A Pilot Study of FOLFIRINOX in Combination With Neoadjuvant Radiation for Gastric and GE Junction Cancers
Phase: PHASE1
Conditions: GastroEsophageal Cancer
Sponsor: Massachusetts General Hospital

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DF/HCC Protocol #: 17-311 
NCT03279237
TITLE:  A pilot study of FOLFIRINOX in combination with neoadjuvant radiation for gastric 
and GE junction cancers  
*Principal Investigator (PI): 
Theodore S. Hong MD
Massachusetts General Hospital 
 
Agent(s):  5-Fluorouracil, Leucovorin calcium, Oxaliplatin, Irinotecan, Carboplatin, Paclitaxel, 
Proton or Photon Beam Irradiation 
Study Exempt from IND Requirements per 21 CFR 312.2(b).  
Protocol Type / Version # / Version Date: 
August 14, 2019 

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SCHEMA 
 
Patients with locally-advanced (T 3/4 or N+) gastric or GE junction cancer 
 
 
 

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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ......................................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objective ....................................................................................................5 
1.3 
Secondary Objectives ...............................................................................................5 
2. 
BACKGROUND .................................................................................................................5 
2.1 
Gastric and GE junction cancers ..............................................................................5 
2.2 
Study Agents ............................................................................................................6 
2.3 
Rationale ................................................................................................................11 
2.4 
Correlative Studies Background ............................................................................13 
2.5 
Patient-Reported Outcomes Background ...............................................................13 
2.6 
Health Care Utilization Background ......................................................................14 
3. 
PARTICIPANT SELECTION ...........................................................................................14 
3.1 
Eligibility Criteria ..................................................................................................14 
3.2 
Exclusion Criteria ..................................................................................................15 
3.3 
Inclusion of Women and Minorities ......................................................................16 
4. 
REGISTRATION PROCEDURES ...................................................................................17 
4.1 
General Guidelines for DF/HCC Institutions ........................................................17 
4.2 
Registration Process for DF/HCC Institutions .......................................................17 
5. 
TREATMENT PLAN ........................................................................................................17 
5.1 
Pre-Treatment Criteria ...........................................................................................17 
5.2 
Agent Administration .............................................................................................18 
5.3 
Radiation Therapy ..................................................................................................20 
5.4 
Other Modalities and Procedures ...........................................................................23 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................24 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................24 
5.7 
Duration of Follow Up ...........................................................................................24 
5.8 
Criteria for Taking a Participant Off Study ...........................................................24 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .........25 
6.1 
Anticipated Toxicities ............................................................................................25 
6.2 
Dose Modifications for Toxicities .........................................................................28 
7. 
ADVERSE EVENT REPORTING REQUIREMENTS ....................................................33 
7.1 
Definitions..............................................................................................................34 
7.2 
Expedited Serious Adverse Event Reporting .........................................................36 
7.3 
Routine Adverse Event Reporting .........................................................................36 
7.4 
Expedited Reporting to Hospital Risk Management .............................................36 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................36 
8.1 
5-Flurouracil (5-FU, fluorouracil, “Adrucil”) ........................................................37 

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8.2 
Oxaliplatin (Eloxatin) ............................................................................................37 
8.3 
Irinotecan (CPT-11, Camptosar) ............................................................................38 
8.4 
Leucovorin .............................................................................................................39 
8.5 
Paclitaxel ................................................................................................................39 
8.6 
Carboplatin .............................................................................................................40 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................41 
9.1 
Blood Based Correlatives ......................................................................................42 
9.2 
Correlative Studies: SNaPshot analysis .................................................................43 
9.3 
Patient-reported outcomes .....................................................................................43 
9.4 
Health care utilization ............................................................................................44 
10. 
STUDY CALENDAR .......................................................................................................44 
11. 
MEASUREMENT OF EFFECT........................................................................................46 
11.1 
Completion .............................................................................................................46 
11.2 
Evaluation of Response ..........................................................................................46 
11.3 
Toxicity ..................................................................................................................47 
11.4 
Definitions..............................................................................................................47 
11.5 
Method for Evaluation of Disease .........................................................................48 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................50 
12.1 
Data Reporting .......................................................................................................51 
12.2 
Data Safety Monitoring ..........................................................................................51 
13. 
STATISTICAL CONSIDERATIONS...............................................................................51 
13.1 
Study Design/Endpoints.........................................................................................51 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................52 
13.3 
Stratification Factors ..............................................................................................52 
13.4 
Interim Monitoring Plan ........................................................................................52 
13.5 
Analysis of Primary Endpoint ................................................................................52 
13.6 
Analysis of Secondary Endpoints ..........................................................................52 
13.7 
Reporting and Exclusions ......................................................................................53 
14. 
PUBLICATION PLAN .....................................................................................................54 
REFERENCES ..............................................................................................................................55 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................58 
 
 
 

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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a single-arm pilot study of the neoadjuvant administration of the FOLFIRINOX regimen 
and pre-operative radiation therapy followed by surgery in patients with locally-advanced (T 3/4 
or N+) gastric or gastroesophageal (GE)-junction cancer. 
 
