 
(adenocarcinoma must be the predominant component of the histology) 
 
3.2.3 Completed 2 cycles of adjuvant chemotherapy composed of 5-fluorouracil, leucovorin, 
oxaliplatin, and irinotecan 
 
3.2.4 Complete resection (R0) or resection with microscopic positive magins (R1) 
 
3.2.5 Adequate healing post-operatively 
 
3.2.6 Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100 × 
109/L; hemoglobin ≥ 9.0 g/dL. Patients may have a transfusion of red blood cells to meet 
the hemoglobin requirement. 
 
3.2.7 Renal function: serum creatinine ≤ 1.5 × upper normal limit of institution’s normal range 
or creatinine clearance ≥ 30 mL/min for subjects with creatinine levels above institutional 
normal 
 
3.2.8 Hepatic function: AST and ALT ≤ 3.0 × the upper normal limit of institution’s normal 
range. Total bilirubin ≤ 1.5 × the upper normal limit of institution’s normal range.  
 
3.2.9 Partial Thromboplastin Time (PTT) must be ≤ 1.5 × upper normal limit of institution’s 
normal range and INR (International Normalized Ratio) < 1.5. Subjects on anticoagulant 
(such as warfarin) will be permitted to enroll as long as the INR is in the acceptable 
therapeutic range as determined by the investigator. 
 
3.2.10 Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1 
 
3.2.11 Prior neoadjuvant chemotherapy is alllowed 
 
3.2.12 Patients must have fully recovered from all effects of surgery.  Patients must have had at 
least two weeks after minor surgery and four weeks after major surgery before starting 
therapy.  Minor procedures requiring “Twilight” sedation such as endoscopies or 


18 
Version 1.0, September 6, 2018 
mediport placement may only require a 24-hour waiting period, but this must be 
discussed with an investigator. 
 
3.2.13 Women of childbearing potential must have a negative serum pregnancy test within 14 
days prior to initiation of treatment and/or postmenopausal women must be amenorrheic 
for at least 12 months to be considered of non-childbearing potential 
 
3.2.14 Patient is capable of understanding and complying with parameters as outlined in the 
protocol and able to sign and date the informed consent, approved by the Institutional 
Review Board (IRB), prior to the initiation of any screening or study-specific procedures 
 
 
Table 1. ECOG Performance Status 
 
 
3.3 
Exclusion Criteria 
 
3.3.1 Ampullary adenocarcinoma 
 
3.3.2 Women who are pregnant or breastfeeding 
 
3.3.3 Macroscopic positive margins (R2) or evidence of residual local or metastatic disease 
 
3.3.4 Resection not including pancreaticoduodenectomy 
 
3.3.5 Known allergy or intolerance to leucovorin, 5-fluorouracil, oxaliplatin, or irinotecan 
 
3.3.6 Prior radiation to the upper abdomen 
 
3.3.7 Inability to swallow pills or bowel obstruction 
 
3.3.8 Any invasive cancer in the previous 3 years requiring chemotherapy, radiation, or 
anticancer therapy following surgery 
 
3.3.9 Insurance unwilling to pre-authorize PRT, FFX, and (if necessary) pegfilgrastim 
 
3.3.10 Clinically significant liver disease 
 
3.3.10.1 Patients with resolved hepatitis B infection are eligible if HBsAg testing is 
negative 
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
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.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
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.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade


19 
Version 1.0, September 6, 2018 
 
3.3.10.2 Patients with resolved hepatitis C infection are eligible if viral RNA PCR is 
negative 
 
3.3.11 Uncontrolled HIV infection (CD4 count must be at least 200 and viral load undectable on 
a stable antiretroviral regimen to be eligible for enrollment) 
 
3.3.12 Major surgery within 4 weeks prior to enrollment 
 
3.4 Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements) that the subject is receiving at Screening up to the Final Visit must 
be recorded in source documents and the case report forms (CRFs). The reason for use, date(s) 
of administration (including start and end dates), and dosage information (including dose and 
frequency) must be recorded. Any change in concomitant therapy during the study period must 
be similarly recorded. Questions regarding prior or concomitant therapy should be directed to 
one of the investigators. 
 
3.4.1 Prior Anti-Cancer Therapy 
For purposes of this protocol, anti-tumor treatment may be defined as, but is not limited to, anti-
cancer agents (cytotoxic chemotherapy, immunotherapy, or biologic therapy), radiotherapy, and 
investigational agents. An investigational agent is any drug or therapy not currently approved for 
use in humans. No anti-cancer therapy is allowed while patients are on trial except for FFX and 
PRT. Prior neoadjuvant chemotherapy is allowed, but prior radiation to the upper abdomen is 
not. 
 
3.4.2 Prior Surgery 
Patients must have fully recovered from all effects of surgery.  Patients must have had at least 
two weeks after minor surgery and four weeks after major surgery before starting therapy.  
Minor procedures requiring “Twilight” sedation such as endoscopies or mediport placement may 
only require a 24 hour waiting period, but this must be discussed with an investigator. 
 
3.4.3 Supportive Care 
Subjects should receive best supportive care and treatment of symptoms during the study as 
appropriate, including transfusion of blood and blood products, oxygen therapy, nutritional 
support, intravenous fluids, and treatment with appropriate medications (antibiotics, antiemetics, 
antidiarrheals, and analgesics, etc.).  Medications, including steroids, which are given for 
supportive care, such as appetite stimulation, may be given concurrently. 
 
3.4.3.1 Bisphosphonates and denosumab 
Bisphosphonates and denosumab are permitted for the treatment of osteoporosis. Chronic 
concomitant bisphosphonate/denosumab therapy for the prevention of bone metastasis is not 
permitted. 
 
3.4.3.2 Hematopoietic growth factors 
Hematopoietic growth factors may be used according to ASCO guidelines. Pegfilgrastim is 
recommended as outlined in Section 5.0. 
 


20 
Version 1.0, September 6, 2018 
4.0 TRIAL DESIGN AND DETAILED STUDY PROCEDURES 
4.1 Treatment Plan Overview 
The study is a phase I, single-arm study to establish safety and feasibility of proton-based 
radiation therapy integrated within adjuvant FFX for patients with resected PDAC. Patients who 
have completed 2 cycles of FFX for resected pancreatic adenocarcinoma of the head of the 
pancreas will be eligible for enrollment. PRT will occur between cycles 6 and 7.  
In dose level 1 (DL1), patients will complete cycle 6 chemotherapy (days 1-3) and then receive 
5 days of daily 5 GyE proton therapy on days 15-19 (excluding weekend days) in a 28 day cycle, 
prior to starting cycle 7 (see Figure 1). In DL2, patients will complete cycle 6 chemotherapy 
(days 1-3) and then receive 5 days of daily 5 GyE proton therapy on days 8-12 (excluding 
weekend days) in a 21 day cycle, prior to starting cycle 7. A 3+3 dose-escalation schema will be 
used, requiring 3-12 patients to be enrolled. 
 
