Phase II Feasibility Study of FOLFIRINOX-Losartan Followed by Accelerated Short Course Radiation Therapy With Capecitabine for Locally Advanced Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreatic Cancer
Sponsor: Massachusetts General Hospital



Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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TABLE OF CONTENTS 
1. OBJECTIVES ........................................................................................................................... 8 
1.1 
Study Design ........................................................................................................................8 
1.2 
Primary Objective ................................................................................................................8 
1.3 
Secondary Objectives ...........................................................................................................8 
2 
BACKGROUND ............................................................................................................... 9 
2.1 
Study Agents ........................................................................................................................9 
2.2 
Disease Background...........................................................................................................17 
3 
ELIGIBILITY CRITERIA ............................................................................................ 27 
3.1 
Inclusion Criteria: ..............................................................................................................27 
3.2 
Exclusion Criteria ............................................................................................................29 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ......................31 
4 
REGISTRATION PROCEDURES ............................................................................... 31 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...............................................31 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ...........................................31 
5 
TREATMENT PLAN ..................................................................................................... 31 

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5.1 
Phase II FOLFIRINOX-Losartan Treatment .....................................................................31 
5.2 
Pre-Treatment Criteria .......................................................................................................35 
5.3 
Agent Administration .........................................................................................................36 
5.4 
General Concomitant Medication and Supportive Care Guidelines: .................................40 
5.5 
Duration of Therapy ...........................................................................................................41 
5.6 
Duration of Follow Up .......................................................................................................41 
5.7 
Criteria for Removal from Study .......................................................................................41 
6 
EXPECTED TOXICITIES AND DOSING DELAYS/MODIFICATIONS .............. 42 
6.1 
Anticipated Toxicities ........................................................................................................42 
6.2 
Toxicity Management ........................................................................................................49 
7 
DRUG FORMULATION AND ADMINISTRATION ................................................ 56 
7.1 
5-Fluorouracil (5-FU; fluorouracil; Adrucil" ) ..................................................................56 
7.2 
Leucovorin Calcium (Folinic Acid) Leucovorin Calcium (calcium folinate; 
citrovorumfactor; N 5-formyltetrahydrofolate; 5-formyl-FH4; folinic acid). ...............................57 
7.3 
Oxaliplatin [Eloxatin] ........................................................................................................58 
7.4 
Irinotecan (CPT-11, CAMPTOSAR®) .............................................................................58 
7.5 
 Capecitabine…………………………………………………………………………...….59        
7.6      Losartan…………………………………………………………………………..……….57 
8 
OPTIONAL CORRELATIVE STUDIES .................................................................... 64 
8.1 
Laboratory Correlative Studies ..........................................................................................64 
9 
STUDY CALENDAR ..................................................................................................... 68 
10 
MEASUREMENT OF EFFECT ................................................................................... 71 

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10.1 
Evaluation Of Response .....................................................................................................71 
10.2 
Definitions..........................................................................................................................71 
10.3 
Disease Parameters ............................................................................................................72 
10.4 
Methods for Evaluation of Measurable Disease ................................................................72 
10.5 
Response Criteria ...............................................................................................................73 
10.6 
Duration of Response .........................................................................................................74 
11 
ADVERSE EVENT REPORTING REQUIREMENTS.............................................. 74 
11.1 
Definitions..........................................................................................................................74 
11.2 
Procedures for AE and SAE Recording and Reporting .....................................................77 
11.3 
Reporting Requirements ....................................................................................................78 
11.4 
Reporting to the Study Sponsor .........................................................................................78 
11.5 
Reporting to the Institutional Review Board (IRB) ...........................................................80 
11.6 
Reporting to Hospital Risk Management ...........................................................................80 
11.7 
Monitoring of Adverse Events and Period of Observation ................................................80 
12 
DATA AND SAFETY MONITORING ........................................................................ 81 
12.1 
Data Reporting ...................................................................................................................81 
12.2 
Safety Meetings .................................................................................................................82 
12.3 
Monitoring .........................................................................................................................83 
13 
REGULATORY CONSIDERATIONS ........................................................................ 83 

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13.1 
Protocol Review and Amendments ....................................................................................83 
13.2 
Informed Consent...............................................................................................................84 
13.3 
Ethics and Good Clinical Practice (GCP) ..........................................................................84 
13.4 
Study Documentation.........................................................................................................85 
13.5 
Records Retention ..............................................................................................................86 
14 
STATISTICAL CONSIDERATIONS .......................................................................... 86 
14.1 
Feasibility ........................................................................... Error! Bookmark not defined. 
14.2 
Analysis of Secondary Endpoints ......................................................................................86 
14.3 Reporting and Exclusions ......................................................................................................88 
15 
PUBLICATION PLAN .................................................................................................. 88 
16 
REFERENCES ................................................................................................................ 90 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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1. OBJECTIVES
1.1 
Study Design 
This is a single-arm, Phase II study of the FOLFIRINOX regimen in combination with the 
angiotensin II type I receptor blocker Losartan, followed by restaging and radiation therapy with 
capecitabine, in the treatment of patients with locally advanced unresectable pancreatic 
adenocarcinoma. 
1.2 
Primary Objective 
1.2.1 To determine the rate of R01 resection in patients with locally advanced unresectable 
pancreas cancer treated with the combination of FOLFIRINOX-Losartan followed by 
restaging and radiation therapy with capecitabine. 
1.3 
Secondary Objectives 
1.3.1
To determine the progression-free survival of patients with locally advanced disease who 
receive FOLFIRINOX-Losartan and radiation therapy.  
1.3.2
To determine overall survival in patients treated with FOLFIRINOX-Losartan and 
radiation therapy. 
1.3.3
To determine the overall survival of patients with locally advanced disease who receive 
FOLFIRINOX-Losartan without radiation (i.e. patients who demonstrate progression at 
restaging.)   
1.3.4
To determine the toxicity of FOLFIRINOX – Losartan in patients with locally advanced 
pancreatic cancer. 
1.3.5
To determine the toxicity of FOLFIRINOX – Losartan and radiation in patients with 
locally advanced pancreatic cancer. 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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1.3.6
To determine the rate of downstaging to surgical resection of FOLFIRINOX-Losartan 
followed by radiation in patients with locally advanced pancreatic cancer. 
1.3.7
To determine the correlation between a panel of somatic genetic mutations (SNaPSHOT) 
and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-Losartan 
+/- radiation/capecitabine. 
1.3.8
To determine the correlation between circulating biomarkers of TGF-β1 downregulation, 
including circulating Collagen I levels, and outcome in locally advanced pancreatic cancer 
treated with FOLFIRINOX-Losartan +/- radiation/capecitabine. 
1.3.9
To describe quality of life, symptom burden and mood in the study population. 
1.3.10 To measure utilization of health services (emergency room, hospital and intensive care 
unit, palliative care) in the study population. 
2 
BACKGROUND 
2.1 
Study Agents 
2.1.1 5-Fluorouracil 
5-Fluorouracil (5-FU) is a pyrimidine antagonist that interferes with nucleic acid biosynthesis.
The deoxyribonucleotide of the drug inhibits thymidylate synthetase, thus inhibiting the 
formation of thymidylic acid from deoxyuridylic acid, thus interfering in the synthesis of DNA.  
It also interferes with RNA synthesis. It is systemically metabolized, with the enzyme 
dihydropyrimidine dehydrogenase (DPD) being rate-limiting.  It forms the backbone of treatment 
for most gastrointestinal malignancies, and is a crucial component of the FOLFIRINOX regimen, 
in which it is administered as a 400 mg/m2 bolus, followed by a 2400 mg/m2 46-48 hour 
infusion.  Neutropenia and diarrhea are the dose limiting toxicities of 5-fluorouracil.  Nausea and 
vomiting with 5-fluorouracil tends to be mild but patients often become dehydrated due to 
diarrhea.  Stomatitis is a common complication of 5-fluorouracil and typically occurs 5-8 days 
after initiating treatment.  Ileus may occur as a result of 5-fluorouracil enteritis. Anemia and 
thrombocytopenia are also associated complications. Dermatologic side effects are common, and 

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include dryness of skin, palmar-plantar erythrodysesthesias (Hand-Foot syndrome), alopecia, 
loss of nails/brittle nails and a maculopapular rash.  Neurological complications are rare and 
consist of ataxia.  Cardiotoxicity is another very rare complication of 5-fluorouracil, manifested 
as ischemia and sometimes asymptomatic S-T changes.  Excessive lacrimation is common and 
less common is eye duct stenosis.  5-FU may also increase the INR in patients taking warfarin. 
2.1.2 Oxaliplatin 
Oxaliplatin is a platinum compound classified with the alkylating agents. Its mechanism of 
action is via intra-strand cross-linking, thereby inhibiting DNA replication and transcription. In 
the FOLFIRINOX regimen it is administered as an 85 mg/m2 infusion over 2 hours. 
Neurotoxicity is generally the dose-limiting toxicity of the drug, as it causes both immediate and 
delayed neuropathy manifesting as cold sensitivity (immediate) and parasthesias, numbness, and   
ataxia (incoordination, including abnormal gait) (delayed.) It is also associated with CNS 
complaints such as insomnia, mood alteration (depression, anxiety) neuropathy cranial (ptosis), 
vertigo, neuropathy sensory (including acute laryngeo-pharyngeal dysesthesias, L’Hermitte’s 
sign, paresthesia). Oxaliplatin is associated with allergic and hypersensitivity reactions including 
chills, flushing, or anaphylaxis. It is associated with mild ototoxicity. Bone marrow suppression 
(particularly thrombocytopenia), cardiac arrythmia, and hepatic toxicity, specifically increased 
alkaline phosphatase, increased bilirubin, increased GGT (gamma-glutamyl-transpeptidase), 
hepatic enlargement, increased AST (AST) (serum glutamic oxaloacetic transaminase), increased 
SGPT (ALT) (serum glutamic pyruvic transaminase) have been observed. It is associated with 
rare but serious pulmonary fibrosis.   
2.1.3 Irinotecan 
Irinotecan is a camptothecin topoisomerase I inhibitor commonly used in gastrointestinal 
malignancies. In the FOLFIRINOX regimen it is delivered as a 180 mg/m2 infusion over 90 
minutes on Day 1 of treatment. Diarrhea and neutropenia are the major dose-limiting toxicities of 
irinotecan. Diarrhea can occur either acutely (within the first 24 hours) and delayed (after 2-4 
days.) Acute diarrhea is thought to be mediated by non-competitive inhibition of acetyl 
cholinesterase activity by irinotecan, and is readily treatable with atropine, 0.25-1 mg, 
intravenously. Delayed diarrhea often manifests after the second or third weekly dose of 

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irinotecan, and is thought to be secretory in nature, resulting from abnormal intestinal ion 
transport. Anti-diarrheal agents, such as loperamide, diphenoxylateatropine (Lomotil®), 
octreotide, scopolamine and bismuth are typically ineffective once grade IV diarrhea has 
occurred. The diarrhea usually lasts 5-7 days before resolving. Early recognition of diarrhea and 
prompt institution of an intensive and prolonged course of loperamide appears to be the most 
effective approach to this problem. Myelosuppression is manifested primarily as leukopenia and 
neutropenia. Other toxicities include nausea, vomiting, alopecia and cumulative fatigue or 
asthenia. Instances of possible drug related hepatic toxicity have occurred, but are rare. 
2.1.4 Leucovorin 
Leucovorin is a reduced folate which, when combined with 5FU, augments 5FU cytotoxicity by 
increasing the inhibition of TS by the 5FU active metabolite FdUMP. It is well-tolerated but can 
be associated with allergic reactions (rash, urticaria, anaphylaxis) and is contraindicated in 
patients with B12 deficiency and pernicious anemia. 
2.1.5  Losartan 
Losartan is an angiotensin II type I receptor blocker (ARB) used in the treatment of essential 
hypertension and diabetic nephropathy. It is a selective competitive angiotensin II receptor 
antagonist that acts as an antihypertensive by blocking angiotensin II and its two major 
downstream pathways: direct vasoconstriction, and stimulation of aldosterone secretion. Its 
mechanisms of action in the cancer milieu will be discussed separately. It is administered orally 
and the usual starting dose in adults with hypertension is 50 mg, with doses up to 100 mg based 
on blood pressure response. Patients with baseline volume depletion are started on a dose of 25 
mg PO daily with the dose titrated up as tolerated. There are no specific dosing adjustments for 
hepatic or renal impairment, but use in patients with chronic kidney disease whose calculated 
GFR is less than 30mL/minute/1.73m2 is not recommended. Losartan is associated with the 
significant adverse reactions (>10% incidence) of chest pain, fatigue, hypoglycemia, diarrhea, 
urinary tract infection, anemia, weakness, back pain, and cough. Less common, but important, 
adverse reactions include hypotension, orthostatic hypotension, dizziness, hyperkalemia, 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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gastritis, muscle weakness, bronchitis. Rarely, losartan is associated with life-threatening 
angioedema, acute psychosis, and cardiac arrhythmia. 
2.1.6 Capecitabine 
Capecitabine is a rationally designed oral fluoropyrimidine.(1, 2) Given its lack of a 
need for an implantable access device or portable infusion pump and patient convenience, it has 
become an attractive agent to be combined with radiation therapy.  Capecitabine undergoes three 
steps of enzymatic activation before converting to the active drug.  It is readily absorbed from 
the gastrointestinal tract. In the liver, a 60 kDa carboxyesterase hydrolyzes much of the 
compound to 5’-deoxy-5-fluorocytidine (5’-DFCR). Cytidine deaminase, an enzyme found in 
most tissues, including tumors, subsequently converts 5’-DFCR to 5’-deoxy-5-fluorouridine (5’-
DFUR). The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5’-DFUR to the 
active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase . Some 
human carcinomas express this enzyme in higher concentrations than surrounding normal 
tissues.  Capecitabine is rapidly and extensively absorbed with the peak plasma concentrations 
for the drug and its two main metabolites occurring shortly (0.5 - 1.5 hours) after administration.  
Then concentrations decline exponentially with a half-life of 0.5 - 1 hour.  Plasma concentrations 
of the cytotoxic moiety 5-FU are very low. 
Capecitabine is generally well tolerated.  Major side effects include diarrhea, nausea, 
hand-and-foot syndrome, vomiting, fatigue, and stomatitis.  The most frequent grade 3 or 4 
laboratory abnormality was elevated total bilirubin and alkaline phosphatase, or abnormal liver 
function tests.  Myelosuppression has been  rarely reported (< 2%). 
Its role as a radiosensitizer has been most studied in rectal cancer.  Dunst et al reported 
the results of a phase I study using capecitabine in T3 and T4 rectal cancer.(3) Thirty-six patients 
with rectal cancer received treatment in the adjuvant, neoadjuvant, or palliative setting with a 
total radiation dose of 50.4 Gy.  Capecitabine was administered at escalating doses from 250 to 
1,250 mg/m2 twice a day concurrently with radiation.  They were able to escalate the 
capecitabine dose to 825 mg/m2 twice a day.  Dose-limiting grade 3 hand-and-foot syndrome 
was observed in two of six patients treated at 1,000 mg/m2 bid.  Other toxicities were generally 
rare and/or mild.  One pathologic complete remission of a T3N1 tumor and nine partial 
remissions were observed in 10 patients treated in the neoadjuvant setting.  In another study, 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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capecitabine was administered concurrently with radiotherapy in locally advanced rectal 
cancer.(4)  The treatment consisted of 2 cycles of 14-day oral capecitabine (825 mg/m2 BID) and 
leucovorin (10 mg/m2 BID), each of which was followed by a 7-day rest period.  The overall 
downstaging rate, including both primary tumor and nodes, was 84%. A pathologic complete 
response was achieved in 31% of patients. Twenty-one patients had tumors located initially 5 cm 
or less from the anal verge; among the 18 treated with surgery, 72% received sphincter-
preserving surgery.   Grade 3 toxicities included hand-foot syndrome (7%), fatigue (4%), 
diarrhea (4%), and radiation dermatitis (2%).   NSABP is planning a prospective randomized 
trial to compare capecitabine with infusional 5-FU in patients undergoing preoperative radiation 
therapy.  Preliminary results from a trial combining capecitabine with radiation therapy in 
patients with locally advanced pancreatic cancer demonstrated the combination to be safe and 
tolerable at a dose of 825 mg/m2 twice daily.(5) 
2.1.7 Proton Beam Radiation Therapy  
There have been unprecedented efforts in radiation oncology to develop and use sophisticated, 
conformal photon techniques in order to improve the outcome for cancer patients. The aim of 
these new techniques is to concentrate the radiation dose distribution more completely on the 
disease target, thereby sparing critical normal tissues and increasing the target dose. Toward this 
end, many advances have been made and examples of new developments include tomotherapy 
and intensity modulated photon therapy. At the same time, heavy, charged-particle programs, 
particularly those for proton therapy, have been developed. Proton therapy dose distributions are 
superior to those of photon therapy and this provides the potential to further improve clinical 
outcomes. Several institutions have committed to build dedicated proton therapy centers such as 
the Francis H. Burr Proton Therapy Center (FHBPTC) at the Massachusetts General Hospital 
(MGH) and the Loma Linda University Medical Center proton therapy facility. Several more 
proton therapy centers are in the final planning stage. 
2.1.7.1
The Advantages of Protons for Delivery of Conformal Therapy 

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Characteristics of Proton Beams 
The basis for the advantages of 
proton beams lies in the physical laws 
that determine the absorption of energy 
in tissues exposed to photon or proton 
beams. In a specific tissue, photons are 
absorbed exponentially whereas protons 
have a finite range dependent upon the 
initial proton energy. Therefore, the 
depth dose characteristics of the two 
beams are qualitatively different (see Figure 1). Protons lose their energy in tissue mostly by 
coulombic interactions with electrons in the constituent atoms; however, a small fraction of 
energy is transferred through nuclear collisions. The energy loss per unit path length is relatively 
small and constant as the proton traverses the tissue until near the end of the proton range where 
the residual energy is lost over a short distance (approximately 0.7 cm in width at 80% of the 
maximum dose) and the proton comes to rest, resulting in a distinctive sharp rise in the tissue 
absorbed dose (energy absorbed per unit mass) - known as the Bragg peak (see the curve labeled 
"unmodulated proton beam" in Figure 1). In physical terms, the magnitude of the transfer of 
energy to tissue per unit path length traversed by the protons is inversely proportional to the 
square of the proton velocity. The low dose region between the entrance and the Bragg peak is 
called the plateau of the dose distribution and the dose there is 30-40 percent of the maximum 
dose. 
The Bragg peak is too narrow in extent to irradiate any but the smallest of targets, 
ablation of the pituitary gland for example. For the irradiation of larger targets/tumors the beam 
energy is modulated - several beams of closely spaced energies (ranges) are superimposed to 
create a region of uniform dose over the depth of the target. These extended regions of uniform 
dose are called "spread-out Bragg peaks" (SOBP). This is shown in Figure 1 as the “modulated 
proton beam”.  