1.2 
Primary Objective 
 
To determine the FOLFIRINOX completion rate of neoadjuvant chemotherapy followed by 
chemoradiation delivered in the pre-operative or definitive setting to patients with gastric and GE 
junction cancers. 
 
1.3 
Secondary Objectives 
 
1) To describe the toxicities of neoadjuvant FOLFIRINOX and chemoradiation given to 
patients with gastric and GE junction cancers 
2) To investigate the clinical response rate of patients with gastric and GE junction 
cancers treated with neoadjuvant FOLFIRINOX and chemoradiation  
3) To investigate the pathologic complete response rate at time of surgery in patients 
with gastric and GE junction cancers treated with neoadjuvant FOLFIRINOX and 
chemoradiation. 
4) To investigate the progression-free survival (PFS) of patients with gastric and GE 
junction cancers treated with neoadjuvant FOLFIRINOX and chemoradiation 
5) To investigate the overall survival (OS) at 5 years of patients with gastric and GE 
junction cancers treated with neoadjuvant FOLFIRINOX and chemoradiation 
6) To investigate the relationship between tissue, cell and plasma biomarkers and 
response rate in patients with gastric and GE junction cancers treated with 
neoadjuvant FOLFIRINOX and chemoradiation 
7) To investigate quality of life, symptom burden, mood, and nutrition in patients with 
gastric and GE junction cancers treated with neoadjuvant FOLFIRINOX and 
chemoradiation. 
8) To investigate utilization of health services (emergency room, hospital and intensive 
care unit) in patients with gastric and GE junction cancers treated with neoadjuvant 
FOLFIRINOX and chemoradiation. 
 
2. BACKGROUND 
 
2.1 
Gastric and GE junction cancers 
 
Gastric cancer is a lethal disease. While the incidence has been decreasing (Siegel 2017), it 

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remains a major cause of cancer related death in the United States.  The high death rate is related 
to late presentation in Western countries, where the majority of patients present with locally 
advanced or metastatic disease (Agboola), which portends a poor prognosis.  Surgery remains 
the mainstay of therapy, with cure being only feasible if the disease is completely extirpated. 
Numerous standards of care exist to improve upon surgery alone including perioperative 
chemotherapy, postoperative chemotherapy, and postoperative chemoradiation. 
 
2.2 
Study Agents 
 
2.2.1 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-hour infusion. 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.  
 
2.2.2 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. 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.   
 
2.2.3 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. 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. 
 
2.2.4 Leucovorin 
 
Leucovorin is a reduced folate which, when combined with 5-FU, augments 5-FU cytotoxicity 
by increasing the inhibition of thymidylate synthase (TS) by the 5-FU 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. 
 

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2.2.5 Paclitaxel 
 
Paclitaxel is a cyclodecane isolated form the bark of the Pacific yew tree Taxus brevifolia. 
Palitaxel binds to tubulin and inhibits the diassembly of microtubules, thereby resulting in the 
inhibition of cell division.  
 
2.2.6 Carboplatin 
 
Carboplatin is a second-generation platinum compound with a broad spectrum of anti-neoplastic 
properties. It contains a platinum atom complexed with two ammonia groups and a cyclobutane-
dicarboxyl residue. This agent is activated intracellularly to form reactive platinum complexes 
that bind to nucleophilic groups such as GC-rich sites in DNA, thereby inducing intrastrand and 
interstrand DNA cross-links, as well as DNA-protein cross-links. These carboplatin-induced 
DNA and protein effects result in apoptosis and cell growth inhibition. 
 
2.2.7 Radiation Therapy 
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. 
 
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”.  
 
For comparison, Figure 1 also shows the depth-dose curve for a 10 MV x-ray beam, an x-ray 
Figure 1. Proton (Bragg peak and modulated 
Peak) and 10 MV depth dose curves. 
 