Using a 3+3 dose-escalation design, if 0 of 3 patients experience a dose-limiting toxicity (DLT) 
at DL1, then 3 patients will then be enrolled in DL2. If 1 of 3 patients experiences a DLT at DL1, 
then 3 additional patients will be enrolled at DL1. If 2-3 of 3 patients experience a DLT at DL1, 
then the study is terminated. If 1 of 6 patients experiences a DLT at DL1, then 3 patients will be 
enrolled at DL2. If 0-1 of 3 patients experiences a DLT at DL2, then 3 additional patients will be 
enrolled at DL2. If 2-3 patients experience a DLT at DL2, treatment will continue at DL1 until 6 
patients are enrolled at DL1. If 0-1 of 6 patients experiences a DLT at DL2, then DL2 is the 
recommended phase 2 dose and schedule (RP2D). Conversely, if 0-1 of 6 patients experiences 
a DLT at DL1 AND 2 or greater patients experience a DLT at DL2, then DL1 is the RP2D.  
All cycles will be 14 days, except cycle 6 which is extended to 28 days in DL1, including the 5 
daily doses of PRT on days 15-19 (excluding weekend days), and 21 days in DL2, including the 
5 daily doses of PRT on days 8-12 (excluding weekend days, see Figure 1 below). 
 
If a scheduled PRT dose falls on a weekend or holiday, then the next daily dose falls on the next 
business day. The 5 daily doses should be completed in the shortest possible time interval (e.g. 
7 days total if 2 are weekend days). 


21 
Version 1.0, September 6, 2018 
Figure 1. Study Schema  
 
DL = dose level, FFX = mFOLFIRINOX, G = pegfilgrastim on-body injector (optional), P = proton 
radiation (5 GyE). 
 
4.2 Detailed Study Plan 
4.2.1 Screening 
Study activities are detailed in Tables 2 (DL1) and 3 (DL2), and a study activity checklist in 
Table 4. Screening will occur within 28 days prior to Cycle 6 Day 1 of FFX. Signed informed 
consent will be obtained from the subject or the subject’s legally acceptable representative 
before any study-specific procedures are undertaken.  For procedures performed at screening 
and repeated, the later procedure performed prior to dosing, will serve as a baseline for clinical 
assessment.  A complete history and physical will be obtained at the screening visit.  
Additionally, labs will be reviewed/ordered during the screening visit, prior to the initiation of 
therapy.   
 
Patients who pass screening will undergo PRT planning and a full evaluation on Cycle 6 Day 1, 
including a physical examination, vital signs, performance status, chemistry, hematology, 
medication review, and adverse event evaluation.  If any abnormality is identified at subject 
assessment on Cycle 6 Day 1, the patient will be deemed a screen failure and will not start 
treatment.   
 
All patients who start study treatment on cycle 6 day 1 will be eligible for the primary 
safety analysis. We will substitute patients who screen fail or screen and do not begin 
study treatment as above. 
 


22 
Version 1.0, September 6, 2018 
The screening procedures include the following listed below. 
 
4.2.1.1 Informed Consent 
Signed informed consent will be obtained from the subject or the subject’s legally acceptable 
representative before any study-specific procedures are undertaken.   
 
4.2.1.2 Medical History 
The following information will be collected during the Screening Period: 
1) Complete medical history, including documentation of any clinically significant medical 
conditions  
2) History of tobacco and alcohol use 
3) Presence and severity of any symptoms/conditions associated with metastatic 
pancreatic cancer 
4) Detailed oncology history, including: 
a. Date of primary cancer diagnosis 
b. Pathology (histology or cytology) of primary tumor 
c. Surgical history 
d. Anti-cancer treatments administered (including dates and type of modality) 
5) At each visit, the subject’s medical history will be reviewed and any changes from 
baseline will be recorded in the case report form (CRF). On C6D1, any changes 
observed from the screening assessments, prior to dosing, will be recorded in the 
subject’s medical history. All medications (prescription or over-the-counter, including 
vitamins and/or herbal supplements) will be recorded beginning with the screening visit 
and continuing up through the date of the off study visit. 
 
4.2.1.3 Demographics 
Age, gender, race and ethnicity will be recorded. 
 
4.2.1.4 Review subject eligibility criteria 
 
4.2.1.5 Review previous and concomitant medications 
 
4.2.1.6 Physical exam including vital signs, height, and weight 
A complete physical examination will be performed at the screening visit.  Body weight will be 
recorded during every physical exam. The subject will wear lightweight clothing and no shoes 
during weighing.  Height will be measured at the screening visit only; the subject will not wear 
shoes. 
 
4.2.1.7 Vital sign determinations 
Vital sign determinations of heart rate, blood pressure and body temperature will be obtained at 
the screening visit. If possible, blood pressure and heart rate measurements should not 
immediately follow scheduled blood collections. 
 
4.2.1.8 Performance Status 
Performance status will be evaluated prior to study entry according to Table 1. 
 
4.2.1.9 Hematology 
Hematology samples (CBC with differential) will be collected and assessed using a certified 
laboratory.  The Investigator will review, initial and date all laboratory results. Any laboratory 
value outside the reference range stated in the inclusion criteria will preclude the patient from 
study participation. 
 
4.2.1.10 Serum chemistries 


23 
Version 1.0, September 6, 2018 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT, AST, 
BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and 
total bilirubin. Any laboratory value outside the reference range stated in the inclusion criteria 
will preclude the patient from study participation. 
 
4.2.1.11 Pregnancy Test 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
screening visit within 28 days of C6D1 and a urine pregnancy test will be done at the C6D1 visit 
prior to the first dose of study drug. Subjects considered not of childbearing potential must be 
documented as being surgically sterile or post-menopausal (for at least 1 year).  The test results 
must be reviewed and determined to be negative prior to dosing. If the urine pregnancy test is 
positive at C6D1, it should be confirmed by a serum pregnancy test. The test may be repeated 
at the discretion of the investigator at any time during the study.  Should a female study subject 
become pregnant or suspect she is pregnant while participating in this study, she should inform 
the treating Investigator immediately. 
 
4.2.1.12 Tumor assessment 
Only patients with no evidence of local recurrence or metastatic disease will be eligible to enter 
onto the study. Patients with suspected disease recurrence will have to be evaluated to rule out 
disease recurrence prior to study enrollment. 
 
4.3 Patient Study Number Assignment and Sample Labeling 
 
4.3.1.1 Patient Study Number Assignment 
Patients will be de-identified and assigned with a 3-digit study label (XXX). 
 
4.4 Detailed Patient Assessments 
Subject assessments (physical examinations, vital signs, performance status, chemistry, 
hematology, medication review, and adverse event evaluations) will be conducted at screening, 
C6D1, C6D15 (DL1) or C6D8 (DL2), and D1 of every subsequent cycle (every 14 days ± 3 
days). Details are provided in Tables 2 and 3, and a checklist highlighting the important events 
for screening through the completion of the trial is provided below in Table 4. Patients will meet 
with the radiation oncologist during screening (prior to C6D1), during PRT, and at follow-up 
visits as outlined below.  
 