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target volumes receiving 76, 66, and 56 Gy, respectively). The two plans were subject to 
identical dose constraints on normal tissues. The proton dose distribution (left) is clearly 
excellent; the photon distribution on the right is also very good.  However, the presentation of the 
dose in the top panels does not adequately reveal the significant differences between the two 
distributions.  The lower panels show the dose difference between the plans. X-rays deliver an 
additional “bath” of from 5 to 15 Gy throughout the brain and, in the region of the right eye 
(which is magnified in the lower left), up to 40 Gy more than the protons.  (The constraint on the 
right eye’s retina was 50 Gy; had it been reduced, x-rays could certainly have reduced the dose in 
that region – but at the price of increased dose elsewhere and, perhaps, of greater non-uniformity 
of dose in the target volumes.) 
Pancreatic tumors also have a number of normal structures in close proximity that have 
limited radiation tolerance including kidneys, liver, spinal cord and stomach.  The lack of exit 
dose from proton beam radiation can allow for reduced dose to these and other normal tissues. 
2.2 
Disease Background 
2.2.1 Chemotherapy and chemoradiation in locally advanced pancreatic adenocarcinoma 
Locally advanced unresectable pancreatic tumors represent 30 to 40% of all newly diagnosed 
pancreatic cancers. These patients lie on a continuum with patients diagnosed with metastatic 
disease at the outset, as surgical resection offers the only path to cure. Unresectable tumors are 
classified by the NCCN based on location (6).  Tumors of the head that have greater than 180 
degrees of SMA encasement or any celiac abutment, unreconstructable SMV or portal occlusion, 
or aortic invasion or encasement are unresectable. Body tumors with SMA or celiac encasement 
of greater than 180 degrees, unreconstructable SMV or portal occlusion, or aortic invasion are 
unresectable. Tumors of the tail with SMA or celiac encasement of greater than 180 degrees are 
unresectable. Irrespective of location, all tumors with evidence of nodal metastasis outside of the 
resection field are deemed unresectable. 
Patients who present with locally advanced unresectable disease appear to benefit from both 
local control and timely systemic therapy. In rare cases, combination therapy provides tumor 
downstaging and conversion to potential surgical resectability. The rate of downstaging to 
surgery varies by institution – the Massachusetts General Hospital experience is less than 8%, 

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owing likely to the low threshold to perform early resection in cases of borderline resectability 
with venous reconstructive surgery.  
In the absence of surgery, radiation therapy alone is associated with very high early failure 
rates, approximately 72 % (7).  Since patients diagnosed with locally advanced, unresectable 
tumors are at very high risk for occult metastatic disease at presentation, subjecting all-comers to 
upfront chemoradiation delivers toxic therapy to a subset of patients who will not derive benefit. 
Chemotherapy alone, followed by restaging and selection of the subset of patients who have 
persistent local disease without metastatic progression, selects out patients who will potentially 
benefit. This was the basis for the GERCOR series, a retrospective evaluation of 181 patients 
with locally advanced pancreatic cancer enrolled in prospective phase II and III GERCOR 
studies (evaluating GEMOX, FOLFUGEM, gemcitabine alone)(8).  In this series, 29.3% of 
patients demonstrated metastatic disease after three months of chemotherapy. Among the 70.3% 
of remaining patients (128 patients), 56% received chemoradiation while 44% received 
additional chemotherapy alone. Median progression-free survival in the chemoradiation group 
was 10.8 months, versus 7.4 months in the chemotherapy alone group (p=0.005), corresponding 
to median OS of 15.0 and 11.7 months, respectively (p=0.0009). Similar results were observed in 
a cohort of patients at MD Anderson, where a retrospective analysis demonstrated 76 patients 
(out of a cohort of 323) treated with upfront chemotherapy (a median of 2.5 months of 
gemcitabine) followed by chemoradiation(9).  The median survival in patients receiving 
chemotherapy followed by chemoradiation was 11.9 months (6.4 month PFS), greater than for 
those receiving chemoradiotherapy from the outset (8.5 months OS and 4.2 months PFS, 
respectively (both p<0.01). These data have made the practice of chemotherapy, followed by 
restaging and chemoradiation in persistent locally advanced disease, the standard practice at our 
institution. 
The optimal treatment sequence in the management of resectable pancreatic cancer is 
intensely controversial, as is the role of chemotherapy versus chemoradiation in the pre- and 
postoperative setting. In borderline-resectable disease, the case for neoadjuvant treatment is more 
compelling but data for the definitive benefit is lacking, with case series rather than prospective 
clinical trials predominating the literature. The current trial will enroll patients with borderline 
resectable disease, and upfront higher-risk body and tail lesions. Based on potential 
unresectability and/or micrometastatic spread at presentation, these two groups represent the 

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opportune population to offer the combination of highly active systemic chemotherapy (the 
FOLFIRINOX regimen) with preoperative radiation therapy. 
2.2.2 The FOLFIRINOX regimen in advanced pancreatic cancer 
In advanced pancreatic cancer (M1 disease), the standard of care of gemcitabine monotherapy 
was challenged in 2010 with the presentation of the final results of the Prodige 4 – ACCORD 
11/04023 trial.  This large Phase III trial arose from promising interim results from a randomized 
phase II trial comparing FOLFIRINOX to gemcitabine in which a 31.8% response rate was 
detected in the FOLFIRINOX arm, compared to an 11.4% response rate in the gemcitabine arm 
(10).  
In the Phase III trial, patients were randomized to FOLFIRINOX versus gemcitabine therapy, 
with CT assessment every two months and six months planned upfront therapy (11). The 
FOLFIRINOX regimen was delivered as a 14-day cycle consisting of oxaliplatin 85 mg/m2 
infused over two hours; 5FU 400 mg/m2 bolus with leucovorin 400 mg/m2 infused over two 
hours, followed by infusional 5FU with 2400 mg/m2 delivered over 46 hour infusion; and 
irinotecan 180 mg/m2 delivered over 90 minutes.  Gemcitabine was delivered in the standard 
fashion of 1000 mg/m2 over 30 minutes given weekly on weeks 7/8 and then weekly ¾ (12).  
Patients were stratified by center, performance status (0 versus 1), and site of primary tumor 
(head of the pancreas versus body and tail.)  The study excluded patients with biliary obstruction, 
enrolling patients only with serum bilirubin values of 1.5x the upper limit of normal and lower. 
Notably, lesions in locations other than the head of the pancreas comprised the majority of the 
study population in both arms – 63.7% in the FOLFIRINOX arm and 64.9% in the gemcitabine 
arm. The primary endpoint of the study was overall survival, with the secondary endpoints of 
objective response rate (by RECIST), toxicity, progression-free survival, and quality of life 
measured on the EORTC QLQ-C30 v3.0 scale. One hundred seventy one patients were observed 
by intention-to-treat in each arm. 

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The hematologic adverse event profile of the FOLFIRNOX regimen was significantly greater 
compared to gemcitabine. Rates of Grade 3/4 neutropenia (45.4% versus 18.7%), febrile 
neutropenia (5.4 versus 0.6%), and thrombocytopenia (9.1 versus 2.4%) were significantly higher. 
This resulted in 42.5% of patients in the FOLFIRINOX arm requiring G-CSF injection, versus 
5.3% in the gemcitabine arm. Nonhematologic Grade 3/4 toxicities were also more prevalent, with 
peripheral neuropathy, vomiting, fatigue, diarrhea, and alopecia all occurring in the FOLFIRINOX 
arm at a significantly greater rate.  
Despite greater toxicity, the FOLFIRINOX regimen outperformed gemcitabine in all outcomes 
measures. The partial response rate was 31% [24.7-39.1, 95% CI] versus 9.4% [5.9 – 15.4%, 95% 
CI] in the gemcitabine arm. Stable disease rates were more comparable, with 38.6% SD rate in the
FOLFIRINOX arm and 41.5% in the gemcitabine arm. Overall this led to superior disease control 
rates (CR+PR+SD) for FOLFIRINOX versus gemcitabine, 70.2% and 50.9%, respectively.With a 
median follow-up of 26.6 months [95% CI: 20.5 – 44.9], progression-free survival of patients in 
the FOLFIRINOX arm was 6.4 months, versus 3.3 months in the gemcitabine arm (HR 0.47, 95% 
CI [0.37-0.59].)  This translated to a median overall survival of 11.1 months in the FOLFIRINOX 
arm versus 6.8 months in the gemcitabine arm (HR 0.57, p<0.0001), with a 48.4% one-year 
survival rate (versus 20.6% one-year survival in the gemcitabine arm.)  
The compelling features of the Prodige-4/ACCORD results that mandate moving the regimen 
into the locally advanced setting are twofold: first, its demonstrated superiority in systemic disease 
control, and second, its superior objective response rates. In the setting of locally advanced disease, 
the goal of providing chemotherapy to potentially downstage to surgical resectability while 
controlling local spread is paramount. The FOLFIRINOX regimen (without Losartan) is currently 
under investigation in the locally advanced setting in the CALGB/ECOG trial.  
2.2.3 The role of ARBs in the treatment of pancreatic cancer 
While the epidemiologic data are mixed regarding the contribution of angiotensin converting 
enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARBs) to cancer risk, data on 
clinical outcomes of patients who continue to receive ACEI and ARB therapy during treatment for 

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21
a diagnosed cancer more consistently suggest a benefit. In a cohort of 287 patients with advanced 
non-small cell lung cancer, Wilop et al. observed a 3.1 month median survival advantage among 
ACEI or ARB recipients which could not be attributed to other established risk factors or dose 
intensity of chemotherapy (11.7 vs 8.6 months, HR 0.56, p=0.03) (13). In a cohort of patients with 
locally advanced or metastatic pancreatic cancer, Nakai et al observed an 8.7 month median PFS 
among patients receiving ACEI or ARB therapy (n=27) versus 4.5 months in a cohort receiving 
other antihypertensive therapy (n=25) versus 3.6 months in a cohort not receiving any 
antihypertensive therapy (n=103) (p=0.032) (14). The mechanisms by which ARB and ACEI 
therapy appear to convey a protective benefit are under intense exploration, and explanations for 
this potential benefit have implicated the role of the renin-angiotensin system (RAS) in 
angiogenesis, cell proliferation, apoptosis, inflammation and intratumoral drug delivery.  The RAS 
appears active in pancreatic tissue, more so in malignancy. Ohta et al explored the presence of the 
local RAS in pancreatic tissue while investigating the observation that pancreatic tumors have 
vascular-rich and hypovascular regions on angiography of surgically resected specimens (15). 
Angiotensin II (ATII) can be generated in the pancreas from its proenzyme angiotensinogen by 
active trypsin, ubiquitous in pancreatic tissue. ATII and ACE levels were measured in a panel of 
surgical specimens: normal pancreas, pancreatic adenocarcinoma, colon cancer, and hepatocellular 
cancer. Tissue ATII levels, but not ACE levels, were significantly higher in pancreatic 
adenocarcinoma samples relative to all other tissue types – suggesting that local vasoconstriction 
may result in focal hypovascularity and necrosis in an ACE-independent manner. Following this 
observation, Amaya et al measured angiotensin II type 1 receptor (AT1) expression in three 
pancreatic cell lines and found strong expression, while one non-pancreatic cell line (the colorectal 
line HT-29) showed very weak expression (16). The group found that ATII stimulated the growth 
of pancreatic cancer cells through MAP kinase activation, and also prevented cisplatin-induced 
apoptosis through NF-kappa B activation and subsequent upregulation of the anti-apoptotic 
molecules survivin and Bcl-XL. Subsequently, Gong et al demonstrated that administration of 
losartan to a panel of pancreatic adenocarcinoma cell lines induced dose-dependent decrease in cell 
survival, increasing p53, p21, p27, and Bax, and reducing Bcl-2 and Bcl-xl expression (17). 
The renin-angiotensin pathway in pancreatic carcinoma is also thought to signal through an 
angiogenesis-mediated pathway.  ATII can upregulate VEGF production. Arafat et al analyzed 
expression and localization of ACE, AT1R, and VEGF levels in 25 human pancreatic tumors 

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relative to matched surrounding non-malignant tissue, and found that ACE and AT1R levels were 
upregulated in 75% of tumor samples, and that VEGF expression was much higher in the subset of 
tumors in which ACE and AT1R were upregulated (18). When cells were incubated with the ACEI 
captopril or the ARB losartan, cell proliferation was significantly suppressed. Noguchi et al 
subsequently investigated the synergistic effect of gemcitabine and losartan in a murine pancreatic 
cancer model (19). While the administration of gemcitabine or losartan alone provided moderate 
inhibitory effect, the combination of therapies provided a significant inhibition of tumor volume in 
treated mice.  In tumors treated with losartan and gemcitabine they found significantly less CD31-
positive vessels, corresponding with a significantly lower intratumoral expression of VEGF.  
A final path of inquiry, and the preclinical data forming the basis for the current trial, comes 
from recent findings showing that the elevated fibrillar collagen content – associated with tumor 
desmoplasia – is a significant barrier to drug delivery in pancreatic tumor models and other tumor 
types (20-23).  Independent of its potential role in angiogenesis inhibition, losartan has been shown 
to minimize collagen accumulation and fibrosis in cardiac and renal disease (22, 23).  The 
inhibition of ATII signaling by losartan and other RAS inhibitors reduces the expression and 
activity of profibrogenic molecules like TGF-, thrombospondin-1 – an activator of the latent-form 
of TGF-–, connective tissue growth factor and osteopontin (10, 26-29). In a recent study, the Jain 
group investigated the effect of losartan on collagen I levels in several tumor models in mice 
including an orthotopic pancreatic cancer model (30).  Losartan decreased the intratumoral 
expression of the TGF- activator TSP-1, and losartan doses of 20 and 60 mg/kg/d for 2 weeks 
significantly reduced the intratumoral collagen content, while the 10mg/kg/d dose did not affect 
collagen accumulation.  To test if the reduction in collagen content would improve the intratumoral 
distribution of large therapeutics, nanospheres were injected intratumorally or intravenously 
following the losartan pre-treatment.  The reduction in collagen levels led to enhanced nanospheres 
diffusion and distribution in tumors.  In mice with orthotopic pancreatic cancers losartan did not 
change the fraction of perfused vessels, but the penetration of nanospheres – injected intravenously 
– at distance from blood vessels was greater in losartan-treated than control tumors. Furthermore,
losartan enhanced the efficacy of the nanotherapeutic Doxil.  Interestingly, the administration of 
Doxil or losartan alone did not affect the growth of pancreatic tumors, but tumors were 50% 
smaller in mice treated with losartan and Doxil.  Thus losartan shows potential as an adjunct to 

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safely enhance the intratumoral penetration and efﬁcacy of therapeutics in patients with pancreatic 
cancer.   
The impact of angiotensin II blockade on collagen remodeling has been clinically validated in 
the connective tissue disorder Marfan’s Syndrome (26). The genetic defect, a mutation in the gene 
encoding fibrillin-1, leads to excessive TGF- signaling and a disorganized collagen matrix. 
Patients with this disorder are susceptible to the life-threatening clinical sequel of aortic root 
dilatation. In a retrospective cohort analysis of pediatric patients with Marfan’s syndrome who had 
been initiated on an ARB (losartan in 17 patients and ibesartan in 1 patient), the mean change in 
aortic-root diameter during the period patients were on ARB therapy was far less rapid (0.46 +/-
0.62 mm per year), relative to a baseline rate of increase of 3.54 mm per year.  Notably, the 
Marfan’s trial represents a dose escalation schema in which the pediatric patients enrolled were not 
hypertensive at baseline per se, and were often transitioned from beta blocker monotherapy to 
ARB therapy. Drug dose was escalated from 0.7 mg/kg to 1.4 mg/kg (a dose corresponding to 50-
100 mg for the average adult patient) and median change in systolic BP on maximum dose therapy 
was non-significant when compared to prior monotherapy – i.e. losartan monotherapy does not 
represent particularly potent anti-hypertensive effects. In normotensive patients with chronic 
hepatitis C the daily administration of losartan (50 mg/d) reduced liver fibrosis, significantly 
decreased the systolic pressure by 10 mm Hg but did not affect the mean arterial blood pressure 
(31).   
A recent Phase I trial in advanced and locally advanced PDAC employed candesartan along 
with gemcitabine chemotherapy in normotensive patientsi. Candesartan was given orally at an 
escalating dose (4, 8, 16, and 32 mg) q.d. daily, and gemcitabine was given at standard dosing 
(1000 mg/m(2) 30 min i.v. on days 1, 8, and 15, repeated every 4 weeks.) The study enrolled a 
total of 14 patients and found that hypotension was the limiting DLT at the 32 mg dose (which 
would be the biologic equivalent of Losartan at 100mg PO qd). Response rate and disease control 
rate were 0% and 79%, respectively. Progression-free survival and overall survival were 7.6 and 
22.9 months, respectively – less so in patients with advanced disease. The 16 mg dose in 
combination with gemcitabine was the recommended Phase II dose in this cohort (equivalent to 
Losartan at 50 mg, the planned dose in the current study). 