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energy commonly used to treat deep seated tumors. Note that the x-ray beam dose rises to a 
maximum value at relatively shallow 
depths, and then falls off exponentially to 
lower doses at the treatment depth.  A 
clinical comparison of single-beam proton 
and photon beams is shown in Figure 2 
where a single posterior beam is used for 
the treatment of the spinal axis in the 
treatment of medulloblastoma. Note that, 
for the photon treatment, the heart, 
mediastinum, esophagus, lung and spinal 
cord are irradiated by the treatment beam 
whereas for the proton treatment, the beam 
stops abruptly distal to the target volume 
and there is no irradiation of the tissues 
and organs distal to the target volume.   
 
In the usual clinical situation, more than 
one radiation beam is used in both x-ray 
and proton treatments. However, the 
advantage shown for protons using single beams is present for each and every beam used. 
Therefore, one cannot overcome the physical disadvantage of x-rays by the use of multiple 
beams or complex beam arrangements. In modern proton therapy facilities, which have 
isocentric gantries and sophisticated beam delivery and control systems, proton therapy 
capabilities are equivalent to those for state-of-the-art, conformal therapy using x-rays with 
respect to numbers of beams, beam directions and complex delivery techniques such as intensity 
modulation.  
Intensity Modulated Radiation Therapy 
 
Intensity-modulated x-ray therapy (IMXT) – the use of x-ray beams each of which is purposely 
made non-uniform over its cross-section – provides a new degree of freedom in treatment 
delivery and can lead to more conformal dose distributions.  Protons, too, can be used in an 
intensity modulated mode (IMPT) similar to that for photons and, in an additional degree of 
freedom, are also made non-uniform in depth. The advantage that single beams of protons have 
over single beams of x-rays, which is maintained when multiple cross-firing beams of uniform 
intensity are employed, is similarly maintained when intensity modulation is employed. 
Figure 2. Posterior, single-beam treatment of the spinal 
axis

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2.3 
Rationale 
 
Chemotherapy and chemoradiation both have defined roles in the management of 
esophagogastric cancers. In patients with esophagogastric junction (GE junction) and esophageal 
cancer, neoadjuvant chemoradiation has been established as the standard of care. In the setting of 
inoperable esophageal/GE junction cancers, chemoradiation produces long term control in some 
patients.  Patients with node positive gastric cancer similarily benefit from multi-agent 
chemotherapy and chemoradiation. 
 
2.3.1 Neoadjuvant chemoradiation in resectable GE junction adenocarcinoma 
 
A phase III trial called the CROSS trial (van Hagen) randomized patients with T1-3 or N+ 
esophageal or GE junction cancer to neoadjuvant chemoradiation followed by surgery, versus 
surgery alone. Patients randomized to chemoradiation received 41.4 Gy with weekly carboplatin 
and paclitaxel.  pCR was achieved in 29% of patients receiving chemoradiation.  Patients with 
adenocarcinoma achieved a pCR rate of 23%, compared with 49% for squamous cell carcinoma. 
Overall survival at 5 years was improved from 34% to 47% (p<0.001).  There was no increased 
risk of postoperative mortality with neoadjuvant chemoradiation (P=0.85) 
 
2.3.2 Definitive chemoradiation in inoperable GE junction adenocarcinoma 
 
Many patients will have unresectable cancer due to either unresectable tumor (T4 disease or 
extensive nodal involvement) or medical comorbidities. Chemoradiation was established as 
optimal therapy based on Radiation Therapy Oncology Group (RTOG) 8501, which randomized 
patients between 64 Gy of radiation alone or 50 Gy of chemoradiation with cisplatin and 5-FU.  
5-year overall survival improved with the addition of chemotherapy from 0% to 27% (P<0.0001) 
(Cooper).  However, at two years, 45% of patients experienced a local recurrence. 
 
To decrease this risk of local failure, a follow up trial was conducted by the US Intergroup (INT 
0123) to determine if dose escalation could reduce the risk of local recurrence (Minsky).  
Patients with inoperable esophageal cancer were randomized to 50.4 Gy or 64.8 Gy with 
concurrent cisplatin/5-FU.  There was no improvement in local control or overall survival. 
 
Because of the high rate of toxicity seen with cisplatin and 5-FU, a randomized trial was 
conducted comparing radiation to 50 Gy with either cisplatin/5-FU or FOLFOX (Conroy) in 
patients with inoperable esophageal or GE junction cancer. This study showed equivalent overall 
survival between the two regimens but markedly lower early and toxic death rate.  
 