4.4.1 Physical Examinations 
A complete physical examination will be performed at the screening visit, on C6D1, C6D15 (DL1) 
or C6D8 (DL2), and D1 of every subsequent cycle (every 14 days ± 3 days). Any significant 
physical examination findings after the administration of the first doses PRT will be recorded as 
adverse events.  Body weight will be recorded during every physical exam. The subject will 
wear lightweight clothing and no shoes during weighing.  Weight will be measured on the same 
scale at each visit. Height will be measured at the screening visit and C6D1 only; the subject will 
not wear shoes. 
 
4.4.2 Medical History 
At each visit, the subject’s medical history will be reviewed and any changes from baseline will 
be recorded as an adverse event.  On C6D1, any changes observed from the screening 
assessments, prior to dosing, will be recorded in the subject’s medical history. All medications 
(prescription or over-the-counter, including vitamins and/or herbal supplements) will be recorded 
beginning with the screening visit and continuing up through the date of the final visit. 
 
4.4.3 Vital Signs 


24 
Version 1.0, September 6, 2018 
Vital sign determinations of body temperature (in degrees Celsius), heart rate, respiratory rate, 
blood pressure and pain (using a 0-10 Numeric Ranking Scale) will be obtained at the screening 
visit, on each day the subject is seen by the treating physician, and at the final visit. If possible, 
blood pressure and heart rate measurements should not immediately follow scheduled blood 
collections. 
 
4.4.4 Clinical Laboratory Tests 
All subjects will undergo the laboratory assessments outlined in Tables 2 and 3.  
1) A complete blood count (CBC) with differential will be collected at the screening visit, on 
C6D1, C6D15 (DL1) or C6D8 (DL2), and D1 of every subsequent cycle (every 14 days ± 
3 days). 
2) Serum chemistries (total protein, albumin, total bilirubin, AST, ALT, alkaline phosphatase, 
sodium, potassium, chloride, bicarbonate, BUN, creatinine, and calcium) will be collected 
at the screening visit, on C6D1, C6D15 (DL1) or C6D8 (DL2), and D1 of every 
subsequent cycle (every 14 days ± 3 days). 
3) PT/INR and aPTT will be collected at the screening visit (this may be repeated during 
the course of the study at the discretion of the investigator but is not required). 
 
Laboratory samples for this study will be assessed using the certified laboratory at the 
investigators’ institutions, or at a clinical laboratory such as Quest or LabCorp and these data 
will be used for all data analysis.  The Principal Investigator or sub-investigator will review, initial 
and date all laboratory results. Any laboratory value outside the reference range that is 
considered clinically significant by the investigator will be followed as appropriate. Clinically 
significant laboratory values will be recorded as adverse events if they meet the criteria as 
specified in Section 6.0. 
 
4.4.5 Adverse Event Evaluation 
The Principal Investigator or sub-investigators will assess adverse events, laboratory data and 
vital signs throughout the study.  Adverse events will be assessed by NCI CTCAE Version 5.0. 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf. The investigators will monitor each subject for clinical and laboratory 
evidence of adverse events on a routine basis throughout the study. The investigator will assess 
and record any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course, duration and outcome, relationship of the adverse event to 
study drug, and any action(s) taken. For serious adverse events not considered “probably 
related” to study drug, the investigator will provide an “Other” cause of the event. For adverse 
events to be considered intermittent, the events must be of similar nature and severity. Adverse 
events, whether in response to a query, observed by site personnel, or reported spontaneously 
by the subject will be recorded. All adverse events will be followed to a satisfactory conclusion. 
 
4.4.6 Imaging and Evaluation 
Patients will undergo a baseline tumor evaluation with imaging studies within 28 days prior to 
C6D1. Imaging studies should include a diagnostic CT scan of the chest, abdomen, and pelvis 
with PO and IV contrast (unless medically contraindica ed). If a patient has an allergy to IV 
contrast, appropriate pre-medication can be given to prevent a contrast reaction. Patients may 
undergo other modalities such as an MRI instead of a CT scan at the treating physician’s 
discretion if appropriate (such as severe allergy to CT contrast, extremity tumors, bone 
metastases requiring bone scans, etc.).   
 
The first follow-up surveillance scan will occur within 14 days of the End of Treatment (EOT) 
visit which will be scheduled following completion of C12 or the last cycle of FFX administered. 
Follow-up visits including scans (CT or MRI) and blood work including CA19-9 will then occur 
every 3 months up to 24 months. 


25 
Version 1.0, September 6, 2018 
 
4.4.7 Removal of Subjects from Therapy or Assessment 
4.4.10.1 Reasons for Removal of Subjects from Therapy or Assessment 
Each subject has the right to withdraw from study treatment at any time. In addition, the 
investigator may discontinue a subject from the study treatment at any time for any reason if the 
investigator considers it necessary, including the occurrence of an adverse event or 
noncompliance with the protocol.  Each subject will be withdrawn from the study if any of the 
following occur: 
1) The subject experiences either clinical or radiographic progressive disease.  
2) The subject requires other radiotherapy or alternate antineoplastic agents during the 
study period. 
3) The investigator believes it is in the best interest of the subject. 
4) Clinically significant deterioration of the subject’s medical status as determined by the 
investigator. 
5) Subject becomes pregnant or begins breastfeeding during the treatment portion of the 
study. 
6) The subject or subject’s legally acceptable representative decides to withdraw consent 
for any reason.  
7) Any other medical reason that the study investigator deems appropriate. 
 
4.4.10.2 Discontinuation of Individual Subjects 
When a subject discontinuation from the study (without reaching a protocol-defined endpoint) is 
planned, the investigator will notify the PI as soon as possible (provided, in each case, subject 
care and safety are not compromised).  When a subject discontinues the study, a final visit will 
be conducted (preferably prior to the initiation of another anticancer therapy). However, these 
procedures should not interfere with the initiation of any new treatments or therapeutic 
modalities that the investigator feels are necessary to treat the subject’s condition. Following 
discontinuation of the study drug, the subject will be treated in accordance with the 
investigator’s best clinical judgment.  At the final visit, the reason(s) for the discontinuation from 
the study will be recorded and a physical examination, body weight, vital signs measurement, 
laboratory analyses, performance status, tumor assessment, and an assessment of adverse 
events will be performed as soon as possible after discontinuation from the study.  All subjects 
will have one final visit, which does not need to be performed for subjects who have had a visit 
greater than 30 days after discontinuation of the study drugs.  If a subject is discontinued from 
the study with an ongoing adverse event or an unresolved clinically significant laboratory result, 
personnel will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory 
result or adverse event is achieved.  In the event that a positive result is obtained on a 
pregnancy test for a subject during the study, the administration of study drug to that subject 
must be discontinued immediately.   
 
4.4.10.3 Discontinuation of Entire Study 
The investigators may terminate this study provided that written notice is submitted at a 
reasonable time in advance of the intended termination.  The following procedures for 
discontinuation will be followed:  
1) If the investigators have decided to prematurely discontinue the study, the investigators 
will promptly notify in writing the IRB of the decision and give detailed reasons for the 
discontinuation. 
2) The PI must promptly notify enrolled subjects of the premature discontinuation and 
administer appropriate treatments such as replacement of protocol therapy by other 
appropriate regimens. 
 