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2.2.4 Proton-based Short Course Radiation Therapy for pancreatic cancer: MGH Experience 
The safety and efficacy of a one-week course of preoperative proton beam therapy and 
capecitabine followed by early pancreaticoduodenectomy (PD) was explored in a prior study in 
our institution in a different study population.  Patients with radiographically resectable, biopsy-
proven pancreatic cancer of the head of the pancreas were enrolled from May 2007-March 2010 
on this IRB-approved, NCI-sponsored clinical trial. Eligibility included no CT involvement of 
the SMA or celiac arteries; adequate renal, hepatic and hematopoetic function; and ECOG PS 
0/1. Dose level 1 consisted of PBT delivered 3 Gy x 10 Monday to Friday. Pts in subsequent 
dose levels received 5 Gy x 5 in progressively shortened schedules: level 2 (wk 1 M W F, wk 2 T 
Th), level 3 (wk 1 M T Th F, wk 2 M), level 4 (wk 1 M-F). Proton beam therapy was targeted at 
pancreatic mass with elective nodal coverage. Pts received Capecitabine 825 mg/m2 BID wk 1 
and 2 M-F.  Surgery was performed 1-6 wks after completion of chemotherapy.  Patients were 
recommended to receive 6 months of gemcitabine after surgery.  31 pts were enrolled on study.  
27 patients are eligible for this analysis. Three patients were treated at each of dose levels 1-3. 
Six patients were at dose level 4, which was selected as the MTD. No dose limiting toxicities 
were observed.  There were no unexpected 30-day post-op complications noted in comparison to 
historical controls. 4/21 resected patients had positive margins. 17/21 had positive nodes. Median 
follow up is 10 months. There have been 2 local failures/progression in ALL patients, both with 
synchronous metastatic disease (at 10 mo and 17 mo). Metastatic failure has occurred in 15 out 
of 27 patients (56%). In summary, we found pre-operative CRT with 1 week of PBT and 
capecitabine followed by early surgery feasible and associated with satisfactory local control.  
2.2.5 Photon based short course chemoradiation in locally advanced pancreatic cancer 
Dholakia and colleagues have studied fractionated stereotactic body radiation therapy (SBRT) 
of 33 Gy photons in five fractions for locally advanced pancreatic cancer.  They demonstrated 
local control of 83% at one year with minimal acute or late gastrointestinal toxicity and 
favorable survival compared to historical data. (33)  This correlates well with our five fraction 
proton studies. 
2.2.6 Summary 

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This research study combines several key tenets. First, we hypothesize that pre-radiation 
FOLFIRINOX therapy will optimize the treatment of patients with locally advanced pancreatic 
adenocarcinoma based on its superior response rate demonstrated in patients with advanced 
pancreatic cancer in the Prodige-4/ACCORD trial. Based on compelling preclinical data 
regarding Losartan’s many potential synergistic benefits in angiogenesis inhibition and collagen 
matrix stabilization, we posit that the addition of this agent will further potentiate the benefit of 
FOLFIRINOX therapy via enhanced drug delivery. The subsequent use of radiation therapy aims 
to consolidate upfront chemotherapy treatment in an effective manner, with tolerable toxicity.  
2.3 
Patient-reported outcomes (PRO) background 
There are few published studies measuring patient-reported symptoms and quality of life (QOL) 
outcomes in patients with pancreatic cancer. Most of the existing studies assessing QOL in 
patients with pancreatic cancer are focused on individuals with advanced disease.[30, 31] The 
few studies that have included patients with operable pancreatic cancer included small sample 
sizes in heterogeneous patients.[32, 33] Despite the fact that depression is a frequently reported 
symptom in patients with pancreatic cancer, the prevalence among different stages of disease has 
not been thoroughly investigated.[34] A more detailed and comprehensive understanding of the 
burdens faced by patients with locally advanced pancreatic cancer will identify areas for 
clinicians to enhance their supportive care efforts. 
Studying patients’ symptom burden and QOL while they are participating in a clinical trial 
provides an opportunity to better understand their disease- and treatment-related outcomes. 
Patients’ symptom burden and QOL are better indicators of their treatment tolerability than 
clinician-reported toxicity monitoring. Combining objective endpoints, such as response rate, 
with subjective patient-reported outcomes has become increasingly important in determining 
efficacy, toxicity, and safety and for allowing comparisons across treatment arms.[35] 
Additionally, evaluating patient-reported measures may help highlight patients’ difficulties with 
treatment adherence by demonstrating additional side effects and toxicities of therapy.[36] 
Increased attention to patients’ symptom burden and QOL while they are participating in a 
clinical trial provides an opportunity to improve their quality of care.[37, 38] Thus, we aim to 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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describe QOL, symptom burden and mood in this study population to help us better identify the 
side effects and challenges faced by patients with locally advanced pancreatic cancer. 
A randomized trial comparing the efficacy of gemcitabine and FOLFIRINOX in metastatic 
pancreatic cancer also assessed QOL, using the European Organization for the Research and 
Treatment of Cancer QOL Questionnaire C30 (EORTC QLQ-C30).[31]  The authors 
demonstrated that FOLFIRINOX not only prolonged survival, but also significantly reduced 
QOL impairment compared to gemcitabine for patients with metastatic cancer.  Thus, in addition 
to the utility of describing the symptom burden and QOL in patients with locally advanced 
pancreatic cancer, it will also be useful to compare these outcomes in patients receiving different 
chemotherapy regimens. 
We will use the EORTC QLQ-C30, a validated instrument designed for prospective clinical trials 
that evaluates five functions (physical, role, cognitive, emotional, and social), and nine 
symptoms (fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation, 
diarrhea, and financial difficulties) to measure QOL.[39] We will use the Edmonton Symptom 
Assessment System-revised (ESAS-r) to measure symptoms, which has been previously 
validated in patients with advanced cancer.[40] The ESAS-r consists of ten items assessing pain, 
fatigue, drowsiness, nausea, anorexia, dyspnea, depression, anxiety, well-being, and a free-
response item. We will include constipation as the free-response item. The ten items are scored 
on a scale of 0-10 (0 reflecting no reported presence of the symptom and 10 reflecting the worst 
possible severity of the symptom). We will instruct patients that items are to be rated based on 
the previous 24-hour period. We will use the Hospital Anxiety and Depression Scale (HADS) to 
assess symptoms of depression and anxiety.[41] The HADS is a 14-item questionnaire that 
contains two 7-item subscales assessing depression and anxiety symptoms during the past week. 
The questionnaire consists of a four-point item response format that quantifies the degree to 
which participants experience a particular emotion. Scores on each subscale range from 0 to 21, 
with a cutoff of 8 or greater denoting clinically significant depression or anxiety symptoms. 

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2.4  Health care utilization background 
As oncologists strive to improve care quality and lower health care costs, their focus has turned 
to reducing avoidable admissions and decreasing hospital length of stay (LOS) for patients with 
cancer.[42, 43]  Patients with pancreatic cancer often experience symptoms related to the cancer 
itself or the therapies used to treat it.[32] Symptom management for these patients may 
necessitate frequent clinic visits, surgical interventions, and ultimately admissions to the hospital. 
Avoiding unnecessary hospitalizations is an area needing improvement for patients with cancer, 
but a better understanding of health care utilization is necessary in order to develop future 
interventions.[44] Thus, we propose to collect data on study participants’ health care utilization 
including hospital admissions, intensive care unit stays and emergency room visits.  Similar to 
measuring patient-reported outcomes, assessing health care utilization will help us better 
understand study patients’ experience with their cancer treatment. 
3
ELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria: 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1
 Cytologic or histologic proof pancreatic ductal carcinoma is required prior to study entry. 
Diagnosis must be confirmed by a DFHCC institution pathology department prior to 
registration.   
3.1.2 No evidence of metastatic disease as determined by chest CT scan, abdomen/pelvis CT 
scan (or MRI with gadolinium and/or manganese). All patients must be staged with a 
physical exam, chest CT, abdominal CT with intravenous contrast (or Abdominal MRI 
with gadolinium and/or manganese).  
3.1.3
 Patients with locally advanced, unresectable disease will be included. Locally advanced 
unresectable disease is defined by the NCCN as:  

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1) Tumors of the head that have greater than 180 degrees of SMA encasement or any
celiac abutment, unreconstructable SMV or portal occlusion, or aortic invasion or 
encasement. 
2) Tumors of the body with SMA or celiac encasement of greater than 180 degrees,
unreconstructable SMV or portal occlusion, or aortic invasion. 
3) Tumors of the tail with SMA or celiac encasement of greater than 180 degrees.
4) Irrespective of location, all tumors with evidence of nodal metastasis outside of
the resection field are deemed unresectable (6). 
3.1.4
Patients must be 18 years old or older. There will be no upper age restriction. 
3.1.5
ECOG-Performance Status of 0 or 1 are eligible. 
3.1.6
Life expectancy of greater than 3 months. 
3.1.7
Baseline SBP > 100mm Hg. This is based on the average of two values - separate seated, 
resting measurements taken five minutes apart. BP does not need to be checked in both 
arms unless a reading is below 110 mm Hg, in which case the other arm can be checked as 
well, If BP is checked in both arms, the higher value is deemed accurate for calculating the 
average. 
3.1.8 Lab Values: 
ANC  1500 cells/mm3 
Platelet count 100,000 cells/mm3. 
AST and ALT  2.5 x upper limit of normal OR two downtrending values 
Total Bilirubin  1.5 x upper limit of normal if no biliary stenting has been done;  
OR 2.0 x upper limit of normal if patient is s/p biliary stenting;  
OR two downtrending values 
Serum Creatinine ≤ 1.5 mg/dlCreatinine Clearance  30ml/min (as estimated by 
Cockroft Gault Equation):  
(140 - age [yrs]) (body wt [kg]) 
Creatinine clearance for males = 
———————————— 
(72) (serum creatinine [mg/dL])

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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Creatinine clearance for females =  0.85 x male value 
3.1.9 The effects of radiation on the developing human fetus are known to be teratogenic. 
Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study treatment plus 30 days from the last date of study drug administration. 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately. 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
3.2 
Exclusion Criteria 
Patients who fulfill any of the following criteria will be excluded: 
3.2.1 Serious concomitant systemic disorders incompatible with the study (at the discretion of 
the investigator), such as significant cardiac or pulmonary morbidity e.g. congestive heart 
failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled 
with medication) or myocardial infarction within the last 12 months, ongoing infection as 
manifested by fever.  
3.2.2
Patients cannot be already treated on ACE or ARB therapy for hypertension or renal 
protection (with diabetes) at the time of enrollment.  
3.2.3
Patients cannot have baseline hypotension, defined as systolic BP lower than 100 mm Hg 
on two readings obtained on two separate days prior to study enrollment.  
3.2.4
Pregnant or lactating women. Women of childbearing potential with either a positive or no 
pregnancy test (serum or urine) at baseline.  (Postmenopausal woman must have been 
amenorrheic for at least 12 months to be considered of non-childbearing potential). 
3.2.5
Any prior chemotherapy, radiation therapy, or biologic therapy (“targeted therapy”) for 
treatment of the patient’s pancreatic tumor.  

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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3.2.6
Treatment for other invasive carcinomas within the last five years who are at greater than 
5% risk of recurrence at time of eligibility screening. Carcinoma in-situ and basal cell 
carcinoma/squamous cell carcinoma of the skin are allowed. 
3.2.7
Other serious uncontrolled medical conditions that the investigator feels might 
compromise study participation. 
3.2.8
Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome. 
3.2.9
Known, existing uncontrolled coagulopathy. 
3.2.10 Unwillingness to participate or inability to comply with the protocol for the duration of the 
study. 
3.2.11 Prior systemic fluoropyrimidine therapy. Prior topical flouropyrimidine use is allowed. 
Prior unanticipated severe reaction to fluoropyrimidine therapy, or known hypersensitivity 
to 5-fluorouracil or known DPD deficiency. 
3.2.12 Participation in any investigational drug study within 4 weeks preceding the start of study 
treatment. 
3.2.13 History of uncontrolled seizures, central nervous system disorders or psychiatric disability 
judged by the investigator to be clinically significant, precluding informed consent, or 
interfering with compliance or oral drug intake. 
3.2.14 Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, 
without complete recovery. 
3.2.15 Patients should not be on cimetidine as it can decrease the clearance of 5-FU.  Another 
H2-blocker or proton pump inhibitor may be substituted before study entry. 
3.2.16 Participants may not be receiving any other study agents. 
3.2.17 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to 5-fluorouricil, irinotecan, oxaliplatin, or losartan. 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
We do not expect the inclusion and exclusion criteria to either over or underrepresent women, 
minorities, or underrepresented populations.
4 
REGISTRATION PROCEDURES  
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
Institutions will register eligible participants with the ODQ in the Clinical Trials 
Management System (CTMS) OnCore.  Registration must occur prior to the 
initiation of therapy. Any participant not registered to the protocol before treatment 
begins will be considered ineligible and registration will be denied.  
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
Following registration, participants may begin protocol treatment. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If 
a participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed.  Registration cancellations must be made in OnCore 
as soon as possible. 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
DF/HCC Standard Operating Procedure for Human Subject Research titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed. 
5
TREATMENT PLAN 
5.1 
Phase II FOLFIRINOX-Losartan Treatment 
Treatment will be administered on an outpatient basis and will include intravenous 
administration of the FOLFIRINOX regimen every 14 days +3/-1 days at physician discretion 
(unless a further delay is mandated by toxicity criteria) along with daily oral patient self-

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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32
administered Losartan. All chemotherapy will be administered according to institutional 
standard of care. 
Table 1: FOLFIRINOX-Losartan Standard Dosing Schedule 
Losartan 
FOLFIRINOX 
Dose 
25 mg PO qd starting 
on C1 Day 1. If this 
dose is tolerated during 
week 1, escalation to 
50 mg PO qd at C1D8, 
to continue daily until  
the completion of  C8 
Day 14. Losartan 
treatment will continue 
during any holds for 
FOLFIRINOX unless 
losartan is the agent 
responsible for the 
treatment hold. (See 
BP criteria as outlined 
below) 
Q14 day cycle: 
Day 1-3:OXALIPLATIN (85 mg/m2) 
IV BOLUS QD Days: 1 
Infuse over 2 hours. Any adjustments 
will follow institutional standard of 
care.  Mix in D5W. 
Infuse prior to irinotecan. Infusion time 
should be lengthened to 6 hours for 
ACUTE larngopharyngeal dysesthesias 
occurring during or after previous 
treatment 
IRINOTECAN (180 mg/m2) IV 
BOLUS QD Days: 1 Infuse over 90 
minutes. Any adjustments will follow 
institutional standard of care. 
Instructions: Mix in 500cc. Administer 
prior to leucovorin and 5-FU on day 1. 
May infuse irinotecan and leucovorin at 
the same time, in separate bags, using 
Y-line. Leucovorin is compatible with
both Oxaliplatin and Irinotecan IF
MIXED IN D5W. It may be started 1
hour and 30 minutes after start of
oxaliplatin IF MIXED IN D5W and
continued throughout the irinotecan
infusion so that Leucovorin and
Irinotecan infusions are completed at
the same time.
FOR PATIENTS REQUIRING 
LEUCOVORIN/IRINOTECAN 
MIXED IN NORMAL SALINE, infuse 
after oxaliplatin after line flush with 
D5W. 
LEUCOVORIN CALCIUM (400 
mg/m2) IV BOLUS QD Days: 1 
Infuse over 2 hours. Any adjustments 
will follow institutional standard of 
care.  Instructions: Administer 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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following irinotecan and before 5-FU 
on day 1. May infuse irinotecan and 
leucovorin at the same time, in separate 
bags, using Y-line. Leucovorin is 
compatible with both Oxaliplatin and 
Irinotecan IF MIXED IN D5W. It may 
be started 1 hour and 30 minutes after 
start of oxaliplatin IF MIXED IN D5W 
and continued throughout the irinotecan 
infusion so that Leucovorin and 
Irinotecan infusions are completed at 
the same time. 
FOR PATIENTS REQUIRING 
LEUCOVORIN/IRINOTECAN 
MIXED IN NORMAL SALINE, infuse 
after oxaliplatin after line flush with 
D5W. 
FLUOROURACIL (400 mg/m2) IV 
BOLUS QD Days: 1 
Infuse over 2-4 minutes. Any 
adjustments will follow institutional 
standard of care. 
FLUOROURACIL (1200 mg/m2) IV 
CONTINUOUS INFUSION QD 
Days: 1,2 
Instructions: Begin after fluorouracil 
bolus dose. Any adjustments will follow 
institutional standard of care. 
For OUTPATIENTS:The IVCI dose is 
for each of days 1 and 2 and should be 
delivered as one continuous infusion 
over 46-48 hours. Pump can be 
disconnected in a return visit to 
infusion, by a visiting nurse at home, or 
by patient self-disconnect at home. 
For INPATIENTS: Prepare day 1 and 
day 2 doses as separate doses, for a total 
of 2 doses. Each dose will be infused 
over 23 hours, without interruption 
between doses. 
ATROPINE SULFATE 
0.4-1 MG IV 
QD 
PRN: For early cholinergic syndrome 
related to irinotecan infusion 
Hold if: Giving sc 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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ATROPINE SULFATE 
0.4-1 MG SC 
QD 
PRN: For early cholinergic syndrome 
related to irinotecan infusion 
Hold if: Giving IV 
Day 3 or 4: 
Neulasta 
(Pegfilgrastim)administration 6 mg 
SC x1 At DFCI, standard has become 
to administer Pegfilgrastim at the 
time of 5FU pump disconnect. At 
MGH, standard is to administer 
Pegfilgrastim 24 hours after pump 
disconnect. Both methods are 
allowed in the protocol. Patients may 
self-administer at home or have the 
injection administered in clinic. Any 
adjustments will follow institutional 
standard of care. 
Per Standard of Care, central line will 
be placed for chemo infusions 
 
Patients will be restaged after four cycles of therapy (interim scans) as well as following 
completion of induction chemotherapy (eight cycles of therapy.) Restaging scans may be done in 
the second week of the preceding cycle. Up to one week’s delay between cycles for restaging is 
allowed. Patients who do not demonstrate progression on either restaging scan will undergo 
Radiation Therapy with standard dose capecitabine (825 mg/m2 bid x 5 days per week x 2 
weeks) in the week of, and the week following, proton beam radiation therapy. Patients who 
receive photon radiation therapy will take capecitabine (825 mg/m2 bid x 5 days per week x 2 
weeks) for the two weeks of radiation treatment. Radiation therapy with concurrent capecitabine 
must begin 15-43 days from Day 1 of the last cycle of FOLFIRINOX chemotherapy.  Expected 
toxicities and potential risks as well as dose modifications for FOLFIRINOX, Losartan, 
Capecitabine, and Radiation are described in Section 6 (Expected Toxicities and Dosing 
Delays/Dose Modification). No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant’s malignancy. 