2.3.3 Chemotherapy and chemoradiation in resectable gastric cancer 
 
Multiple standards of care exist for adjuvant therapy in resected, locally advanced gastric cancer.  
The development of both chemoradiation and chemotherapy-alone adjuvant approaches 
highlights the two competing risks of recurrence in patients with locally advanced gastric cancer: 
locoregional recurrence and metastatic recurrence.  In the US, the high rates of locoregional 
failure observed after surgery alone led to the design of Intergroup 0116 (Smalley), in which 
patients with margin-negative gastrectomy were randomized to observation or post-operative 

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chemoradiation with 5-fluorouracil (5FU), sandwiched between three cycles of Mayo Clinic 
schedule 5-FU. This study demonstrated a survival benefit of ~10% directly related to an 
improvement in locoregional control, but no difference in rates of distant metastases. Despite 
these results, significant skepticism remained regarding the impact of this trial outside the United 
States as over half the patients had an insufficient, D0, lymphadenectomy. In Europe, the 
MAGIC study evaluated peri-operative chemotherapy with epirubicin, cisplatin and 5-FU (ECF) 
versus surgery alone (Chua). Patients receiving chemotherapy received three cycles before and 
after surgery.  Similarly, this study demonstrated a survival benefit of ~ 10%, though this time 
due to a substantial improvement in distant metastases. 
 
To evaluate the role of radiation in patients receiving chemotherapy after a D2 lymph node 
dissection, the ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial 
randomized patients between capecitabine and cisplatin (XP) for 6 cycles vs. XP for 2 cycles, 
followed by chemoradiation with capecitabine to 45 Gy, followed by XP for 2 more cycles 
(XP/XRT/XP) (Lee). 458 patients were randomized between the two arms.  Patients were 
generally high risk, with >85% enrolled having node (+) disease. Over half the patients had 
diffuse type disease, as opposed to intestinal type.  As expected from this high-volume surgical 
center, all patients had a D2 dissection, with a median of 40 lymph nodes evaluated in both arms.  
With a median follow up of 53.2 months, the 3-year DFS was 78.2% in the XP/XRT/XP arm 
compared to 74.2% in the XP arm (p=0.0862). While this difference did not reach statistical 
significance, the node-positive patients appeared to derive benefit from the addition of radiation, 
with a 3-year DFS was 77.5 % in the XP/XRT/XP arm compared to 72.3% in the XP arm 
(p=0.0365). Interestingly, locoregional recurrence was quite low in both arms (4.8% in 
XP/XRT/XP arm vs. 8.3% in XP arm; p=0.3533). 
 
2.3.4 Neoadjuvant FOLFIRINOX and Chemoradiation 
 
A study of preoperative chemotherapy and chemoradiation for localized gastric and 
gastroesophageal junction adenocarcinoma (LGCA) was conducted (Elimova). Patients with 
LGCA with baseline endoscopic ultrasound (eus) T2-T3 any N, M0 (M stage by laparoscopy and 
imaging) were eligible. Patients received 4 or fewer doses of oxaliplatin and infusional 5-FU 
every 2 weeks then oxaliplatin and infusional 5-FU with 45 Gy of conformal radiation in 25 
fractions. 5-6 weeks after chemoradiation, patients underwent an attempted D2 dissection and 
were followed. Between February 2004 and November 2010, a total of 58 patients were enrolled. 
Most patients were men (66%) and had clinical stage IIIA cancer (52%). 14% (95%CI: 6%, 
25%) of patients achieved a pathologic CR. With a median follow-up of 37.4 months, the median 
survival was 39.4 (95%CI: 27.6, NR) months. 72% of patients proceeded to surgery and 86% of 
these had an R0 resection. The 5-year OS for patients who had surgery was 56%. 44.8% of 
patients experienced grade 3 and/or 4 toxicities (commonly, fatigue, anorexia and insomnia) due 
to induction chemotherapy. 58.6% experienced grade 3 and/or 4 toxicities due to chemoradiation 
(commonly, fatigue, myelosuppression, vomiting, and dysphagia). No treatment-related death 
occurred.  
 
The 5-yr OS for all patients treated on this study was 44% and the 5-year Progression Free 
Survival (PFS) was 42%. Our data show that if LGCA patients can complete the described 
therapeutic strategy (i.e., including surgery), their outcome may be excellent.  