4.4.8 Protocol Deviations 


26 
Version 1.0, September 6, 2018 
The investigator should not implement any deviation from the protocol without prior review and 
agreement by the Sponsor and in accordance with the IRB and local regulations, except when 
necessary to eliminate an immediate hazard to study subjects.  
 
 


27 
Version 1.0, September 6, 2018 
Table 2. Study Activities – Dose Level 1 
  
Screeninga 
C6D1b 
C6D2 
C6D3 
C6D15 
C6D16 
C6D17 
C6D18 
C6D19 
D1 of 
C7c-
C12 
EOTd 
F/Ue 
Informed 
Consent 
X 
  
  
  
  
 
 
 
 
 
  
  
Demographics 
X 
  
  
  
  
 
 
 
 
 
  
  
Medical History 
X 
  
  
  
  
 
 
 
 
 
  
  
ECOG PSf 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
Concomitant 
Medications 
Collection 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
Adverse Events 
Assessment 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
Height 
X 
X 
  
  
  
 
 
 
 
 
  
 
Weight 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
History and 
Physical Exam 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
CT or MRI Scan 
Tumor 
Evaluation and 
Assessmentg 
X 
  
  
  
 
 
 
 
 
 
Xh 
X 
β-hCGi 
X 
X 
  
 
  
 
 
 
 
 
  
 
CBC with 
differential 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
CMPj 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
PT/INR and 
aPTT 
X 
  
  
  
  
 
 
 
 
 
  
 
CA19-9 
X 
X 
  
 
 
 
 
 
 
X 
X 
X 
mFOLFIRINOX 
  
X 
X 
X 
  
 
 
 
 
X 
 
 
Proton Beam 
Planning 
X 
 
 
 
 
 
 
 
 
 
 
 
Proton Beam 
Therapy 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Survival 
  
X 
 
 
X 
 
 
 
 
X 
X 
X 
aScreening visit must occur within 28 days of C6D1 of mFOLFIRINOX 
bThis assumes proton therapy will be administered during C6 (may be delivered during C6-C11 if necessary) 
cC6 is a 28 day cycle in dose level 1 (C7D1 = C6D29), all other cycles are 14 days in length 
dEnd of treatment (D1 of last cycle of mFOLFIRINOX, typically C12) 
eFollow-up assessments will be performed every 3 months for up to 24 months 
fEastern Cooperative Oncology Group Performance Status 
gScreening scans should be done within 2 months of C6D1 
hCan be performed within 14 days of the EOT visit 
iSerum (screening) and urine (C6D1) pregnancy tests (for women of childbearing potential only) 
jComprehensive metabolic panel: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, AST, ALT, alkaline 
phosphatase, total bilirubin, total protein, and albumin 
 


28 
Version 1.0, September 6, 2018 
Table 3. Study Activities – Dose Level 2 
 
  
Screeninga 
C6D1b 
C6D2 
C6D3 
C6D8 
C6D9 
C6D10 
C6D11 
C6D12 
D1 of 
C7c-
C12 
EOTd 
F/Ue 
Informed 
Consent 
X 
  
  
  
  
 
 
 
 
 
  
  
Demographics 
X 
  
  
  
  
 
 
 
 
 
  
  
Medical History 
X 
  
  
  
  
 
 
 
 
 
  
  
ECOG PSf 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
Concomitant 
Medications 
Collection 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
Adverse Events 
Assessment 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
Height 
X 
X 
  
  
  
 
 
 
 
 
  
 
Weight 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
History and 
Physical Exam 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
CT or MRI Scan 
Tumor 
Evaluation and 
Assessmentg 
X 
  
  
  
 
 
 
 
 
 
Xh 
X 
β-hCGi 
X 
X 
  
 
  
 
 
 
 
 
  
 
CBC with 
differential 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
CMPj 
X 
X 
 
 
 X 
 
 
 
 
X 
X 
X 
PT/INR and 
aPTT 
X 
  
  
  
  
 
 
 
 
 
  
 
CA19-9 
X 
X 
  
 
 
 
 
 
 
X 
X 
X 
mFOLFIRINOX 
  
X 
X 
X 
  
 
 
 
 
X 
 
 
Proton Beam 
Planning 
 
 
 
 
 
 
 
 
 
 
 
 
Proton Beam 
Therapy 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Survival 
  
X 
 
 
X 
 
 
 
 
X 
X 
X 
aScreening visit must occur within 28 days of C6D1 of mFOLFIRINOX 
bThis assumes proton therapy will be administered during C6 (may be delivered during C6-C11 if necessary) 
cC6 is a 21 day cycle in dose level 1 (C7D1 = C6D15), all other cycles are 14 days in length 
dEnd of treatment (D1 of last cycle of mFOLFIRINOX, typically C12) 
eFollow-up assessments will be performed every 3 months for up to 24 months 
fEastern Cooperative Oncology Group Performance Status 
gScreening scans should be done within 2 months of C6D1 
hCan be performed within 14 days of the EOT visit 
iSerum (screening) and urine (C6D1) pregnancy tests (for women of childbearing potential only) 
jComprehensive metabolic panel: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, AST, ALT, alkaline 
phosphatase, total bilirubin, total protein, and albumin 
 
 
 
 
 
 


29 
Version 1.0, September 6, 2018 
Table 4. Study Activities Checklist 
 
Screening 
Informed Consent             _______ 
Demographics               _______ 
Medical History               _______ 
ECOG PS                   _______ 
Concomitant Medications Collection _______ 
Adverse Events Assessment      _______ 
Vital Signs                  _______ 
Height                     _______ 
Weight                     _______ 
History and Physical Exam       _______ 
CT or MRI Scan 
Tumor Evaluation and Assessment  _______ 
β-hCG                     _______ 
CBC with Differential           _______ 
Comprehensive Metabolic Panel   _______ 
PT/INR and aPTT             _______ 
CA19-9                    _______ 
Proton Beam Planning          _______ 
 
Cycle 6 Day 1 
ECOG PS                   _______ 
Concomitant Medications Collection _______ 
Adverse Events Assessment      _______ 
Vital Signs                  _______ 
Height                     _______ 
Weight                     _______ 
History and Physical Exam       _______ 
β-hCG                     _______ 
CBC with Differential           _______ 
Comprehensive Metabolic Panel   _______ 
CA19-9                    _______ 
mFOLFIRINOX (Days 1-3)       _______ 
Survival                    _______ 
 
Cycle 6 Day 15 (Dose Level 1) or Cycle 6 Day 8 (Dose Level 2) 
ECOG PS                   _______ 
Concomitant Medications Collection _______ 
Adverse Events Assessment      _______ 
Vital Signs                  _______ 
Weight                     _______ 
History and Physical Exam       _______ 
CBC with Differential           _______ 
Comprehensive Metabolic Panel   _______ 
Proton Beam Therapy 
(Days 15-19 in Dose Level 1,  
 Days 8-12 in Dose Level 2)      _______ 
Survival                    _______ 
 