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5.2 
Pre-Treatment Criteria 
Prior to study enrollment patients must undergo the following evaluations: 
Within 7 days of study entry: Physical exam, Lab studies (CBC with diff, Na, K, BUN, Cr, 
Glucose, Calcium, Albumin, AST, ALT, Total bilirubin, Alkaline phosphatase.) Acceptable 
laboratory parameters for Day 1 of treatment are as stated in inclusion criteria for the study:  
ANC  1500 cells/mm3 
Platelet count 100,000 cells/mm3. 
AST and ALT  2.5 x upper limit of normal OR two downtrending values 
Total Bilirubin  1.5 x upper limit of normal if no biliary stenting has been done 
OR  2.0 x upper limit of normal if patient is s/p biliary stenting 
OR two downtrending values 
Serum Creatinine ≤ 1.5 mg/dlCreatinine Clearance  30ml/min (as estimated by 
Cockroft Gault Equation):  
(140 - age [yrs]) (body wt [kg]) 
Creatinine clearance for males = 
———————————— 
(72) (serum creatinine [mg/dL])
Creatinine clearance for females =  0.85 x male value 
If a patient has undergone biliary stent placement, the following eligibility guidelines will 
apply. If ALT and AST are elevated out of range of eligibility at time of enrollment, but 
demonstrate two down-trending values, patient should begin treatment without Irinotecan if 
clinically indicated. The agents 5-FU and Oxaliplatin may be given during Cycle 1 with 
Irinotecan incorporated in Cycle 2 if laboratory values permit. If total bilirubin is elevated 
above 2.0 mg/dl at time of enrollment, the patient may begin Cycle 1 with full dose 5-FU and 
Oxaliplatin only, with Irinotecan incorporated in Cycle 2 if laboratory values permit. If total 
bilirubin is elevated between 1.0 mg/dl and 2.0 mg/dl at time of enrollment, the patient may 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
36
receive full dose 5-FU and Oxaliplatin, with dose-reduced Irinotecan. Irinotecan may be 
increased to full dose in second cycle if laboratory values permit 
Additionally, baseline blood pressure should be documented twice during the enrollment visit in 
a resting, seated position at least five minutes apart. SBP will be documented as the average of 
the two SBP readings. If SBP is borderline (below 110 mm Hg), it can be checked in the other 
arm, and the higher of the two arms can be used to calculate the average. Average SBP should 
exceed 100 mmHg for enrollment in the study at the starting dose of 25 mg PO qd. 
Evaluations obtained to confirm study eligibility may be used as pre-treatment evaluations 
provided they are done within the above timeframes. 
5.3 
Agent Administration 
Note: all chemotherapy infusion  adjustments will follow institutional standard of care at the discretion 
of the treating physician. 
5.3.1 5-Fluorouricil: 5-FU will be administered at a dose of 400 mg/m2 in a 2-4 minute IV 
push on day one, followed by a 1200 mg/M2/d by continuous infusion via an ambulatory 
infusion pump for the subsequent 46-48h. 5-Fluorouracil is not a vesicant or irritant. 
Initial dose of 5-FU may be reduced if necessary; then gradually increased to full dose if 
tolerated. All dose reductions are to be made at the discretion of the treating medical 
oncologist. 
5.3.2 Oxaliplatin: Oxaliplatin will be administered as a dose of 85 mg/m2 by intravenous 
infusion over 120 minutes on Day 1 of each treatment cycle. Infusion time may be 
prolonged (up to 6 hours) in patients experiencing pharyngolaryngeal dysesthesia. 
Oxaliplatin is unstable in the presence of chloride or alkaline solutions. Do NOT mix or 
administer oxaliplatin with saline or other chloride-containing solutions. Do NOT 
administer other drugs or solutions in the same infusion line. Flush IV lines/catheters with 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
37
Dextrose 5% in Water both before and after oxaliplatin administration. Initial dose of 
oxaliplatin may be reduced if necessary; then gradually increased to full dose if tolerated. 
All dose reductions are to be made at the discretion of the treating medical oncologist. 
5.3.3 Leucovorin (400 mg/m2) will be diluted with 5% dextrose and administered concurrently 
(in separate containers using a Y-type administration set) by IV infusion over 2 hours (+/- 
10 minutes). Any adjustments will follow institutional standard of care per the treating physician. 
5.3.4 Irinotecan: In this study irinotecan will be administered as a dose of 180 mg/m2 by 
intravenous infusion over 90 minutes on Day 1 of each treatment cycle. Early flushing, 
diarrhea, abdominal pain will be recognized and treated with IV atropine by nursing staff 
as per treatment standard with this drug. Initial dose of Irinotecan may be reduced if 
necessary; then gradually increased to full dose if tolerated. All dose reductions are to be 
made at the discretion of the treating medical oncologist. 
5.3.5 Losartan: Losartan will be administered orally as a tablet to be taken by the patient at 
home every day during treatment with FOLFIRINOX (i.e. during the eight cycles of 
induction chemotherapy) without breaks except when appropriate due to toxicity concerns. 
Missed or vomited doses will not be made up. Instances of missed or vomited doses will 
not constitute a violation of the protocol unless expressly deemed so by the overall PI.   A 
dose shall be considered missed if it is 3 hours beyond the time usually taken. In the first 
week of treatment (C1 D1-7), patients will take 25 mg PO qd of Losartan presuming they 
met minimum BP criteria at enrollment of 2 readings with an average SBP greater than 
100 mm Hg. Patients will return for C1 Day 8 at which time blood pressure will be 
rechecked (again, two separate resting, seated readings.) If SBP still exceeds 100mm Hg 
average between two separate, seated checks, patients may be escalated to a dose of 50 mg 
PO qd for the remainder of the study. BP checks will be mandated for each study visit. 
Please refer to the dose reduction section for information on dose reductions for 
hypotension and/or hyperkalemia resulting from Losartan. Study participants will be asked 
to return unused pill bottles at each follow up visit and drug accountability will be 
documented by pill counts.  All dose modifications are to be made at the discretion of the 
treating physician. 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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5.3.6 . Capecitabine: The dose of capecitabine will be given orally 825 mg/m2 BID (total 1650 
mg/m2 per day) for a total of 10 days M-F of weeks 1 and 2 (the week of, and the week 
after, proton beam radiation).  The dose of capecitabine will be fixed unless there are dose 
level reductions. The daily dose will be administered in two divided doses approximately 
12 hours apart.  The medication should be given within 30 minutes after the end of a meal 
or snack and swallowed with about 8 oz. of water.  The dose of capecitabine will be 
calculated on the basis of milligrams of drug per square meter of body surface area 
(BSA).Doses will be rounded to the nearest multiple of whole tablets.  Capecitabine 
tablets are either 150 or 500 mg in size, so the dose given will be rounded to the nearest 
150 mg tablet, per institutional standard.  The BSA will be rounded to the nearest tenth 
and the investigator will prescribe capecitabine per the institutional standard.  The dose of 
capecitabine will not exceed 2000mg po bid.   A dose shall be considered missed if it is 10 
hours beyond the time usually taken. 
5.3.7 If vomiting occurs around the time of capecitabine ingestion or if doses of capecitabine are 
missed, additional (“make-up”) doses of capecitabine should not be administered.  A drug 
diary will be provided to document appropriate administration. All dose reductions are to 
be made at the discretion of the treating medical oncologist. 
5.3.8 Radiation Therapy 
5.3.8.1 Simulation and Planning 
Tumor volume will be defined on the basis of CT and MRI imaging findings and 
operative notes and findings. The primary tumor and any clinically enlarged lymph nodes will 
be treated with a margin of 2 cm to include peripancreatic nodes.  The porta hepatis, celiac axis, 
superior mesenteric artery (SMA) root, and the pancreaticoduodenal nodes will also be treated 
at the physician’s discretion. For patients treated with photon SBRT, no elective nodal coverage 
will be used. 
Radiation therapy may be delivered with either protons or photons; treatment modality 
assignment will be based on available resources at the time of radiation planning.  Total dose 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
39
will be prescribed to the 95 to 100% isodose line based on coverage and will be 25 CGE in 5 
fractions (5 Gy/day) with multifield techniques.  A dose-painted in-field boost to a potentially 
at risk margin at the SMA, celiac axis, or SMV/PV to 6 Gy/day (30 Gy total) is permitted as 
long as all normal tissue constraints are met. 
Patients will be simulated supine. Intravenous and oral contrast will be administered per 
standard department protocol.  4-D planning CT will be obtained for treatment planning to 
ascertain the extent of tumor motion. 
The Gross Tumor Volume (GTV) is defined as the gross primary tumor and any lymph 
nodes enlarged over 1 cm during simulation using contrast given during CT or MRI.  The 
clinical target volume (CTV) will also include the following at-risk nodal basins: porta hepatis, 
celiac axis, superior mesenteric artery, and pancreaticoduodenal nodes as defined by the inner-
third of the duodenum.  Planning target volume (PTV): PTV will be customized based on 4D CT 
scan. Generally 0.5 cm expansion will be used, except for superiorly/inferiorly 0.7 cm will be 
used. 
Computerized dosimetry is required if more than two fields are used. All fields must be 
simulated using a machine that duplicates the geometry of the actual treatment machine.  Patient 
contours and isodose plots are required.  Isodose plots must account for the effect of all treated 
fields, including any blocking used.  For proton treatments, passively scattered protons and 
pencil beam scanning are both permitted. 
5.3.8.2 Treatment 
 
All radiation treatment will be given with the patient at the Francis H. Burr Proton Therapy 
Center or the Clark Center for Radiation Oncology at MGH.  Film or digital images will be taken 
prior to each treatment in accordance with the Department of Radiation Oncology’s standard 
practice for all patients.  These images are used to verify the position of the patient and the 
aperture.  These digital images are permanently stored electronically for each patient.  If the 
proton center is unexpectedly not functioning for 1-2 days, these fractions may be made up the 
following week. However, if the proton center is not functioning longer than 2 days, patients 
may receive photon radiation for the remaining fractions. If radiation therapy start is delayed 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
40
beyond 4 weeks after completion of FOLFIRINOX due to toxicity, the patient will proceed to 
radiation therapy on study at the discretion of the treating investigator. 
5.3.8.3 Normal tissue volume and dose considerations 
Normal tissue guidelines are as outlined below.  
Table 2: Planning Goals - Normal tissue constraints 
Organ 
Normalized 
Total Dose 
(2 Gy equivalents) 
Threshold Dose- 
5 fraction 
schedule 
(CGE) 
% Above 
threshold 
Liver 
23.0 Gy2 
17.5 
30% 
Kidney 
14.8 Gy3 
13 
30% 
Spinal Cord 
40.6 Gy2 
24 
0% 
Stomach 
38 Gy10 
7 
10% 
Assumed  in subscripts 
•
*  If possible -  Stomach dose threshold is to prevent nausea, an acute effect. No
established guidelines exist. However, in the preliminary MGH IMRT experience, the
above dose threshold is associated with ~ 10% rate of ANY anti-emetic use.  The daily
NTD of the conventional schedule is 1.36 Gy.  This means that that the threshold dose
(NTD) for a five fraction schedule is 6.8 Gy (2 Gy equivalents) and correlates with the
listed dose threshold.
Treatment planning should be adjusted for decreased renal function based on an elevated 
serum creatinine, a history of unilateral or bilateral renal disease, and abnormalities in 
baseline laboratory or radiographic studies.  Additional studies to assess renal function will be 
performed as needed. 
5.4 
General Concomitant Medication and Supportive Care Guidelines:  
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc. when appropriate.  The reason(s) for treatment, dosage, and the 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
41
dates of treatment should be recorded on the flow sheets.  Erythropoietin is allowed.  As the rate 
of Grade 2-4 neutropenia with FOLFIRINOX exceeded 70% in the PRODIGE/Accord trial, 
myeloid growth factors will be used prophylactically, and all patients should receive Neulasta 
(Pegfilgrastim) 6mg SC x1 24-48 hours after disconnection from CI 5FU as clinically indicated 
per institutional standard of care.  Patients may receive all concomitant therapy deemed 
necessary to provide adequate support.  No other cytotoxic therapy or radiotherapy may be used 
during therapy.  
5.5 
Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression 
and tolerance. In the absence of treatment delays due to adverse events, treatment may 
continue until one of the following criteria applies: 
•
Disease progression,
•
Intercurrent illness that prevents further administration of treatment,
•
Unacceptable adverse event(s),
•
Participant decides to withdraw from the study, or
•
General or specific changes in the participant's condition render the participant
unacceptable for further treatment in the opinion of the treating investigator.
5.6 
Duration of Follow Up 
Patients will be followed until documented progression, at which time they will be followed for 
survival only.  Participants removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
5.7 
Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in Section 5.5 
applies. The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will be 
discussed with the participant. Participants who develop disease progression will not be 
removed from the study, but will be followed for survival.  