Day 1 of Subsequent Cycles (7-12) 
ECOG PS                   _______ 


30 
Version 1.0, September 6, 2018 
Concomitant Medications Collection _______ 
Adverse Events Assessment      _______ 
Vital Signs                  _______ 
Height                     _______ 
Weight                     _______ 
History and Physical Exam       _______ 
CBC with Differential           _______ 
Comprehensive Metabolic Panel   _______ 
CA19-9                    _______ 
mFOLFIRINOX (Days 1-3)       _______ 
Survival                    _______ 
 
End of Treatment 
ECOG PS                   _______ 
Concomitant Medications Collection _______ 
Adverse Events Assessment      _______ 
Vital Signs                  _______ 
Height                     _______ 
Weight                     _______ 
History and Physical Exam       _______ 
CBC with Differential           _______ 
Comprehensive Metabolic Panel   _______ 
CA19-9                    _______ 
Survival                    _______ 
 
Follow-Up 
ECOG PS                   _______ 
Concomitant Medications Collection _______ 
Adverse Events Assessment      _______ 
Vital Signs                  _______ 
Height                     _______ 
Weight                     _______ 
History and Physical Exam       _______ 
CBC with Differential           _______ 
Comprehensive Metabolic Panel   _______ 
CA19-9                    _______ 
Survival                    _______ 
 
 


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Version 1.0, September 6, 2018 
5.0 DOSAGES AND DISPENSATION OF DRUGS   
5.1 FFX Administration 
The study drugs are defined as 5-FU, LV, oxaliplatin, and irinotecan (FFX). Due to the infusional 
5-FU, study drugs must be administered via central line (mediport, PICC, or other). Treatment 
cycles are every 14 days ± 3 days (except for C6 which is 28 days in DL1 and 21 days in DL2). 
The study drug dosages and administration are only recommended – dosages and supportive 
medication can be modified at the discretion of the investigator, taking into consideration dose 
modifications during cycles 1-5. Per the PRODIGE 24 trial, the 5-FU bolus is omitted and 
irinotecan is 150 mg/m2. A research infusion nurse will access the patient’s line. Treatment will 
then be administered in the following order (substitutions for prophylactic medications are 
allowed at the treating investigator’s discretion): 
Table 5. Drug Administration 
Drug 
Indication 
Dose/Route 
Duration 
Fosaprepitant 
Nausea prophylaxis 
150 mg IV 
30 minutes 
Ondansetron  
Nausea prophylaxis 
16 mg IV 
15 minutes 
Dexamethasone 
Nausea prophylaxis 
10 mg IV 
15 minutes 
Leucovorin 
Treatment 
400 mg/m2 IV 
60 minutes 
Oxaliplatin 
Treatment 
85 mg/m2 IV 
120 minutes (can be administered 
simultaneously with leucovorin via 
a Y-connector) 
Atropine 
Diarrhea prophylaxis 0.5 mg IV 
IV push 
Irinotecan 
Treatment 
150 mg/m2 IV 
90 minutes 
5-fluorouracil 
Treatment 
2400 mg/m2 IV 
46 hours (continuous infusion) 
Pegfilgrastim on-
pro 
Growth factor 
support 
6 mg SC 
Administered on day 3 (after 5-
fluorouracil pump is unhooked) 
 
The patient will return to the research infusion clinic after 46 hours for disconnection of the 5-FU 
infusional pump and administration of pegfilgrastim on-pro. Use of growth factor support is 
highly recommended but is at the discretion of the investigator. Alternatively, pegfilgrastrim 6 mg 
SC can be administered on day 4 (if not using on-pro administration). 
 
5.2 Packaging, Labeling, Storage, and Handling of Chemotherapy 
5-FU, LV, oxaliplatin,and irinotecan should be stored and handled as per their respective FDA 
labels and following protocols and guidelines of LCCC (see 
http://www.osha.gov/SLTC/hazardousdrugs/index.html).18-20,23 
 
5.3 Proton Beam Therapy 
 
PRT planning will commence following the screening visit with the radiation oncologist. PRT 
volumes will include a clinical target volume of the highest at risk nodal regions: celiac, SMA, 
and para-aortic regions. The porta hepatic nodes have been shown to be at significantly less 
risk for local recurrence and will not be included in the treatment.29,30 The normal tissue 
constraints are as follows: stomach and small bowel: V30 < 0.1 cc, V20 < 5 cc, V15 < 10 cc, 
cord Dmax < 25 Gy, liver V17 < 33%. Target volume coverage should be greater than 95%. Two 
posterior oblique beams or 1 posterior and 1 lateral beam are encouraged. The radiation 
oncology study chair will approve of all treatment plans.  
 
If PRT has  started and becomes unavailable, it will restart when available and the patient will 
resume the treatment schedule following this delay. If greater than 14 days elapse after PRT is 
held, PRT will not be completed and the patient will resume standard adjuvant mFOLFIRINOX 
for remainder of treatment. 


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6.0 SAFETY VARIABLES AND TOXICITY ASSESSMENT 
The Principal Investigator or sub-investigators will assess adverse events, laboratory data and 
vital signs throughout the study.  Adverse events will be assessed by NCI CTCAE Version 5.0: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf. 
 
6.1 Adverse Event Assessment 
The investigators will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study. The investigator will assess and record any 
adverse event in detail including the date of onset, event diagnosis (if known) or sign/symptom, 
severity, time course, duration and outcome, relationship of the adverse event to study drug, 
and any action(s) taken. For serious adverse events not considered “probably related” to study 
drug, the investigator will provide an “Other” cause of the event. For adverse events to be 
considered intermittent, the events must be of similar nature and severity. Adverse events, 
whether in response to a query, observed by personnel, or reported spontaneously by the 
subject will be recorded. All adverse events will be followed to a satisfactory conclusion. 
 
6.2 Study Monitoring 
 
6.2.1 Data Safety Monitoring Committee at Georgetown 
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and 
safety monitoring of this multi-site trial.  As this study is an investigator initiated study phase I 
study, it is considered a high-risk study which requires real-time monitoring by the PI and study 
team and review every 4 months by the LCCC Data and Safety Monitoring Committee (DSMC). 
The Principal Investigator and the Co-Investigators will review the data including safety 
monitoring at their weekly institution based disease group meetings, on monthly disease group 
teleconferences, and monthly teleconferences between study sites.  
All Severe Adverse Events (SAEs) are required to be reported to the IRB.  Based on SAEs, the 
IRB retains the authority to suspend further accrual pending more detailed reporting and/or 
modifications to further reduce risk and maximize the safety of participating patients. 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and 
Safety Monitoring Committee every 4 months from the time the first patient is enrolled on the 
study. Results of the DSMC meetings will be forwarded to the IRB with recommendations 
regarding need for study closure. 
DSMC recommendations should be based not only on results for the trial being monitored as     
well as on data available to the DSMC from other studies.  It is the responsibility of the PI to 
ensure that the DSMC is kept apprised of non-confidential results from related studies that 
become available.  It is the responsibility of the DSMC to determine the extent to which this 
information is relevant to its decisions related to the specific trial being monitored. 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the 
DSMC recommends a study change for patient safety or efficacy reasons the trial PI must act to 
implement the change as expeditiously as possible.  In the unlikely event that the trial PI does 
not concur with the DSMC recommendations, then the LCCC Associate Director of Clinical 
Research must be informed of the reason for the disagreement.  The trial PI, DSMC Chair, and 
the LCCC AD for Clinical Research will be responsible for reaching a mutually acceptable 
decision about the study and providing details of that decision to the IRB.  Confidentiality must 
be preserved during these discussions.  However, in some cases, relevant data may be shared 