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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42
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator Theodore S. Hong, M.D. at 617-724-1159. 
6
EXPECTED TOXICITIES AND DOSING DELAYS/MODIFICATIONS 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE v4.0) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/reporting//ctc.html).   
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
Grade 3 or 4 toxicities that are due to biliary ductal dilatation and resolved with placement of a 
biliary stent or with biliary stent change will not require a dose reduction of FOLFIRINOX, 
capecitabine, proton radiation therapy or Losartan after stent placement. Therapy may be 
withheld for procedures like repeat ERCP, and restarted at the treating physician's discretion per 
standard of care. 
6.1 
Anticipated Toxicities 
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be made or 
whether the event requires expedited reporting in addition to routine reporting. 
6.1.1 FOLFIRINOX Therapy 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
43
6.1.1.1 Anticipated Hematologic adverse events 
Below is the table of adverse events associated with the FOLFIRINOX regimen in the Prodige-
4/ACCORD trial in patients with advanced pancreatic adenocarcinoma (based on ASCO 2010 
presentation). 
AE, % per patient 
Folfirinox 
N=167 
All 
Grade 3/4 
Neutropenia 
79.9 
45.7 
Febrile Neutropenia 
  7.2 
Anemia 
90.4 
7.8 
Thrombocytopenia 
75.2 
9.1 
6.1.1.2 Anticipated Non-Hematologic adverse events 
Below is the table of non-hematologic adverse events associated with the FOLFIRINOX regimen 
in the Prodige-4/ACCORD trial in patients with advanced pancreatic adenocarcinoma. 
AE, % per patient 
Folfirinox N=167 
All 
Grade 3/4 
Infection without neutropenia 
6 
1.2 
Peripheral neuropathy 
70.5 
9 
Vomiting 
61.4 
14.5 
Fatigue 
87.3 
23.2 
Diarrhea 
73.3 
12.7 
Alopecia (grade 2) 
32.5 
(11.4) 
ALT 
64.8 
7.3 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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44
6.1.2 5-Fluourouracil Anticipated Toxicities 
Nausea, diarrhea, taste alteration, vomiting (mild); stomatitis: 5–8 days after treatment initiation; 
myelosuppression: granulocytopenia (9–14 days); thrombocytopenia (7–14 days); Alopecia; loss 
of nails; hyperpigmentation; photosensitivity; Maculopapular rash; palmar–plantar 
erythrodysethesias: (42–82% receiving continuous infusion); CNS effects: cerebral ataxia (rare); 
Cardiotoxicity: MI, angina; asymptomatic S–T changes 68%; ocular effects: excessive 
lacrimation and less commonly, tear duct stenosis. 
6.1.3 Irinotecan Anticipated Toxicities 
Virtually all phase I and II studies of irinotecan have reported neutropenia and/or late diarrhea 
(diarrhea occurring more than 24 hours after irinotecan administration) as the dose-limiting 
toxicities (depending upon the schedule). Other commonly observed adverse events include 
nausea and vomiting, anorexia, abdominal cramping, alopecia, asthenia, lymphocytopenia, and 
anemia. Dehydration has occurred as a consequence of diarrhea, particularly when associated 
with severe vomiting. Patients may have an acute syndrome of lacrimation, diaphoresis, 
abdominal cramping, and diarrhea (early diarrhea) during or shortly after irinotecan 
administration; this syndrome is thought to be cholinergically mediated and may be treated and 
subsequently prevented with atropine. Sporadic cases of pulmonary toxicity, manifested as 
shortness of breath, nonproductive cough, and transient infiltrates on chest X-ray have been 
reported. Infrequent occurrences of mucositis or colitis (sometimes with gastrointestinal 
bleeding) have been observed. Occasionally, abnormalities of serum creatinine, hepatic enzymes, 
or thrombocytopenia have been observed. Further information regarding irinotecan may be 
obtained from the package insert. 
6.1.4 Oxaliplatin Anticipated Toxicities 
The most commonly observed oxaliplatin toxicities include neurotoxicity, GI toxicity, and 
myleosuppression. Three neurotoxicity syndromes have been seen: acute sensory neuropathy 
develops within hours to 2 days after oxaliplatin administration.   Symptoms include, 
paresthesias, dysesthesias, and hypothesia of the hands, feet and perioral region. Jaw spasm, 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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45
abnormal tongue sensation, dyarthria, eye pain and a sensation of chest pressure have also been 
noted. Acute sensory neuropathy symptoms may be exacerbated by exposure to cold temperature 
or cold objects. Symptoms are reversible, usually resolving within 14 days and commonly 
recurring with further dosing. This syndrome has been observed in about 56% of patients 
receiving oxaliplatin with 5-FU and leucovorin. Acute pharyngolaryngeal dysesthesia is reported 
to occur in 1-2% of patients. This syndrome is characterized by a subjective sensation of 
difficulty breathing or swallowing without laryngospasm or bronchospasm or objective evidence 
of hypoxia. Avoidance of cold drinks, food and air is suggested in order to minimize 
pharyngolaryngeal dysesthesia. Antianxiety agents (e.g.lorazepam) may be used to 
treat pharyngolaryngeal dysesthesias once oxygen saturation has been documented 
to be normal. Peripheral neuropathy persisting > 14 days is characterized by paresthesias, 
dysesthesias, and hypothesia. Abnormalities in momioception may also be seen. Symptoms of 
persistent neuropathy may improve upon discontinuation of oxaliplatin. Various agents have 
been used in an attempt to minimize neurotoxicity of oxaliplatin (e.g. carbamazepine, Mg+, 
Ca++). Calcium and magnesium infusions appear to be beneficial in preventing neurotoxicity. 
Gastrointestinal toxicities include nausea, vomiting (oxaliplatin is considered to be moderately 
emetogenic) and diarrhea. Neutropenia is reported in 73% of patients receiving oxaliplatin with 
5-FU and leucovorin (44% grade 3 or 4). Grade 3 or 4 thrombocytopenia is reported to occur in
4% of patients receiving the combination. Allergic reactions, similar to those seen with other 
platinum compounds, have also been observed in patients treated with oxaliplatin. Reactions  
range from rash to anaphylaxis. Rarely, oxaliplatin has been associated with pulmonary fibrosis, 
which may be fatal.  Oxaliplatin should be discontinued in the presence of unexplained 
pulmonary symptoms (e.g. nonproductive cough, dysphagia) or pulmonary infiltrates until 
interstitial lung disease or pulmonary fibrosis have been ruled out. Recent reports of oxaliplatin 
extravasation suggest that tissue necrosis may result and that oxaliplatin should be considered a 
vesicant. No standard treatment exists for oxaliplatin extravasation although heat and sodium 
thiosulfate have both been suggested. Veno-occlusive disease (VOD) of the liver is a rare 
complication associated with oxaliplatin and 5-FU. Clinical manifestations of VOD include 
hepato-megaly, ascites, and jaundice. Histologically, VOD is characterized by diffuse damage in 
the centrilobular zone of the liver. Sequelae of VOD include hepatomegaly, splenomegaly, portal 
hypertension, and esophageal varices. A recent analysis of resected liver metastases in 153 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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46
patients indicated histological findings consistent with VOD in 6/27 patients who received 5-FU 
alone, 4/17 patients who received 5-FU and irinotecan, 20/27 patients who received 5-FU and 
oxaliplatin, and 14/16 who received 5-FU, oxaliplatin and irinotecan. The remaining 66 patients 
had not received chemotherapy prior to resection. There were no such findings in these patients. 
For more information on toxicities associated with oxaliplatin, please see the package insert. 
6.1.5 Leucovorin: Anticipated Toxicities 
6.1.6 The only adverse reactions associated with leucovorin are allergic reactions. These are 
extremely uncommonRadiation Therapy 
The most common toxicities of radiation therapy are fatigue, nausea, abdominal pain, diarrhea, 
indigestion, vomiting, weight loss and anorexia.   Other toxicities may include radiation fibrosis 
if surgery is delayed too long.  Much less common toxicities could include liver damage, kidney 
damage, and late second malignancies. 
6.1.7 Capecitabine 
The most common toxicities of capecitabine are diarrhea, indigestion, nausea, vomiting, weight 
loss, anorexia, and hand-foot syndrome (skin changes and tenderness of hands and feet, 
especially fingers and toes).   Other toxicities may include neutropenia, thrombocytopenia, 
anemia, cutaneous eruptions, alopecia, fever, and fatigue or general malaise.  Much less common 
toxicities could include allergic reactions and coronary vasospasm. 
Patients with moderate renal impairment as measured by serum creatinine (> 1.3) at baseline 
require dose reduction. 
6.1.8 Losartan 
Common and anticipated toxicity related to Losartan is an adverse effect on blood pressure 
(hypotension) and potential for electrolyte imbalance such as hyperkalemia.  
Toxicity (Greater than 1%) 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
47
Hypotension: Symptomatic first dose hypotension was noted following a 100 mg oral dose, 
leading to drug discontinuation during a dose finding clinical study (Goldberg et al, 1995b). 
The incidence appears to be dose-related, increasing from less than 0.5% at doses of 50 mg 
daily or less, to 2.2% at doses of 100 mg daily (Ellis & Patterson, 1996a). 
Hyperkalemia Hyperkalemia has been reported during the postmarketing use of losartan 
(Prod Info Cozaar(R) , 2005). In hypertensive patients with non-diabetic, chronic renal 
disease, serum potassium was increased significantly to 4.6 mmol/L (mmol/L) from baseline 
(4.23 mmol/L) during dosing with 100 mg losartan daily, but not with a lower 50 mg daily 
dose (Gansevoort et al, 1994a). During fixed-dose treatment with losartan 50 mg plus 
hydrochlorothiazide 12.5 mg in over 200 patients, 11% of patients had changes upward or 
downward in serum potassium of at least 0.5 mEq/L after 12 weeks (Critchley et al, 1996b). 
Among 112 hypertensive patients with mild-to-severe renal failure (including 28 on 
hemodialysis) followed for 12 weeks during losartan treatment, 8% to 18% experienced 
decreased serum potassium levels greater than 0.5 mEq/L, while 15% to 23% experienced 
increases greater than 0.5 mEq/L. One patient was withdrawn due to hyperkalemia to greater 
than 6 mEq/L (Toto et al, 1998). 
Hyponatremia 
Hyponatremia has been reported during the postmarketing use of losartan (Prod Info 
Cozaar(R) , 2005). 
Gastrointestinal tract findings 
Diarrhea (2.4%) and dyspepsia (1.3%) were the most common gastrointestinal side effects, 
reported more frequently in losartan patients than those treated with placebo (Prod Info 
Cozaar(R), 2002a). 
Musculoskeletal findings 
Back pain, leg pain, muscle cramps, and myalgia were reported in between 1% and 1.8% of 
patients on losartan monotherapy, and had frequency rates greater than comparable placebo-
treated patients (Prod Info Cozaar(R), 2002a). Although no direct causal relationship can be 
established, the events reported in 2 or more patients but less than 1% of patients in clinical 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
48
trials included arm pain, hip pain, joint swelling, knee pain, shoulder pain, stiffness, 
arthralgia, arthritis, fibromyalgia, muscle weakness, and generalized musculoskeletal pain 
(Prod Info Cozaar(R), 2002a). 
Asthenia 
Incidence: 1% or greater (Prod Info COZAAR(R) oral tablets, 2008). Asthenia occurred in 
1% or greater of patients receiving losartan potassium treatment compared with patients 
receiving placebo during clinical studies (Prod Info COZAAR(R) oral tablets, 2008). 
Dizziness 
Incidence: 3% (Prod Info COZAAR(R) oral tablets, 2008). Dizziness occurred in 3% of 
patients (n=1075) receiving losartan potassium treatment compared with 2% of patients 
(n=334) receiving placebo during clinical studies (Prod Info COZAAR(R) oral tablets, 2008) 
Insomnia 
Incidence: 1% of greater (Prod Info COZAAR(R) oral tablets, 2008). Insomnia occurred in 
1% or greater of patients receiving losartan potassium treatment compared with patients 
receiving placebo during clinical studies (Prod Info COZAAR(R) oral tablets, 2008). 
Cough 
The incidence of cough in clinical trials with losartan monotherapy was 3.4%, with the 
placebo-treatment group reporting an incidence of 3.3% (Prod Info Cozaar(R), 2002a). 
Results from controlled phase III clinical trials suggest that losartan may not produce the 
cough associated with angiotensin-converting enzyme (ACE) inhibitors (Anon, 1994; 
Karlberg, 1993a). Preliminary results from a multicenter trial to investigate the incidence of 
losartan induced cough in patients with a history of ACE-inhibitor (lisinopril) cough support 
this contention (Anon, 1995; Lacourciere et al, 1994). In comparative trials involving nearly 
300 patients using fixed-dose losartan 50 mg plus hydrochlorothiazide, cough was seen 
exclusively in patients over 65 years old, with a frequency of 2.1%. In this age group, cough 
was nearly 5-fold more frequent (9.8%) among patients treated with fixed-dose captopril plus 
hydrochlorothiazide (Critchley et al, 1996b). Additionally, losartan 25 mg induced dry cough 
in 2 elderly diabetic women (age 73- and 80-years-old), who stopped lisinopril therapy due to 
cough. Two weeks after discontinuing losartan, symptoms of cough were resolved 
(Conigliaro, 1999). 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
49
Respiratory finding 
Upper respiratory infection (7.9%) was the most common adverse effect overall in clinical trials 
with losartan monotherapy, although the placebo-treatment frequency was 6.9% (Prod Info 
Cozaar(R), 2002a). Other events with frequencies greater in losartan patients included nasal 
congestion (2%), sinus disorders (1.5%), and sinusitis (1%) (Prod Info Cozaar(R), 2002a). 
6.2 
Toxicity Management 
6.2.1 FOLFIRINOX therapy 
6.2.2 “One cycle” will constitute one administration of FOLFIRINOX therapy, administered on 
Day 1-3. Each cycle will be 14 days long +3/-1 days at physician discretion, unless further 
dose delay is warranted by toxicities. Cycles of FOLFIRINOX administration will be 
repeated every 14 days.  The table below indicates potential dose levels for each of the 
agents for which dose modifications will be allowed. Dose adjustments of each agent may 
be made independently based on the specific types of toxicities observed All dose 
reductions are to be made at the discretion of the treating medical oncologist. 
Patients who require multiple dose reductions for grade 2 toxicity may, at the physician’s 
discretion, begin the following cycle at one dose level higher than the current dose reduction. If 
dose reduction beyond –3 for any agent is required, that agent should be discontinued.  
Agent* 
Oxaliplatin 
Irinotecan 
5-FU Bolus
5-FU
Continuous
Infusion
Initial 
Dose 
85 mg/m2 
180 mg/m2 
400 mg/m2 
2400 mg/m2 
per 46-48 hours 
Level –1 
65 mg/m2 
150 mg/m2 
320 mg/m2 
1920 mg/m2 
per 46-48 hrs 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
50
Level –2 
50 mg/m2 
120 mg/m2 
270 mg/m2 
1600 mg/m2 
per 46-48 hrs 
Level –3 
40 mg/m2 
100 mg/m2 
230 mg/m2 
1360 mg/m2 
per 46-48 hrs 
Leucovorin dose is always 400 mg/m2, IV given prior to bolus 5-FU. If any bolus 5-FU is to be 
skipped, leucovorin can be omitted or alternately can be dose-reduced and given with continuous 
infusion 5-FU at the discretion of the treating physician. 
6.2.2.1 Hematologic toxicities 
The following dose modifications are based on toxicity demonstrated during a mid-cycle visit 
and/or at the time of laboratory assessment for planned administration of the next cycle of 
therapy (for example on the planned day of administration of Cycle 2 Day 1 after completing the 
14-day period constituting Cycle 1.) As the Grade 2-4 neutropenia rate in the PRODIGE-
ACCORD trial was 79.9%, in this trial prophylactic Neulasta (Pegfilgrastim) 6mg SC x1 will be 
administered 24-48 hours after discontinuation of continuous infusion 5-FU as clinically 
indicated per institutional standard of care. 
Dose Reduction Table for Hematologic Toxicity 
(Note: DR = Dose Reduction) 
Hematologic 
Toxicity on the 
Day of Treatment 
(D1) 
Action 
Oxaliplatin 
Irinotecan 
5-FU Bolus
(Leucovorin
follows
protocol for
5FU bolus)
5-FU
Continuous
Infusion
Neutropenia G2  
(ANC 1500-1000) 
– all patients
should have
Neulasta support
per institutional
guidelines
HOLD ALL 
THERAPY 
Hold until 
ANC 
>=1500, 
resume 
without dose 
reduction  
Hold until 
ANC 
>=1500, 
resume 
without dose 
reduction 
Hold until
ANC
>=1500,
resume
without dose
reduction
Hold until 
ANC 
>=1500, 
resume 
without dose 
reduction 
Neutropenia G3-4,
Febrile
neutropenia
HOLD ALL 
THERAPY, 
Supportive 
care and 
Hold until 
ANC 
>=1500, 
resume @ 
Hold until 
ANC 
>=1500, 
resume @ 
Hold until 
ANC 
>=1500, 
resume @ 
Hold until 
ANC 
>=1500, 
resume @ 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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51
(ANC 1000-500, 
<500) 
antibiotics 
per 
institutional 
guidelines 
permanent 
DL-1 level
once
resolved
permanent 
DL-1 level
once
resolved
permanent 
DL-1 level
once
resolved
permanent 
DL-1 level
once
resolved
Thrombocytopenia 
G1 
(LLN – 75K) 
Treat with 
DR 
Oxaliplatin 
Treat at
permanent
DL -1
No
reduction
No
reduction
No
reduction
Thrombocytopenia 
G2 
(75K – 50K) 
HOLD ALL 
THERAPY 
Hold until
resolved to
>100K,
resume at
permanent
DL-1
Hold until 
resolved to 
>100K, no
reduction
Hold until 
resolved to 
>100K, No
reduction
Hold until 
resolved to 
>100K, No
reduction
Thrombocytopenia 
G3-4 
(50K – 25K, 
<25K) 
HOLD ALL 
THERAPY 
Hold until
resolved to
>100K.
Resume @
permanent
DL-1 if
resolved in 1
wk,
permanent
DL -2 if >1
wk to
resolve
Hold until 
resolved to 
>100K.
Resume @
permanent
DL-1.
Hold until 
resolved to 
>100K
Hold until 
resolved to 
>100K
6.2.2.2 Gastrointestinal toxicities: 
Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal cramping, 
diarrhea, or other symptoms of early cholinergic syndrome may occur during or shortly after 
receiving irinotecan. Atropine, 0.25-1.0 mg IV or SC may be used to treat these symptoms. In 
patients with troublesome or recurrent symptoms, prophylactic administration of atropine shortly 
before irinotecan therapy may be considered. Additional antidiarrheal measures may be used at 
the discretion of the treating physician. Anticholinergics should be used with caution in patients 
with potential contraindications (e.g., obstructive uropathy, glaucoma, tachycardia, etc.) 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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52
Late diarrhea (e.g., developing more than 24 hours after irinotecan) should be managed with 
loperamide. The following dose modifications are based on toxicity experienced during a cycle 
(i.e., after Day 1 of any cycle). 
Dose Reduction Table for Non-Hematologic Toxicity (Except Neuropathy) 
(Note: DR = Dose Reduction) 
Non-
hematologic 
Toxicity on the 
Day of 
Treatment (D1) 
Action 
Oxaliplatin 
Irinotecan 
5-FU Bolus
(Leucovorin
DR follows
protocol for
5FU bolus
DR)
5-FU
Continuous
Infusion
Diarrhea G2 
DR 
Irinotecan 
Bolus 5FU, 
and CI 
5FU 
No reduction 
Treat at 
permanent 
DL -1 
Treat at
permanent
DL -1
Treat at 
permanent 
DL -1 
Diarrhea G 3-4 
DR 
Irinotecan 
and CI 
5FU and 
eliminate 
Bolus 5FU 
No reduction 
Treat at 
permanent 
DL -1 
Permanently 
eliminate 
bolus 
Treat at 
permanent 
DL -1 
Mucositis G2 
DR Bolus 
and CI 
5FU 
No reduction 
No reduction 
Treat at 
permanent 
DL -1 
Treat at 
permanent 
DL -1 
Mucositis G3-4 
DR 
Irinotecan 
and CI 
5FU, 
eliminate 
Bolus 5FU 
No reduction 
Treat at 
permanent 
DL -1 
Permanently 
eliminate 
bolus 
Treat at 
permanent 
DL -1 
Nausea/Vomiting 
G3-4 
HOLD 
ALL 
THERAPY 
Maximal 
antiemetic 
therapy.  
Hold until 
resolved to 
G2 or less, 
resume @ 
permanent 
DL-1
Maximal 
antiemetic 
therapy.  
Hold until 
resolved to 
G2 or less, 
resume @ 
permanent 
DL-1
Maximal 
antiemetic 
therapy.  
Hold until 
resolved to 
G2 or less, 
resume @ 
permanent 
DL-1
Maximal 
antiemetic 
therapy.  
Hold until 
resolved to 
G2 or less, 
resume @ 
permanent 
DL-1

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
53
Neurotoxicity 
Toxicity Scale for the Sensory Neuropathies Associated with Oxaliplatin Symptoms: 
Grade 1 
 Paresthesias/dysesthesias* of short duration that resolve and 
do not interfere with function. 
Grade 2 
 Paresthesias/dysesthesias* interfering with function, but not 
in activities of daily living (ADL) 
Grade 3 
 Paresthesias/dysesthesias* with pain or with functional 
impairment that also interfere with ADL. 
Grade 4 
 Persistent paresthesias/dysesthesias* that are disabling or life 
threatening. 
* May be cold induced
For grade 2 neurotoxicity persisting between treatments: Do not hold oxaliplatin, but reduce 
oxaliplatin by one dose level for the next cycle and for all cycles thereafter. 
For grade 3 neurotoxicity resolving to grade 2 between treatments: Do not hold oxaliplatin, but 
reduce oxaliplatin by one dose level for the next cycle and for all cycles thereafter. 
For recurrent grade 3 neurotoxicity resolving to grade 2 between treatments: Do not hold 
oxaliplatin, but reduce oxaliplatin by one additional dose level for the next cycle and for 
subsequent cycles. Oxaliplatin will not be reduced beyond level –3. If further dose reduction is 
required for neurotoxicity, oxaliplatin will be discontinued. Patients should continue to receive 
other protocol therapy. 
For grade 3 neurotoxicity persisting between treatments: Discontinue oxaliplatin. Patients 
should continue to receive other protocol therapy. 
For grade 4 neurotoxicity: Discontinue oxaliplatin. Patients should continue to receive other 
protocol therapy. 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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54
For pharyngo-laryngeal dysesthesia: Increase the duration of oxaliplatin infusion to 6 hours for 
all subsequent treatments.  
6.2.2.3 Extravasation 
Extravasation of oxaliplatin has been associated with necrosis; if extravasation is suspected, the 
infusion should be stopped and the drug administered at another site. Extravasation may be 
treated according to institutional guidelines. 
6.2.2 Losartan-related side effects 
6.2.2.1 Hypotension 
6.2.1 Patients must demonstrate a systolic blood pressure (SBP) of greater than 100 mm Hg 
averaged between two resting, seated readings to qualify for study enrollment and will be 
started at a dose of 25 mg PO qd. They will return for a Day 8 toxicity check at which 
time BP will be rechecked. If SBP remains greater than or equal to an average of100 mm 
Hg on two separate seated checks taken at rest, then the dose will be titrated to 50 mg PO 
qd. Blood pressure monitoring for study visits or urgent visits relating to hypotension 
should be used to determine losartan dosing. Blood pressure measurements taken for other 
reasons do not require losartan dose adjustments or holds. All dose adjustments and 
modifications are to be made at the discretion of the treating physician. 
1.
Week 1 Dose reduction (during 25 mg PO qd dosing). BP is not routinely checked. If
patients experience lightheadedness or have any other need for vital sign check during D1-8 and 
SBP is less than an average of 100 mm Hg on two separate seated rested readings, hold Losartan 
therapy for one week. Patients should have BP recheck at Day 8. If they remain lightheaded or 
have persistent average SBP <100 mm Hg, they should be unenrolled from the study. 
2.
Week 2 onward Dose reduction (during 50 mg PO qd dosing for patients who meet
criteria for escalation). BP should be checked at each chemotherapy visit and/or if a patient 
returns for urgent care evaluation or has symptoms of lightheadedness. If average SBP between 
two separate readings is less than 100 mm Hg, hold Losartan 50 mg PO qd for one week. 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
55
3.
If Losartan is held, the patient should return one week later for BP recheck. If the
patient had specific impetus for hypotension such as infection or dehydration that has resolved, 
and SBP is greater than an average of 100 mm Hg between two rested, seated readings on 
recheck, re-initiate Losartan at 25 mg PO qd. In the case where patients are eligible for re-start, 
patients should return one week later, and if SBP remains greater than an average of 100 mm Hg, 
the dose should be re-escalate dose to 50 mg PO qd. 
4.
If Losartan is held in patients at the 50 mg PO qd dose and when they return for
recheck, they have sustained low BP (average SBP <100 mmHg), or sustained symptoms of 
lightheadedness, Losartan should be permanently discontinued and the patient un-enrolled from 
the clinical trial. 
6.2.2.2 Hyperkalemia 
For patients with serum potassium registering greater than or equal to 5.0 mmol/L at any 
time during treatment cycle (i.e. at any lab check), please first verify that the tube was not 
hemolyzed. If the potassium result is accurate, Losartan at its current dose should be held. 
Serum potassium should be checked one week later. Treatment may resume at current dose 
if serum potassium is less than 4.5 mmol/L. If patients have recurrent hyperkalemia after 
restarting Losartan (K > or equal to 5.0 mmol/L), the drug should be permanently 
discontinued and patients will be unenrolled from the study, Treatment of severe 
hyperkalemia as per routine clinical protocol. All dose adjustments are to be made at the 
discretion of the treating physician. 
6.2.3 Capecitabine and Radiation 
Hematologic and Non-Hematologic Toxicity 
Capecitabine will be held for any Grade 3 or 4 toxicity. After toxicity resolves to < grade 1, 
capecitabine will be resumed at 600 mg/m2 BID to complete the 10 weekdays of therapy. 
Capecitabine can be held a maximum of 7 days. If further grade 3 or 4 toxicity is noted at the 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
56
reduced dose level, after toxicity resolves to < grade 1, capecitabine will be resumed at 500 
mg/m2 BID to complete two weeks of therapy. If the second dose reduction is not tolerated, 
capecitabine will be stopped. Patients will keep a capecitabine diary and will record the number 
of capecitabine tablets and the time that they take the tablets.  
Radiation therapy will be held for Grade 3 or 4 nausea that is not well controlled with anit-
emetic support, until nausea resolves to Grade 2 or less.  It will then be resumed at same dose. 
Grade 3 or 4 toxicities that are due to biliary ductal dilatation and resolved with placement of a 
biliary stent or with biliary stent change will not require a dose reduction of capecitabine or 
radiation therapy after stent placement.  Therapy may be withheld for procedures like ERCP and 
biliary stenting, and restarted at the treating physician's discretion. 
7
DRUG FORMULATION AND ADMINISTRATION 
7.1 
5-Fluorouracil (5-FU; fluorouracil; Adrucil" ) 
Please refer to the package insert for complete product information. 
Availability 
5-FU is commercially available as a 50 mg/mL solution for injection in 10 mL, 20 mL, 50 mL
and 100 mL vials. 
Preparation 
Inspect for precipitate; if found, agitate or gently heat in water bath. Bolus injections 
are prepared using undiluted drug. 46-48 hour infusion of 5-FU should be prepared for 
administration via ambulatory infusion pump according to the individual institution’s standards. 
These solutions may be prepared in D5W or 0.9% NaCl. 5-FU should not be mixed in the same 
solution with most parenteral antiemetics. 
Storage and Stability 
Intact vials should be stored at room temperature and protected from light. Slight yellow discolor 
does not usually indicate decomposition. Stability in ambulatory pumps varies according to the 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
57
pump, manufacturer of drug, concentration and diluent. Please refer to appropriate reference 
sources for additional information.  
Administration 
In this study, 5-FU is administered as a 400 mg/m2 IV bolus followed by 2400 mg/m2 by IV 
infusion over 46 to 48 hours. 
Drug Interactions 
Leucovorin enhances the cytotoxicity of 5-FU by forming a more stable tertiary complex with 
thymidylate synthase. Concommitant adminstration of 5-FU with warfarin has been reported to 
result in increased INR/prolonged prothrombin time. Patients receiving both drugs should be 
followed with weekly INRs.  
7.2 
Leucovorin Calcium (Folinic Acid) Leucovorin Calcium (calcium folinate; 
citrovorumfactor; N 5-formyltetrahydrofolate; 5-formyl-FH4; folinic acid). 
Please refer to the package insert for complete product information. 
Availability 
Leucovorin calcium is commercially available in: 50 mg, 100 mg, 350 mg vials for 
reconstitution. 
Storage and Stability 
Intact vials should be stored at room temperature and protected from light. Solutions 
reconstituted with BWI are stable for at least 7 days at room temperature. 
Preparation 
Leucovorin may be reconstituted with Bacteriostatic Water for Injection (BWI) or with Sterile 
Water For Injection. Solutions should be further diluted in D5W, 0.9% NaCl or Rungers solution 
for infusion over two hours. 
Administration 
Leucovorin will be administered as a 400 mg/m2 IV infusion over 2 hours +/- 10 minutes after 
oxaliplatin/irinotecan administration. Leucovorin may also be administered concurrently with 
oxaliplatin/irinotecan as a separate IV infusion. 
.  

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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58
7.3 
Oxaliplatin [Eloxatin] 
Availability 
Oxaliplatin is commercially available as an aqueous solution in vials containing 50 mg and 100 
mg at a concentration of 5 mg/mL. The vials do not contain any preservative and they are 
intended for single use. Oxaliplatin is commercially available.  
Storage and Stability 
Intact vials should be stored at room temperature. Solutions diluted in D5W are stable for 6 
hours at room temperature or 24 hours under refrigeration. 
Preparation 
The calculated dose of oxaliplatin should be diluted for infusion with 250 mL to 500 mL D5W. 
Oxaliplatin should not be diluted with a sodium chloride solution. Needles, syringes, catheters or 
IV administration sets containing aluminum should not be used with oxaliplatin. As with other 
platinum compounds, contact with aluminum may result in a black precipitate. 
Administration 
Oxaliplatin will be administered by intravenous infusion over 120 minutes +/- 10 minutes. 
Infusion time may be prolonged (up to 6 hours) in patients experiencing pharyngolaryngeal 
dysesthesia. Oxaliplatin is unstable in the presence of chloride or alkaline solutions. Do NOT 
mix or administer oxaliplatin with saline or other chloride-containing solutions. Do NOT 
administer other drugs or solutions in the same infusion line. Flush IV lines/catheters with 
Dextrose 5% in Water both before and after oxaliplatin administration. 
7.4 
Irinotecan (CPT-11, CAMPTOSAR®) 
Availability 
Irinotecan is commercially available as a 20 mg/mL solution for injection in 2 mL and 5 mL 
vials. 
Storage and Stability 
Intact vials should be stored at controlled room temperature 59° to 86° F (15° to 30° C) and 
when protected from light. Solutions diluted in D5W are reported to be stable for 48 hours under 
refrigeration and protected from light. Irinotecan solutions should not be frozen as the drug may 
precipitate. 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
59
Preparation 
Irinotecan is diluted in 5% dextrose (D5W) 500 mL to a final concentration of 0.12 – 1.1 mg/mL. 
Administration 
In this study irinotecan will be administered as an IV infusion over 90 minutes +/- 10 minutes. 
7.5 
Capecitabine 
Description: Capecitabine (Xeloda) is a fluoropyrimidine carbamate with antineoplastic activity.  
It is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) that is 
converted to 5-fluorouracil.  
Form: Capecitabine is supplied as a biconvex, oblong film-coat tablets for oral administration.  
Each light-peach colored tablet contains 150 mg capecitabine, and each peach colored tablet 
contains 500 mg capecitabine.   
Storage and Stability: Store at 25o C (77o F); excursions permitted to 15o to 30o C (59o to 86o F), 
keep bottles or storage devices tightly closed. 
Compatability: Capecitabine and some of its metabolites are converted principally by liver 
enzymes (carboxylesterase and cytidine deaminase and TP in tumor tissues). At present, it is 
unknown whether this metabolism is likely to be influenced by other treatments or alcohol, 
which either induce or inhibit certain liver enzymes. 
Allopurinol:  Oxypurinol, a metabolite of allopurinol, can potentially interfere with 5-FU 
anabolism via orotate phosphoribosyltransferase.  Although this was originally used as a strategy 
to protect normal tissues from 5-FU-associated toxicity, further laboratory studies suggested 
possible antagonism of the anticancer activity of 5-FU in some tumor models.  If a patient is 
receiving allopurinol, the need for taking this medicine should be ascertained.  If possible, 
allopurinol should be discontinued prior to starting on this regimen, and another agent substituted 
for it. 
Sorivudine and Brivudine: A metabolite of the above two investigational antiviral agents, 
5-bromovinyluracil, is a potent inhibitor of dihydropyrimidine dehydrogenase, the enzyme that
catabolizes 5-FU.  Patients should not receive concurrent therapy with either of these antiviral 
agents while receiving capecitabine.  If  a patient has received prior sorivudine or brivudine, then 
at least four weeks must elapse before the patient receives capecitabine therapy 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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60
Anticoagulants: See Warnings and Precautions Section 6.9 In a drug interaction study 
with single dose warfarin administration, there was a significant increase in the mean AUC of S-
warfarin. The maximum observed INR value increased by 91%. This interaction is probably due 
to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.   
Phenytoin: Increased phenytoin plasma concentrations have been reported during 
concomitant use of Xeloda with phenytoin, suggesting a potential interaction. Patients taking 
phenytoin concomitantly with Xeloda should be regularly monitored for increased phenytoin 
plasma concentrations and associated clinical symptoms. 
Laxatives:  The use of drugs with laxative properties should be avoided. 
Warnings and Precautions: 
Renal Insufficiency: Patients with moderate renal impairment as measured by serum 
creatinine (> 1.3) at baseline require dose reduction (see section 4.1.3). Patients with mild and 
moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt 
interruption of therapy with subsequent dose adjustments will be made if a patient develops a 
grade 2 to 4 adverse event.  Capecitabine is contraindicated in patients with a calculated 
creatinine clearance of < 30 ml/min.  Creatinine level will be checked and creatinine clearance 
calculated on Study Day 8 for all subjects to ensure safety of continued administration of 
capecitabine. 
Pregnancy/Nursing: Capecitabine may cause fetal harm when given to a pregnant 
woman. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving 
this drug, the patient should be apprised of the potential hazard to the fetus. Women of 
childbearing potential should be advised to avoid becoming pregnant while receiving treatment 
with capecitabine. Because of the potential for serious adverse reactions in nursing infants from 
capecitabine, the patient will be instructed that nursing must be discontinued when receiving 
capecitabine therapy. 
Coagulopathy: Patients receiving concomitant capecitabine and oral coumarin-derivative 
anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) 
monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically 
important Capecitabine-Warfarin drug interaction was demonstrated in a clinical pharmacology 
trial. Altered coagulation parameters and/or bleeding, including death, have been reported in 
patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
61
warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases 
in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time 
capecitabine was introduced. These events occurred within several days and up to several months 
after initiating capecitabine therapy and, in a few cases, within one month after stopping 
capecitabine. These events occurred in patients with and without liver metastases. Age greater 
than 60 and a diagnosis of cancer independently predispose patients to an increased risk of 
coagulopathy. 
Cardiotoxicity: The cardiotoxicity observed with capecitabine includes myocardial 
infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, 
electrocardiographic changes, and cardiomyopathy.  These adverse events may be more common 
in patients with a prior history of coronary artery disease. 
This treatment is foreseen as a self-administered out-patient treatment, and in certain 
circumstances adverse events that could occur, such as diarrhea, or hand-foot syndrome can 
rapidly become serious. In the case where a patient experiences any toxicity between scheduled 
visits, the patient will be instructed to contact the clinic as soon as possible, for further 
directions, discontinuation of study medication, and/or treatment. 
Handling: Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe disposal 
of capecitabine in a self-contained and protective environment. 
Availability: Capecitabine is commercially available and will not be provided free of charge by 
the study.  It is expected that the study participants or their insurers will be responsible for the 
cost of Capecitabine.   
Preparation 
N/A- Capecitabine comes in tablet formulation 
Administration  
Tablets should be swallowed with water 30 minutes after the end of a meal (breakfast and dinner). 
If necessary, tablets may be crushed. 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
62
Ordering  
Capecitabine will be prescribed by the treating medical oncologist; prescriptions will be filled by 
the study participants at their pharmacy of choice. 
Accountability  
N/A drug is not study supplied. 
Destruction and Return 
N/A drug is not study supplied. 
7.6  Losartan 
Supply 
Losartan will be study supplied for this trial.  Study participants will receive Losartan free of 
charge. 
Availability 
Losartan will be study supplied in 25mg and 50mg tablets.  Study participants will be asked to 
return unused pills at each follow up visit.  Pill counts will be conducted to maintain drug 
accountability.  Once counted, unused pills will be returned to the Research Pharmacy for 
destruction. 
Onset and Duration 
Hypertension, oral: 6 hours (Ohtawa et al, 1993a; Weber, 1992). In some studies, the maximal 
effect occurred in 3 to 6 weeks (Prod Info Cozaar(R), 2000). 
Once-daily oral doses of LOSARTAN 50 to 150 mg have produced significant 
antihypertensive effects for 24 hours (Tsunoda et al, 1993a; Weber, 1992). This was not 
achieved with lower doses (10 or 25 mg), which were similar in efficacy to placebo (Weber, 
1992). Peak and trough responses (adjusted) following 8 weeks treatment with 3 dose levels 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
63
are summarized, showing a lack of clearly distinguishable differences (Elliott, 1998): 
Losartan dose 
Change in Blood Pressure mmHg 
Peak 
Trough 
50 mg 
13.5/7.2 
9.5/4.8 
100 mg 
11.9/5.7 
5.9/4.4 
150 mg 
11.7/7.5 
6.8/4.1 
Metabolism 
Liver, 14% : LOSARTAN is extensively metabolized by cytochrome P450-2C9 and -3A4. 
Metabolites include 5-carboxylic acid (E-3174), (active). Animal studies have suggested that 
E-3174 is up to 40 times as potent as LOSARTAN in angiotensin II blocking activity.
Although LOSARTAN is also pharmacologically active, E-3174 appears responsible for the 
prolonged hypotensive effects observed after oral LOSARTAN administration. 
Storage and Stability 
Protect tablets from light in a tightly closed container stored at controlled room temperature of 
15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit) (Prod Info Cozaar(R), 2002). Shelf life 
stability is 3 years from the date of packaging although the commercially available products 
carry 18 month expiration dating (Tech Info Cozaar(R), 1995). 
Administration 
Patients will self-administer Losartan tablets at 25mg PO QD or 50 mg PO QD. Blood pressure 
monitoring will occur in the clinic, and dose modification based on serial low blood pressure 
will be per toxicity guidelines at the discretion of the treating physician (section 6). 
Drug Interactions (major) 
Lithium 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
64
Interaction Effect: an increased risk of lithium toxicity (weakness, tremor, excessive thirst, 
confusion) There is evidence that angiotensin II receptor antagonists may substantially 
increase steady-state plasma lithium levels, sometimes resulting in lithium toxicity. Patients 
prescribed lithium and losartan should be closely monitored for the development of lithium 
toxicity. Plasma lithium levels should also be followed. 
Naproxen and other NSAIDS 
Interaction Effect: decreased antihypertensive effects and an increased risk of renal 
impairment. Reports indicate that the concomitant use of an NSAID with an angiotensin II 
receptor blocker (ARB) may decrease the antihypertensive effect of the ARB (Prod Info 
CELEBREX(R) oral capsules. Additionally, renal deterioration and acute renal failure may 
result , especially in volume-depleted patients. Renal function should be monitored 
periodically in patients receiving ARB and NSAID therapy  
8
OPTIONAL CORRELATIVE STUDIES 
8.1 
Laboratory Correlative Studies 
8.1.1 Circulating Biomarkers: Anti-fibrotic effects 
In pre-clinical and clinical studies circulating levels of collagen or profibrogenic molecules 
are used as surrogate biomarkers of the efficacy of RAS inhibition or other anti-fibrotic agents.  
We will determine how losartan affects plasma levels of ATII, collagen I and IV, and 
downstream mediators of ATII signaling [transforming growth factor 1 (TGF1), connective 
tissue growth factor (CTGF), thrombospondin-1 (TSP1), osteopontin] and profibrogenic 
cytokines [stromal derived factor-1 (SDF-1), interleukin (IL)-1, IL-4, IL-10, and IL-13].  
Granulocytes are a major source of TGF in PDAC. Therefore, we will measure how losartan 
affects the number of granulocytes in peripheral blood using flow cytometry and CBC.  Because 
losartan modulates the levels of vascular endothelial growth factor (VEGF) and angiogenesis, we 
will also determine the circulating levels of angiogenic molecules.  The changes in plasma 
biomarkers will be correlated with therapeutic response, outcome, tumor uptake of 18F-5FU and 
microvascular imaging parameters (see section 8.1.2).    