33 
Version 1.0, September 6, 2018 
with other selected trial investigators and staff to seek advice to assist in reaching a mutually 
acceptable decision. 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy 
the DSMC will provide an adequate rationale for its decision. If the DSMC recommends that the 
trial be closed for any reason, the recommendation will be reviewed by the Associate Director 
for Clinical Research at G-LCCC.  Authority to close a trial for safety reasons lies with the IRB, 
with the above described input from DSMC and the AD for Clinical Research.   
6.3 Adverse Event and Toxicity Definitions 
6.3.1 Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not the event is considered causally related to the use of the product.  Such an event can result 
from use of the drug as stipulated in the protocol or labeling, as well as from accidental or 
intentional overdose, drug abuse, or drug withdrawal. Any worsening of a pre-existing condition 
or illness is considered an adverse event.  Laboratory abnormalities and changes in vital signs 
are considered to be adverse events only if they result in discontinuation from the study, 
necessitate therapeutic medical intervention, and/or if the investigator considers them to be 
adverse events. 
 
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre-planned prior to study entry.  However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure is 
being done will be considered an adverse event. 
 
6.3.2 Serious Adverse Events 
If an adverse event meets any of the following criteria, it is to be reported to the DSMC as a 
serious adverse event (SAE) within 24 hours of the study personnel being made aware of the 
serious adverse event. 
1) Death of Subject An event that results in the death of a subject. 
2) Life-Threatening An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken. This does not include an 
event that would have been fatal if it had occurred in a more severe form. 
3) Hospitalization or 
4) Prolongation of Hospitalization An event that results in an admission to the hospital 
for any length of time or prolongs the subject’s hospital stay. This does not include an 
emergency room visit or admission to an outpatient facility. 
5) Congenital Anomaly An anomaly detected at or after birth, or any anomaly that results 
in fetal loss.  
6) Persistent or Significant Disability/Incapacity An event that results in a condition that 
substantially interferes with the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical significance such as 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle). 
7) Important Medical Event Requiring Medical or Surgical Intervention to Prevent 
Serious Outcome An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on medical judgment may 


34 
Version 1.0, September 6, 2018 
jeopardize the subject and may require medical or surgical intervention to prevent any of 
the outcomes listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
8) Spontaneous Abortion Miscarriage experienced by study subject.  
9) Elective Abortion Elective abortion performed on study subject. 
 
6.3.3 Adverse Event Severity 
The study investigator will rate the severity of each adverse event according to the NCI CTCAE 
Version 5.0.  For adverse events not captured by the NCI CTCAE Version 5.0, the following 
should be used: 
1) Grade 1 (Mild) The adverse event is transient and easily tolerated by the subject. 
2) Grade 2 (Moderate) The adverse event causes the subject discomfort and interrupts the 
subject’s usual activities.  
3) Grade 3-4 (Severe or Life Threatening) The adverse event causes considerable 
interference with the subject’s usual activities and may be incapacitating or life-
threatening. 
4) Grade 5 (Death) The adverse event resulted in death of the subject. 
 
6.3.4 Relationship to Study Drug 
The investigator will use the following definitions to assess the relationship of the adverse event 
to the use of study drug: 
1) Definitely Related An adverse has a clear temporal relationship to study drug and/or 
recurs on re-challenge and an Other cause of event is extremely unlikely. 
2) Probably Related An adverse event has a strong temporal relationship to study drug or 
recurs on re-challenge and an Other cause of event is unlikely or significantly less likely. 
3) Possibly Related An adverse event has a strong temporal relationship to the study drug 
and an Other cause of event is equally or less likely compared to the potential 
relationship to study drug.  
4) Probably Not Related An adverse event has little or no temporal relationship to the 
study drug and/or a more likely Other cause of event exists.   
5) Not Related An adverse event is due to an underlying or concurrent illness or effect of 
another drug and is not related to the study drug (e.g., has no temporal relationship to 
study drug or has a much more likely Other cause of event). 
If an investigator’s opinion of possibly, probably not, or not related to study drug is given, an 
Other cause of event must be provided by the investigator for the serious adverse event. 
 
6.4 Adverse Event Collection Period 
All adverse events reported from the time of study drug administration until 30 days following 
discontinuation of study drug administration have elapsed will be collected, whether elicited or 
spontaneously reported by the subject. In addition, serious adverse events will be collected from 
the time the subject signed the study-specific informed consent. 
 
6.5 Adverse Event Reporting 
In the event of a serious adverse event, whether related to study drug, study procedure such as 
a biopsy, or even if not directly related to any study intervention, the investigator will notify the 
IRB within 72 hours of being made aware of the serious adverse event.   
 


35 
Version 1.0, September 6, 2018 
The SAE report should comprise a full written summary, detailing relevant aspects of the 
adverse events in question.  Where applicable, information from relevant hospital case records 
and autopsy reports should be included.   
 
6.6 Pregnancy 
In the event of a positive pregnancy test result, study drugs will be immediately discontinued. 
The investigator must report the positive pregnancy test within 72 hours of the study personnel 
becoming aware of the pregnancy to the IRB.  Patients should also notify the investigator if it is 
determined after completion of the study that they become pregnant either during the treatment 
phase of the study or within five days after the treatment period.  Information regarding a 
pregnancy occurrence in a study subject and the outcome of the pregnancy will be collected, 
and the status of the mother and child should be reported to the IRB after delivery.  Pregnancy 
in a study subject is not considered an adverse event but does require discontinuation of the 
subject from the study. However, the medical outcome of an elective or a spontaneous abortion, 
stillbirth or congenital anomaly is considered a serious adverse event and must be reported to 
the IRB within 72 hours of study personnel becoming aware of the event.  Male subjects should 
also notify the investigators if the subject’s partner should become pregnant during the study, 
this should also be reported within 72 hours of study personnel awareness. 
 
6.7 Toxicity Management and Dose Adjustments 
 
6.7.1 Dose Reduction and Delays of FFX 
 
As patients will enter the study already having completed 5 cycles of FFX, discretion is given to 
the investigator to continue patients at the same doses as cycle 5. Therefore, all dose 
modifications are recommended but left to the discretion of the investigator. 
 
Table 6. Dose Levels for Modifications for FFX (Recommended) 
 
Episode # 
Irinotecan 
Oxaliplatin 
5-FU/LV 
1st  
Decrease to 
120 mg/m2 
Decrease to 
75 mg/m2 
Decrease to 
1800 mg/m2 
2nd  
Decrease to 
90 mg/m2 
Decrease to 
65 mg/m2 
Decrease to 
1200 mg/m2 
3rd  
Off Study 
Off Study 
Off Study 
 
 
Table 7. Dose Modifications for FFX (Recommended) 
 
Toxicity 
Instruction 
ANC < 1500/mm3 
Hold until ANC ≥ 1500/mm3 and 
reduce one dose level as above 
Platelets < 75000/mm3 
Hold until platelets ≥ 75000/mm3 
and reduce one dose level as 
above 
Febrile neutropenia or 
Grade 4 neutropenia ≥ 7 
days 
Hold until afebrile and ANC ≥ 
1500/mm3, reduce one dose level 
as above  
Grade 3-4 diarrhea 
Initiate Imodium prn, hold until 
resolved to baseline or grade 1, 
reduce one dose level as above 
Grade 3-4 peripheral 
neuropathy 
Discontinue oxaliplatin 


36 
Version 1.0, September 6, 2018 
Other grade 3-4 toxicity 
Hold until toxicity resolves to 
baseline or grade 1, reduce one 
dose level as above 
 
6.8 Prohibited Concurrent Medications 
 
The following medications must be discontinued at least 2 weeks prior to C6D1 (strong CYP3A4 
inhibitors or inducers, strong UGT1A1 inhibitors): 
 
Atazanavir, 
Atazanavir/ritonavir, 
boceprevir, 
clarithromycin, 
cobicistat, 
conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir, 
indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), posaconazole, ritonavir,  
saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, troleandomycinvoriconazole, 
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampin (rifampicin), St. John's wort (hypericum perforatum), adenine, propofol, indomethacin, 
nilotinib, pazopanib, regorafenib, flunitrazepam, erlotinib, sorafenib, enasidenib, pibrentasvir, 
glecaprevir, rucaparib, ertugliflozin, fostamatinib, dolutegravir, valproic acid, flurbiprofen, 
eltrombopag, silibinin A, and sodium aurothiomalate. 
 
6.9 Dose Limiting Toxicities (DLTs) 
 
Dose limiting toxicities (DLTs) are defined in Table 9 below. The DLT window will start with the 
first dose of PRT and continue for 28 days afterwards. Patients who receive at least one dose of 
PRT will be evaluable for DLT determination. 
 
Table 9. Dose Limiting Toxicities (DLTs) 
 
Toxicity 
Delay in start of C7 (or whichever cycle follows PRT) of ≥ 14 days related to treatment AEs 
Non-hematologic ≥ grade 3 AEs excluding grade 3-4 allergic reaction, grade 3 alopecia, 
grade 3 fatigue < 5 days, and except as listed below 
Grade 3 nausea/vomiting ≥ 48 hours despite optimal anti-emetic therapy 
Grade 3 diarrhea ≥ 48 hours despite optimal anti-diarrheal therapy 
≥ Grade 3 colitis 
≥ Grade 3 chest wall pain 
≥ Grade 2 total bilirubin > 7 consecutive days 
≥ Grade 3 total bilirubin, ≥ grade 2 ALT with a ≥ grade 2 total bilirubin elevation 
≥ Grade 3 ALT lasting > 4 consecutive days 
Grade 4 ALT or AST 
Grade 4 serum alkaline phosphatase > 7 consecutive days 
≥ Grade 3 serum creatinine 
≥ Grade 3 constipation 
≥ Grade 3 gastrointestinal obstruction 
Grade 2 flatulence 
 
 
 


37 
Version 1.0, September 6, 2018 
7.0 EFFICACY ASSESMENT    
7.1 Efficacy Variables 
Disease recurrence will be assessed by a CT scan (or other appropriate modalities such by way 
of MRI consistent with the modality used prior to treatment) utilizing RECIST v1.1 criteria. 
Assessments will be performed within 2 months of C6D1, at EOT, and at follow-up visits.  
 
We will track the success rate in screening patients, completion of PRT planning, completion of 
proton beam treatment, and completion of adjuvant therapy (including number of cycles 
completed and relative dose intensity). 
 
7.2 RECIST v1.1 Criteria for Tumor Response 
Changes in the measurable lesions over the course of therapy will be evaluated using the 
RECIST v1.1 criteria. 
 
7.2.1 Definition of Lesions 
7.2.1.1 Measurable Disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
 
7.2.1.2 Measurable Lesions 
Lesions that can be accurately measured in at least one dimension with longest diameter ≥ 20 
mm using conventional techniques or ≥ 10 mm with CT scan.  
 
7.2.1.3 Non-measurable Lesions 
All other lesions, including small lesions (longest diameter < 20 mm with conventional 
techniques or < 10 mm with a CT scan), bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic 
lesions and also abdominal masses that are suspicious though may or may not be confirmed 
and followed by imaging techniques. 
 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 14 days before the beginning of the treatment.  The same method of 
assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up.  Clinical lesions will only be considered 
measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the size 
of the lesion is required. 
 
7.2.2 Methods of Measurement 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed with 
cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen and 
pelvis. For accurate objective response evaluation, ultrasound should not be used to measure 
tumor lesions. However, ultrasound is a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. Ultrasound might 
also be useful to confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination.  Cytology and histology can be used to differentiate between PR and CR in 
rare cases (e.g., after treatment to differentiate between residual benign lesions and residual 
malignant lesions in tumor types such as germ cell tumors).   
 
 


38 
Version 1.0, September 6, 2018 
7.3 Definition of Disease Recurrence 
Disease progression will be defined as: 
1) Radiologic progression of disease by RECIST v1.1 criteria. 
2) Clinical progression as determined by the investigator, which may be characterized as, 
but is not limited to: 
a. Increase of at least 2 points in ECOG performance status attributable to cancer 
progression. 
b. Requirement for radiation (beyond palliative radiation for bone pain relief as 
outlined in 3.4.3.3), chemotherapy or surgery. 
3) Death from disease progression 
 
 


39 
Version 1.0, September 6, 2018 
8.0 
STATISTICAL CONSIDERATIONS 
 
8.1 Primary Objective: 
To determine the recommended phase II dose and schedule (RP2D) of short-course PRT 
integrated within adjuvant FFX (radiation 12 days following chemotherapy or 5 days following 
chemotherapy) for resected PDAC. The co-primary objectives are to demonstrate the safety and 
feasibility of short short-course proton radiation within systemic adjuvant chemotherapy with 
FFX, including the number of cycles received and relative chemotherapy dose-intensity. 
 