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Blood will be drawn by venipuncture, and the first 7-10 ml blood will be excluded or used for 
other analysis. The following 8 ml will be collected in an EDTA tube. The EDTA tube with the 
blood sample will be shipped in wet ice within 2 hours of drawing for further processing at 
Steele Laboratory at MGH.  
Blood samples will be collected on Day 1, 8, 29 and 92.  The day 29 and 92 blood draws may 
be completed +/- 3 days from their scheduled date.  Blood can be drawn for this study at any 
time most convenient for the study participant.  
Based on findings from preliminary studies, we propose here to evaluate the changes in 
blood circulating SDF1α and circulating myeloid cells throughout the treatment course to 
explore potential associations between the changes in these biomarkers and resistance to 
treatment. In exploratory studies, we will evaluate several other cytokines using multiplex 
protein array (Meso-Scale Discovery, Inc.). We will use ELISA kits to measure plasma 
levels of collagen I (Cosmo Bio Co.), collagen IV (Echelon BioSciences Inc), human 
cross-linked carboxy-terminal telopeptide of collagen I (Cusabio), ATII (Assaypro), 
CTGF, TGF, TSP-1, osteopontin, soluble vascular endothelial growth factor receptor 2, 
angiopoietin 2 and SDF-1 (R&D Systems).  Multiplex ELISA plates (Meso-Scale 
Discovery) will be used to analyze plasma levels of VEGF, placenta growth factor (PlGF), 
soluble VEGF receptor 1 (sVEGFR1), basic fibroblast growth factor (bFGF), VEGF-C, 
VEGF-D, sTie2, tumor necrosis factor alpha (TNF-, and IL-1, IL-4, IL-10, and IL-13.  
Granulocytes (CD11b+Ly6G+CD115-) will be enumerated in fresh samples using a 
standard flow cytometry protocol. In addition, we will analyze the correlation between 
plasma SDF1α and circulating myeloid cells with multiple measures of outcome (ORR, 
TTP, OS) in pancreatic cancer patients after losartan treatment.  
8.1.2.1 Experimental Design 
Blood for correlative research may be drawn via port-a-cath or peripheral venipuncture. The 
blood draw site should remain consistent across all correlative lab timepoints for each patient 
throughout their participation in the trial.  The first 7-10 ml blood will be excluded or used for 
other analyses. The following 8 ml will be collected in an EDTA tube. The EDTA tube with the 
blood sample will be shipped in wet ice within 2 hours of drawing for further processing at 

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Steele Laboratory at MGH.  We will analyze the correlation between plasma cytokines and 
circulating myeloid cells with multiple measures of outcome (ORR, TTP, OS) in patients with 
borderline resectable pancreatic cancer before, during, and after treatment.  
8.1.2.2 Collection 
To this end we will measure circulating biomarkers at the following stages: 
(i)
Pretreatment
(ii) Throughout FOLFIRINOX therapy, including at restaging for C4 and C8
(iii) After proton beam radiation therapy
(iv) One month after completion of capecitabine therapy
(v) One month post-operatively
(vi) At the time of disease progression
Samples (2 tubes) will be collected at the following timepoints: 
a.
Prior to the start of therapy
b.
Day 8 , 29, and 92 of FOLFIRINOX
c.
At restaging for Cycle 4 (and Cycle 8 if received) of FOLFIRINOX
d.
After chemoradiation OR pre-operatively
e.. 
1 month after completion of capecitabine therapy
f.
1 month after pancreaticoduodenectomy (Whipple procedure)
g.
Within 2 weeks after radiologic progression
8.1.2.3 Shipping Instructions 
The tube containing the blood should be shipped with the following information 
1.
Study Number at the DF/HCC
2.
Patient number on the study
3.
Patient’s initials
4.
Treating physician’s name
5.
Date of collection
6.
Date of shipping

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The tube of blood should be placed in a sealable container and placed in a box with the necessary 
information. The box should be marked Biohazard.  
 
The blood will be shipped to:  
 
 
 
 
 
 
 
  
 
8.1.2 Correlative Studies: SNaPshot analysis 
 
Diagnostic specimens (if available) will be tested using the “SNaPshot” profile, a 
multiplex molecular diagnostics platform which is part of routine clinical testing at the 
MGH Cancer Center.  This assay quickly and efficiently identifies 58 separate mutations 
in 13 genes commonly altered in solid tumors: EGFR, KRAS, NRAS, APC, BRAF, 
FLT3, JAK2, Kit, Notch, PI3K, PTEN, TP53, and beta-catenin. It utilizes DNA extracted 
from formalin fixed paraffin embedded tumor tissue. The DNA of interest is amplified 
using multiplexed PCR.  Genotypes are determined using a single-base extension 
sequencing reaction, in which allele-specific probes interrogate loci of interest and are 
extended by fluorescently labeled dideoxynucleotides. The allele-specific probes have 
different sizes and are subsequently resolved by electrophoresis and analyzed by an 
automated DNA sequencer. The SNaPshot profile has been validated and is being 
performed in a CLIA-certified lab.  
Data obtained from SNaPshot will be used in exploratory analyses correlating mutational 
status with chemotherapy response, radiation response, and outcome. 
 

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8.2  Patient-reported outcomes 
 
Pretreatment 
FOLFIRINOX 
ChemoRT  
Post-op 
At time of 
informed consent 
Day 1 of cycles 
2,4,6,8 
[Week 3, 7, 11, 
15] 
Week 2, 
day1 
At 3 month follow up, then  every 6months 
for the first 2 years of follow up, then yearly 
until completion of year 5 
EORTC QLQ-C30 
EORTC QLQ-
C30 
EORTC 
QLQ-C30 
EORTC QLQ-C30 
ESAS-r 
ESAS-r 
ESAS-r 
ESAS-r 
HADS 
HADS 
HADS 
HADS 
 
8.2.1 Patient-reported outcomes  
 
QOL (EORTC QLQ-C30, version 3.0), symptoms (ESAS-r), and mood (HADS) will be assessed 
at time of informed consent prior to neoadjuvant therapy; at weeks 3, 7, 11, and 15 of 
neoadjuvant chemotherapy; at week 2 of capecitabine chemoradiotherapy. During the follow up 
period, these measures will be assessed at the 3 month post-operative follow-up visit, then every 
6 months for the first 2 years of follow up, then yearly until completion of year 5. We will 
include a window of +/- 2 weeks for obtaining the PROs during treatment, to cover timing 
adjustments for treatment delays. In follow up, these outcomes will be assessed within +/- 21 
days of a correlating follow up visit. The patient may complete the questionnaires by hand or 
over the phone with a study team member, as well as an interpreter (if needed). 
 
8.3  Health care utilization 
 
Hospital admissions, emergency department (ED) visits, intensive care use and palliative 
care consultation will be monitored and recorded for each patient throughout the study. 
 
9 
STUDY CALENDAR 
Baseline laboratory evaluations are to be conducted within seven days prior to study 
entry. Non-laboratory evaluations (imaging, etc) must be done <42 days (6 weeks) prior 
to study entry. All assessments must be performed prior to administration of any study 
medication, unless otherwise noted. All study assessments and medications should be 

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69
administered within + 3 days of the protocol-specified date, unless otherwise noted. All 
follow up assessments may be performed +/- 21 days of the protocol-specified date. 
Required Data Table 
Tests and Observation 
Prior to 
treatment  
Cycles 1-8 of 
FOLFIRINOX/ 
Losartan 
After cycles 4 and 8 of 
FOLFIRINOX/Losartan 
 (re-staging) (5) 
Radiation  Follow Up Post-
Proton RT (2) 
Signed informed 
consent 
X 
 
 
 
 
History 
X 
 
 
 
 
Physical Examination 
X 
X once per cycle 
X 
X weekly 
X 
Vital Signs and 
performance status 
X 
X once per cycle 
X 
X weekly 
X 
Height/Weight/Surface 
Area 
X 
X once per cycle 
 
 
 
Blood Pressure 
Assessments and 
Monitoring 
X 
X once per cycle 
 
 
 
Toxicity Assessment 
X 
X weekly during 
cycle 1; every 
other week 
during 
subsequent 
cycles unless 
clinically 
indicated 
X 
X weekly 
X 
Laboratory :  
 
 
 
 
 
CBC/plts/diff 
X (1) 
X weekly during 
cycle 1; every 
other week 
during 
subsequent 
cycles unless 
clinically 
indicated 
X 
X weekly 
X 
Serum chemistries (Na, 
K, BUN, Cr, Glucose, , 
Calcium, Albumin, 
AST, ALT, Total 
bilirubin, Alkaline 
phosphatase) 
X (1) 
X weekly during 
cycle 1; every 
other week 
during 
subsequent 
cycles unless 
clinically 
indicated 
X 
X weekly 
X 

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Tests and Observation 
Prior to 
treatment  
Cycles 1-8 of 
FOLFIRINOX/ 
Losartan 
After cycles 4 and 8 of 
FOLFIRINOX/Losartan 
 (re-staging) (5) 
Radiation  Follow Up Post-
Proton RT (2) 
Creatinine clearance 
calculation (Cockroft 
Gault) 
X (1) 
X weekly during 
cycle 1; every 
other week 
during 
subsequent 
cycles unless 
clinically 
indicated 
X 
X D1 and 
D8 of 
capecitabi
ne 
 
CA19-9 
X (1) 
X Monthly 
X 
 
X 
CEA 
X (1) 
X Monthly 
X 
 
X 
Pregnancy test* 
X (1) 
 
 
 
 
Research Blood for 
Correlative Analysis: 
Antifibrotic Effect (6) 
 
X D1 (pre-
treatment), D8, 
D29, and D92 
 
 
 
Tumor submitted for 
SNaPSHOT mutational 
analysis 
X 
 
 
 
 
Staging: 
 
 
 
 
 
Chest CT Abd-pelvic 
CT (or MRI) 
X (3) 
X Mid-treatment 
and post-
treatment 
X 
 
X (4) 
Radiation Planning 
 
 
 
X prior to 
RT start 
 
Tumor measurements 
(8) 
X 
 
X 
 
X 
PRO (EORTC QLQ-
C30, ESAS-r, HADS) 
(7) 
X 
X 
X 
X 
X 
Notes 
(1) Pre-study Laboratory values need to be obtained within 7 days of study entry. 
(2) Post-study follow up schedule is clinic visit and labs every three months until disease 
progression. The first visit will be 1 month after surgery. Then  follow up visits will be every 3 
months. CT scans will be at least every six months for the first two years and yearly for years 3-
5. All follow up assessments will be performed +/- 21 days of protocol-specified date. 
(3) Staging CT or MRIs need to be obtained within 42 days of study entry   
(4) CT scans will be performed at least every 6 mo for the first 2 years and yearly for years 3-5. 
All follow up CT scans will be performed +/- 21 days of protocol-specified date 
(5)Restaging scans can be performed after pump disconnect during FOLFIRINOX cycles 4 and 
8. 

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(6) Blood for correlative studies will be obtained with clinical labs at pretreatment, day 8 of 
Cycle 1 FOLFIRINOX, at mid-FOLFIRINOX restaging, at post-FOLFIRINOX restaging, 
after chemo radiation therapy, 1 month after completion of capecitabine therapy, 1 month 
post-operatively (if surgery is performed), and within two weeks of radiographic progression 
(these blood draws are optional). 
(7) See section 8.2 for patient reported outcomes assessment timing.  
(8) Tumor measurements will be completed within +/-6 months of the scans. These 
measurements will be completed by the overall PI of the study. 
10 MEASUREMENT OF EFFECT  
10.1 Evaluation Of Response 
 
10.1.1 Imaging Response: Standard Imaging 
       Response to therapy and/or progression after induction chemotherapy with 
FOLFIRINOX will be evaluated in this study using the international criteria proposed by the 
RECIST (Response Evaluation Criteria in Solid Tumors) committee.  Changes in only the largest 
diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. In 
the event that CT staging cannot be utilized, restaging MRI will be the substitute modality. 
10.1.2 Progression-free survival 
Progression-free survival will be defined as the time from the start date of protocol 
therapy to first objective documentation of progressive disease (distant or local) or death.  
Patients who die without a reported prior progression will be considered to have progressed on 
the day of their death.  
 
10.1.3 Time to death 
Time to death will be calculated as the time from the start date of protocol therapy to date 
of death 
10.2 Definitions 
10.2.1 Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
10.2.2 Evaluable for objective response. Only those participants who have measurable 
disease present at baseline, have completed induction chemotherapy, and have had 

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72
their disease re-evaluated will be considered evaluable for response. These participants 
will have their response classified according to the definitions stated below. 
(Note: Participants who exhibit objective disease progression or die prior to the end of 
induction chemotherapy will also be considered evaluable.) 
10.3 Disease Parameters 
10.3.1 Measurable disease. Measurable disease is the presence of at least one (1) 
lesion that can be accurately measured in at least one dimension with longest 
diameter  >20 millimeters (mm) using conventional techniques (CT, MRI, x-ray) or  
>10 mm with spiral CT scan. Measurable lesions must be at least 2 times the slice 
thickness in mm. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
10.3.2 Target lesions: The primary tumor is the target lesion.  
10.4 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or digital 
measurement tool. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
anti-tumor effect of a treatment. 
10.4.1 Clinical lesions. 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 recommended. 
10.4.2 Conventional CT and MRI. These techniques 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 

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pelvis. Head and neck tumors and those of extremities usually require specific 
protocols. 
10.4.3 Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective 
tumor response should be restricted to validation purposes in reference centers. 
However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained. 
10.4.4 Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable disease 
(an effusion may be a side effect of the treatment) and progressive disease. 
10.5 Response Criteria  
10.5.1  Evaluation of Target Lesions 
10.5.1.1 Complete Response (CR): Disappearance of all target lesion. 
10.5.1.2 Partial Response (PR):  At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesion, taking as reference the baseline sum LD. 
10.5.1.3 Progressive Disease (PD):  At least a 20% increase in the sum of the longest diameter 
(LD) of target lesion, taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions  (new lesions must be > 
slice thickness).  

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10.5.1.4 Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
10.5.1.5 Unknown (UN): Assessment of target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
Note: If tumor response data is missing for target lesions, the overall assessment must be UN 
unless there is new disease that would result in an overall assessment of PD. However, if there 
is missing or unevaluable data for non-target lesions, but data is available for all target lesions, 
the overall response for that time point will be assigned based on the sum LD of all target 
lesions. Additionally, the assessment of CR cannot be made if there is missing or unevaluable 
data for non-target lesions. In this case, the overall assessment would be PR. 
10.6 Duration of Response 
10.6.1 Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrence or PD is objectively documented, taking as reference for PD the 
smallest measurements recorded since the treatment started. 
10.6.2 Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that recurrent disease 
is objectively documented. 
10.6.3 Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
 
11 ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 Definitions 
11.1.1 Adverse Event (AE) 
 

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An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
11.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more sever form. 
• Requires or prolongs inpatient hospitalization(i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 

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76
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
respite care  
For the purposes of this study, the following grade 4 toxicities are expected in the setting of 
dehydration, diarrhea or reduced oral intake and will not require expedited serious adverse event 
reporting: low magnesium, low potassium, and  low phosphorus. The following grade 4 toxicities 
are expected and will not require expedited serious adverse event reporting:  low white blood cell 
count, and neutropenia.  
 
 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
11.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   

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Refer to Section 6.1 for a listing of expected adverse events associated 
with the study agent(s). 
11.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 Procedures for AE and SAE Recording and Reporting 
 
Reporting Participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 

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Except as described in Section 4.2.1.5, the descriptions and grading scales found in the 
CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be utilized for AE reporting. The CTEP Active Version of the CTCAE is 
identified and located on the CTEP website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
All appropriate treatment areas should have access to a copy of the CTEP Active 
Version of CTCAE. 
11.3 Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal 
investigator, each participating investigator is required to abide by the reporting 
requirements set by the DF/HCC. The study must be conducted in compliance with 
FDA regulations, local safety reporting requirements, and reporting requirements of the 
principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to 
report serious adverse events to the study sponsor and/or others as described below.  
11.4 Reporting to the Study Sponsor 
11.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the DF/HCC Overall Principal Investigator on the local institutional SAE form. 
This includes events meeting the criteria outlined in Section 11.1.2, as well as the 
following: 
 

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• Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at 
least possibly related/associated with the intervention. 
 
• All Grade 4 (life-threatening or disabling) events  unless expected AND 
specifically listed in the protcol as not requiring expedited reporting. 
 
• All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  
 
Participating investigators must report each serious adverse event to the DF/HCC 
Overall Principal Investigator within 24 hours of learning of the occurrence. In 
the event that the participating investigator does not become aware of the serious 
adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it 
and document the time of his or her first awareness of the adverse event. Report 
serious adverse events by telephone, email or facsimile to: 
 
 
 
Theodore S. Hong, M.D. 
 
 
 
 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information should 
describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study 
participation. 
11.4.2 Non-Serious Adverse Event Reporting  
 

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81
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.   
 
12 DATA AND SAFETY MONITORING 
 
12.1 Data Reporting 
12.1.1 Method  
The ODQ will collect, manage, and monitor data for this study.  
12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the ODQ is as follows: 
 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ 

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On Study Form 
Within 14 days of registration 
Lab Form 
Within 14 days of registration; and within 14 
days of protocol defined laboratory assessment 
Tumor Measurement/Staging 
Form 
Within 14 days of registration; and within 14 
days of protocol defined restaging assessment 
Chemotherapy Treatment 
Form 
Within 10 days of the last day of the cycle of 
FOLFIRINOX-Losartan therapy 
Chemoradiation Treatment 
Form 
Within 10 days of completion of combined 
capecitabine and proton radiation 
Toxicity/Adverse Event 
Report Form 
Every two weeks during FOLFIRINOX - 
Losartan; weekly during chemoradiation; and 
within 14 days of protocol defined follow up visit 
Surgery/Pathology Form 
Within 14 days of surgery, if applicable 
Off Treatment/Off Study Form Within 14 days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up 
visit date 
 
12.2 Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 

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Pancreatic Cancer August 7, 2018 
 
 
83
The DSMC will meet as required to review toxicity and accrual data.  Information to be 
provided to the committee may include:  up-to-date participant accrual; current dose 
level information; DLT information; all grade 2 or higher unexpected adverse events 
that have been reported; summary of all deaths occurring within 30 days for Phase I or 
II protocols; for gene transfer protocols, summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
12.3 Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall Principal Investigator (or Protocol Chair) or 
DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion.  
 
13 REGULATORY CONSIDERATIONS 
 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
 
 
84
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
13.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
13.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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85
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr50 02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
13.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
 
 
86
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
14 STATISTICAL CONSIDERATIONS   
14.1 Study Design  
 
14.2 The single-arm protocol is a phase II study to investigate  combining Losartan with 
FOLFIRINOX for induction chemotherapy followed by restaging and radiation 
therapy with capecitabine in the treatment of patients with locally advanced pancreatic 
cancer. The primary endpoint is the rate of R0 (negative margin) resection determined 
by final pathology of the surgical specimen. Our historical data show a <10% rate of 
R0 resection among unresectable patients treated with induction chemotherapy 
followed by chemoradiation. The protocol will have demonstrated an improvement in 
efficacy if R0 resection were achieved in at least 9 of 50 patients. The decision rule is 
associated with 91% power if FOLFIRINOX-Losartan with short-course radiation and 
capecitabine were to improve the R0 resection rate to 25%. In contrast, the probability 
of a type 1 error is only 6% if the underlying rate of R0 resection were truly the same 
as the historical level of 10%. All protocol patients who start induction chemotherapy 
will be included in the denominator for R0 resection analysis, including those who do 
not undergo surgery due to early progression or other reasons. Sample Size/Accrual 
Rate The accrual goal of 50 patients is projected to be enrolled over a total period of 4.5 
years. The estimate is based on the overall rate of accrual  based on the first 32 patients since 
the protocol was first open to patient entry. Therefore, we project the enrollment of the 
remaining 18 patients will require no more than 1.5 years.   
14.3  Analysis of Secondary Endpoints 
 

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87
14.3.1 Progression-free survival: All patients who start induction chemotherapy will be analyzed 
based on the definition in Section 10.1.2. The progression-free survival duration of 
patients who are alive and progression will be censored at their date of last follow-up. The 
Kaplan-Meier method will be used to estimate progression-free survival with 90% 
confidence intervals constructed by Greenwood’s formula. 
 
14.3.2 Overall survival: Overall survival will be defined as the duration between the start date of 
protocol therapy and death. The survival time of patients who are not known to have died 
will be censored at the date they are last known to be alive. The Kaplan-Meier method will 
be used to estimate overall survival estimation with 90% confidence intervals constructed 
by Greenwood’s formula. 
 
14.3.3 Toxicities: All patients who begin induction chemotherapy will be included in the toxicity 
profile of Losartan combined with induction FOLFIRINOX. Summaries of toxicities will 
include the frequency and proportion of patients experiencing each toxicity, as well as 
summaries by toxicity category and toxicity grade. We shall report separately the 
additional treatment-related toxicity following radiation in patients who do not have 
progressive disease at the restaging interval after induction chemotherapy. 
 
14.3.4 Downstaging: A fraction of patients may proceed to surgical resection following the 
conclusion of protocol therapy if the tumor shrinkage were sufficient to be considered 
resectable. The rate of downstaging to surgical resection will be determined as the 
proportion of initially unresectable patients who eventually undergo 
pancreaticoduodenectomy or distal pancreatectomy. The pathologic downstaging rate will 
be calculated as the proportion of resected patients with the primary tumor and nodes 
downstaged based on final pathology of the surgical specimen.  
 
14.3.5 Correlation of biomarkers with outcome:  Correlative studies will be conducted to 
characterize circulating collagen and angiogenesis biomarkers (8.1.1), as well as somatic 
genetic mutations characterized by the SNaPshot platform (8.1.2). Due to the modest 
patient numbers, analysis will be limited generally to two-group comparisons of each 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
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88
biomarker. Continuous values will be dichotomized at the median or a biologically 
meaningful threshold. The logrank test will be used to assess differences in progression-
free survival and overall survival by biomarker status if at least 5 failure events have been 
observed within each subgroup.  The correlative analysis will be purely exploratory due to 
the limited numbers expected per biomarker subgroup. In particular, analysis will be 
descriptive when the frequency of a genetic mutation is low. 
 
 
14.3.6 Patient-reported outcomes: We will use descriptive statistics to describe QOL (EORTC 
QLQ-C30), symptom burden (ESAS-r) and mood (HADS) for the entire study cohort. 
Mean values and standard deviations will be used to describe QOL and symptom burden 
(T-test or Wilcoxon as appropriate). We will score the HADS subscales for depressive and 
anxiety symptoms categorically, using a cut-off of >7 to describe the proportion of patients 
with these symptoms. We will use Chi-square or Fisher’s Exact Test, as appropriate, to 
analyze the categorical variables.  
14.3.7 Health care utilization: We will use descriptive statistics to describe hospitalizations, ICU 
stays, ED visits and palliative care use for the entire study cohort. Mean values and 
standard deviations will be used to describe continuous variables (T-test and Wilcoxon 
rank sum, as appropriate).  We will use Chi-square or Fisher’s Exact Test, as appropriate, 
to analyze the categorical variables. 
 
4.3 Reporting and Exclusions 
 
All patients who begin protocol treatment will be included in the primary and 
the relevant secondary endpoints.  
15 PUBLICATION PLAN 
 
The results will be made public within 24 months of the end of data collection for the primary 
objective.  If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 

Phase II Study of FOLFIRINOX-Losartan with Short Course Radiation and Capecitabine in Locally Advanced 
Pancreatic Cancer August 7, 2018 
 
 
89
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of data collection. 

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Pancreatic Cancer August 7, 2018 
 
 
90
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Pancreatic Cancer August 7, 2018 
 
 
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Maejima, Y., et al., Telmisartan, a unique ARB, improves left ventricular remodeling of 
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Li, C., et al., Combined effects of losartan and pravastatin on interstitial inflammation 
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28. 
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distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci U S A, 2011. 
108(7): p. 2909-14. 
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34. 
Boyd, A.D. and M. Riba, Depression and pancreatic cancer. J Natl Compr Canc Netw, 
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35. 
Edgerly, M. and T. Fojo, Is there room for improvement in adverse event reporting in the 
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Berry, D.L., Patient-reported symptoms and quality of life integrated into clinical cancer 
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37. 
Oberguggenberger, A., et al., Is the toxicity of adjuvant aromatase inhibitor therapy 
underestimated? Complementary information from patient-reported outcomes (PROs). 
Breast Cancer Res Treat, 2011. 128(2): p. 553-61. 
38. 
Meyers, F.J., et al., Simultaneous care: a model approach to the perceived conflict 
between investigational therapy and palliative care. J Pain Symptom Manage, 2004. 
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Aaronson, N.K., et al., The European Organization for Research and Treatment of 
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40. 
Watanabe, S.M., et al., A multicenter study comparing two numerical versions of the 
Edmonton Symptom Assessment System in palliative care patients. J Pain Symptom 
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41. 
Zigmond, A.S. and R.P. Snaith, The hospital anxiety and depression scale. Acta 
Psychiatr Scand, 1983. 67(6): p. 361-70. 
42. 
Earle, C.C., et al., Aggressiveness of cancer care near the end of life: is it a quality-of-
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43. 
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44. 
Brooks, G.A., et al., Identification of potentially avoidable hospitalizations in patients 
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32 Nakai Y, Isayama H, Ijichi H, Sasaki T, Kogure H, Yagioka H, Miyabayashi K, Mizuno S, 
Yamamoto K, Mouri D, Kawakubo K, Yamamoto N, Hirano K, Sasahira N, Tateishi K, Tada M, 
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Dholakia AS, Chang DT, Goodman KA, Raman SP, Hacker-Prietz A, Griffith ME, 
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93
APPENDICES  
Appendix A: Performance Status Criteria 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., 
light housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities. Up 
and about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 

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94
 
 
                                                 

DOSING LOG
SYMPTOMS/SIDE EFFECTS
FOLFIRINOX Cycle: ___
Losartan
For each  dose take: _____
Please record any side effects experienced during this cycle.
Include the date the particular symptom started and when it
ended. Please evaluate the severity of the symptom according 
Please indicate the date, time, amount taken and any comments. 
to the following scale:
Mild: Awareness of sign or symptom; easily tolerated and did 
not affect ability to perform normal daily activities. Symptom 
Ex:
6/1/2009
vomited AM pills
did not require medication or therapeutic intervention.
Day 1
Day 2
Moderate: Significant  discomfort which interfered with ability 
Day 3
to perform normal daily activities. Symptom was easily resolved  
Day 4
with at home medication or simple therapeutic intervention.
Day 5
Day 6
Severe: Marked discomfort with an inability to carry out 
Day 7
normal daily activities. Symptom required new medication 
Day 8
and/or therapeutic intervention in order to resolve.
Day 9
Day 10
Please Note: The severity should reflect the most severe level 
Day 11
experienced during the time period. 
Day 12
Day 13
Symptom
Start Date End Date Severity
Day 14
Comments
# of Tablets Taken
Date
AM dose
2

ENGLISH 
 
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
bbbb 
Your birthdate (Day, Month, Year): 
cececdde 
Today's date (Day, Month, Year):  
31 cececdde 
__________________________________________________________________________________________ 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 

ENGLISH 
 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 

Edmonton Symptom Assessment System:
(revised version) (ESAS-R)
Please circle the number that best describes how you feel NOW:
 
No Pain
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Possible
Pain
 
 
No Tiredness
(Tiredness = lack of energy) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Possible
Tiredness
No Drowsiness
(Drowsiness = feeling sleepy)
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Possible
Drowsiness
No Nausea
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Possible
Nausea
No Lack of
Appetite
 
Worst Possible
Lack of Appetite
No Shortness
of Breath
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Possible
Shortness of Breath
No Depression
(Depression = feeling sad)
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Possible
Depression
No Anxiety
(Anxiety = feeling nervous)
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Possible
Anxiety
Best Wellbeing
(Wellbeing = how you feel overall) 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Possible
Wellbeing
No __________
Other Problem (for example constipation)
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Patient’s Name __________________________________________ 
Date _____________________ 
Time ______________________ 
Completed by (check one):
 
Patient
 
Family caregiver
 
Health care professional caregiver
 
Caregiver-assisted
BODY DIAGRAM ON REVERSE SIDE
ESAS-r
Worst Possible
_______________
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Revised: November 2010

Please mark on these pictures where it is that you hurt:  
 

 
Appendix D: HADS  
 
 
f:\institut\cultadap\project\4480\study4480\questionnaire\original\forproject\hadsukoriq03_mapi.doc_18/01/08_aja 
 
 
Hospital Anxiety and 
Depression Scale (HADS) 
 
 
 
FOLD HERE 
Name: ______________________________________________________  Date: _______________  
Clinicians are aware that emotions play an important part in most illnesses. If your clinician knows about 
these feelings he or she will be able to help you more. 
This questionnaire is designed to help your clinician to know how you feel. Read each item below and 
underline the reply which comes closest to how you have been feeling in the past week. Ignore the 
numbers printed at the edge of the questionnaire. 
Don’t take too long over your replies, your immediate reaction to each item will probably be more 
accurate than a long, thought-out response. 
FOLD HERE 
 
 
Now check that you have answered all the questions 
 
 
 
 
A 
D 
 
 
TOTAL
 
 
 
 
 
HADS copyright © R.P. Snaith and A.S. Zigmond, 1983, 1992, 1994.  
Record form items originally published in Acta Psychiatrica Scandinavica, 67, 361–70,  
copyright © Munksgaard International Publishers Ltd, Copenhagen, 1983. 
This edition first published in 1994 by nferNelson Publishing Company Ltd,  
9th Floor, 389 Chiswick High Road, London W4 4AL 
GL Assessment is part of the GL Education Group 
This form may not be reproduced by any means without first obtaining permission from the publisher.  
Email: permissions@gl-assessment.co.uk 
 
 
 
A 
D 
 
 
 
 
 
I feel tense or ‘wound up’ 
 
3 
 
 
Most of the time 
 
2 
 
 
A lot of the time 
 
1 
 
 
From time to time, occasionally 
 
0 
 
 
Not at all 
 
 
 
 
I still enjoy the things I used to enjoy 
 
 
0 
 
Definitely as much 
 
 
1 
 
Not quite so much 
 
 
2 
 
Only a little 
 
 
3 
 
Hardly at all 
 
 
 
 
I get a sort of frightened feeling as if 
something awful is about to happen 
 
3 
 
 
Very definitely and quite badly 
 
2 
 
 
Yes, but not too badly 
 
1 
 
 
A little, but it doesn’t worry me 
 
0 
 
 
Not at all 
 
 
 
 
I can laugh and see the funny side of things 
 
 
0 
 
As much as I always could 
 
 
1 
 
Not quite so much now 
 
 
2 
 
Definitely not so much now 
 
 
3 
 
Not at all 
 
 
 
 
Worrying thoughts go through my mind 
 
3 
 
 
A great deal of the time 
 
2 
 
 
A lot of the time 
 
1 
 
 
Not too often 
 
0 
 
 
Very little 
 
 
 
 
I feel cheerful 
 
 
3 
 
Never 
 
 
2 
 
Not often 
 
 
1 
 
Sometimes 
 
 
0 
 
Most of the time 
 
 
 
 
I can sit at ease and feel relaxed 
 
0 
 
 
Definitely 
 
1 
 
 
Usually 
 
2 
 
 
Not often 
 
3 
 
 
Not at all 
A
D
I feel as if I am slowed down 
 
 
 
 
Nearly all the time 
 
 
3 
 
Very often 
 
 
2 
 
Sometimes 
 
 
1 
 
Not at all 
 
 
0 
 
I get a sort of frightened feeling like 
‘butterflies’ in the stomach 
 
 
 
 
Not at all 
 
0 
 
 
Occasionally 
 
1 
 
 
Quite often 
 
2 
 
 
Very often 
 
3 
 
 
I have lost interest in my appearance 
 
 
 
 
Definitely 
 
3 
I don’t take as much care as I should 
 
2 
I may not take quite as much care 
 
1 
I take just as much care as ever 
 
0 
I feel restless as if I have to be on the move 
 
 
 
 
Very much indeed 
 
3 
 
 
Quite a lot 
 
2 
 
 
Not very much 
 
1 
 
 
Not at all 
 
0 
 
 
I look forward with enjoyment to things 
 
 
 
 
As much as I ever did 
 
 
0 
 
Rather less than I used to
1
Definitely less than I used to 
 
 
2 
 
Hardly at all 
 
 
3 
 
I get sudden feelings of panic
 
 
 
Very often indeed 
 
3 
 
 
Quite often 
 
2 
 
 
Not very often 
 
1 
 
 
Not at all 
 
0 
 
 
I can enjoy a good book or radio or 
television programme
 
 
 
 
Often 
 
 
0 
 
Sometimes 
 
 
1 
 
Not often
2
Very seldom 
 
 
3