8.2 Exploratory Objectives: 
 
To determine, in patients with resected PDAC undergoing PRT integrated within adjuvant FFX: 
 
8.2.1 Median recurrence-free survival (mPFS) 
 
8.2.2 Median overall survival (mOS)  
 
8.3 Primary Endpoint: 
The primary endpoint is to determine the RP2D between the 2 proposed schedules. Using a 
3+3 dose-escalation schema, 2-12 patients will be required to determine the RP2D. 
Co-primary endpoints: 
 
8.3.1 Safety: adverse event data will be collected and presented as descriptive statistics using 
the CTCAE version 5.0. 
 
8.3.2 Feasibility: we will track the success rate in screening patients, completion of proton beam 
planning, completion of proton beam treatment, and completion of adjuvant therapy (including 
number of cycles completed and relative dose intensity). 
 
8.4 Exploratory Endpoints: 
 
8.4.1 Recurrence-free survival (RFS), defined as time from surgery until evidence of disease 
recurrence. 
 
8.4.2 Overall survival (OS), defined as time from surgery until death from any cause or last 
follow-up. 
 
8.5 Study Design and Sample Size Calculation 
 
The study is a phase I, single-arm study to establish safety and feasibility of proton-based 
radiation therapy integrated within adjuvant mFOLFIRINOX for patients with resected PDAC. 
Patients who have completed 2 cycles of mFOLFIRINOX for resected pancreatic 
adenocarcinoma will be eligible for enrollment. Proton therapy will occur between cycles 6 and 7.  
In dose level 1 (DL1), patients will complete cycle 6 chemotherapy (days 1-3) and then receive 
5 days of daily 5 GyE proton therapy on days 15-19 (excluding weekend days) in a 28 day cycle, 
prior to starting cycle 7 (see Figure 1). In DL2, patients will complete cycle 6 chemotherapy 
(days 1-3) and then receive 5 days of daily 5 GyE proton therapy on days 8-12 (excluding 
weekend days) in a 21 day cycle, prior to starting cycle 7. A 3+3 dose-escalation schema will be 
used, requiring 3-12 patients to be enrolled. 
 


40 
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Using a 3+3 dose-escalation design, if 0 of 3 patients experience a dose-limiting toxicity (DLT) 
at DL1, then 3 patients will then be enrolled in DL2. If 1 of 3 patients experiences a DLT at DL1, 
then 3 additional patients will be enrolled at DL1. If 2-3 of 3 patients experience a DLT at DL1, 
then the study is terminated. If 1 of 6 patients experiences a DLT at DL1, then 3 patients will be 
enrolled at DL2. If 0-1 of 3 patients experiences a DLT at DL2, then 3 additional patients will be 
enrolled at DL2. If 2-3 patients experience a DLT at DL2, treatment will continue at DL1 until 6 
patients are enrolled at DL1. If 0-1 of 6 patients experiences a DLT at DL2, then DL2 is the 
recommended phase 2 dose and schedule (RP2D). Conversely, if 0-1 of 6 patients experiences 
a DLT at DL1 AND 2 or greater patients experience a DLT at DL2, then DL1 is the RP2D.  
All cycles will be 14 days, except cycle 6 which is extended to 28 days in DL1, including the 5 
daily doses of PRT on days 15-19 (excluding weekend days), and 21 days in DL2, including the 
5 daily doses of PRT on days 8-12 (excluding weekend days). 
 
8.6 Analytic plan for explorary objectives 
 
8.6.1 The nonparametric Kaplan-Meier method will be used to estimate median RFS. 
 
8.6.2   The nonparametric Kaplan-Meier method will be used to estimate median OS. 
 
8.7 Safety Assessments 
 
8.7.1 The safety of FFX and PRT will be assessed by evaluating study drug exposure, adverse 
events, serious adverse events, oncology-related events, all deaths, as well as changes in 
laboratory determinations and vital sign parameters.   
 
8.7.2 A summarization of the number of days and/or cycles subjects were exposed to FFX and 
PRT will be provided. 
 
8.7.3 Analyses of adverse events (and serious adverse events) will include only "treatment-
emergent" events, i.e., those that have an onset on or after the day of the first dose of study 
drug. Analyses will not include those that have an onset greater than 30 days after the treatment. 
Treatment emergent adverse events will be summarized by system organ class and preferred 
term according to the MedDRA adverse event coding dictionary. The percentage of subjects 
experiencing an adverse event at a given severity, NCI CTCAE toxicity grade, and relationship 
to study drug will be provided.  
 
8.7.4 The number of subject deaths will be summarized (1) for deaths occurring while the 
subject was still receiving study drug in this study, (2) for deaths occurring off treatment within 
30 days after the last dose of study drug, and (3) for all deaths in this study regardless of the 
number of days after the last dose of study drug.  The relatedness of the deaths to the study 
drugs will also be provided. 
 
 


41 
Version 1.0, September 6, 2018 
9.0 
ETHICAL CONSIDERATIONS 
9.1 Institutional Review Board (IRB) 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the 
Investigator's Brochure, the informed consent and all other forms of subject information related 
to the study (e.g., advertisements used to recruit subjects) and any other necessary documents 
be reviewed by an IRB. IRB approval of the protocol, informed consent and subject information 
and/or advertising, as relevant, will be obtained prior to the authorization of drug shipment to the 
study site.  Any amendments to the protocol will require IRB approval prior to implementation of 
any changes made to the study design.  Any serious adverse events that meet the reporting 
criteria, as dictated by local regulations, will be reported to the IRB. During the conduct of the 
study, the investigator should promptly provide written reports to the IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  
 
9.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical study 
conduct and the ethical Principals that have their origin in the Declaration of Helsinki.  
 
9.3 Subject Information and Consent 
Prior to the initiation of any screening or study-specific procedures, the investigator or his/her 
representative will explain the nature of the study to the subject and answer all questions 
regarding this study. A separate informed consent is also required from subjects who provide 
blood for genetic testing or fresh biopsy tissue samples for analyses. Each informed consent will 
be reviewed, signed and dated by the subject and the person who administered the informed 
consent. A copy of each informed consent will be given to the subject and each original will be 
placed in the subject's medical record. An entry must also be made in the subject's dated 
source documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.  Tissue sample collection for analysis 
will only be performed if the subject has voluntarily consented to participate after the nature of 
the testing has been explained and the subject has had the opportunity to ask questions. If the 
subject does not consent to the tissue sample collection, it will not impact the subject's 
participation in the study. 
 
9.4 Ethical Consideration for Enrollment 
Only patients with advanced cancer, for whom no curative therapy exists, will be considered for 
enrollment.  The only treatment options for these patients are enrollment in a Phase I clinical 
trial, or treatment off protocol, with a non-standard therapy.  As described above, the 
combination of fluorouracil, leucovorin, and nanoliposomal irinotecan is a rational and promising 
combination for such patients 
 
9.5 Protection of Patient Confidentiality 
All patient records, questionnaires, and tissue specimens will be de-identified using a letter and 
number assigned to their case at the time of enrollment on study.  No record or specimen will 
contain information which could identify the patient.  The key which connects patient identifiable 
information with this assigned number will be held by the Principal investigator.  For computer 
records, the key will be protected by a double password protection system.  Any paper records 
will be contained in a locked cabinet within a locked office to ensure patient’s privacy is 
protected.  
 
 
 
 
 


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