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2.4 
Correlative Studies Background 
 
Preclinical and clinical work in the Steele Labs and elsewhere has identified the plasma and 
tissue hepatocyte growth factor (HGF), carbon anhydrase IX (CAIX), stromal-derived factor 1 
alpha (SDF1α) as candidate biomarkers of response or resistance to various therapies, but their 
role after proton beam radiation therapy in gastric cancer is unknown. Based on findings from 
preliminary studies, we propose here to evaluate the baseline and changes in blood circulating 
protein biomarkers and circulating and tumor-infiltrating immune cells to explore potential 
associations between the changes in these biomarkers and resistance to treatment in this disease. 
These biomarkers will be monitored from baseline throughout FOLFIRINOX therapy, before 
and after chemoradiation, after surgical resection, and at time of disease progression.  In 
exploratory studies, we will evaluate several other cytokines using multiplex protein array 
(Meso-Scale Discovery, Inc.). 
 
Circulating cell populations will be evaluated by fluorescence-based flow cytometry. Protein 
concentration in plasma will be measured using ELISA kits for HGF, CAIX, and SDF-1 (RnD 
Systems) and MSD multiplex kits for cytokines (Human ProInflammatory Panel 1 V-PLEX™ 
Plus IFN-γ, IL-1β, IL-10, IL-12 p70, IL-13, IL-2, IL-4, IL-6, IL-8, TNF-α; Meso-Scale 
Discovery #K15049G-1), and vascular growth factors (Human Angiogenesis Panel 1 V-PLEX 
Kit: bFGF, Flt-1, PlGF, sTie-2, VEGF, VEGF-C, VEGF-D; Meso-Scale Discovery #K15190D-
1). These techniques have been used in the Steele Lab for over 15 years to evaluate patients’ 
samples. 
 
In gastric cancer, mutations of interest do not occur randomly, but rather a relatively small 
number of well-characterized mutations comprise the majority of activating mutations.  Other 
genes of interest already mentioned include APC, CTNNB1 (β-catenin), Braf, PTEN, and 
PIK3CA.  Our institution uses an adaptation of SNaPSHOT (Applied Biosystems) as our clinical 
method of determining KRAS mutational status in tumors, as described by Dias-Santagata, et al. 
This testing is routinely done on all newly diagnosed GI cancer patients. 
 
2.5 
Patient-Reported Outcomes Background 
 
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 (Edgerly). 
Additionally, evaluating patient-reported measures may help highlight patients’ difficulties with 
treatment adherence by demonstrating additional side effects and toxicities of therapy (Berry). 
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 (Oberguggenberger, 
Meyers). Thus, we aim to describe QOL, symptom burden and mood in this study population to 
help us better identify the side effects and challenges faced by patients with gastric cancer. 
 

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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 (Aaronson). The EORTC QLQ-STO22 is a 
22-item gastric cancer site-speciﬁc supplemental module to augment the QLQ-C30 to enhance 
the sensitivity and speciﬁcity for gastric cancer QOL measures (Blazeby). We will use the 
Edmonton Symptom Assessment System-revised (ESAS-r) to measure symptoms, which has 
been previously validated in patients with advanced cancer (Watanabe). 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 (Zigmond). 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. 
 
We will use the Mini-Nutritional Assessment (MNA) to assess nutrition (Cohendy, Kaiser). The 
MNA has been established as one of the most valid and most frequently used nutritional 
screening tools. 
 
2.6 
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 (Earle, Sadot). Patients with gastric cancer often experience symptoms related to the 
cancer itself or the therapies used to treat it (Crippa). 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 (Brooks). 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 and the differences 
between the two treatment regimens. 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
Participants must meet the following criteria in order to be eligible to participate in the study: 
 

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3.1.1 Histologically or cytologically confirmed T 3/4 or N+ (> 1 cm in size or FDG avid) 
gastric or gastroesophageal (GE) junction cancer. Diagnosis must be confirmed by a 
DF/HCC institution pathology department prior to registration.  
 
3.1.2 Age 18 years or older. There will be no upper age restriction. 
 
3.1.3 ECOG performance status ≤ 1  
 
3.1.4 Life expectancy of greater than 3 months 
 
3.1.5 Participants must have adequate organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
≥ 1,500 cells/mm3 
− 
platelets 
≥ 75,000 cells/mm3 
− 
total bilirubin 
≤ 1.5 x upper limit of normal, or, for patients who have  
 
 
undergone biliary stenting, total bilirubin of ≤ 2 or two 
 
 
 down trending values.  
− 
AST(SGOT)  
 
 
≤ 2.5 × upper limit of normal 
− 
ALT (SGPT)  
 
 
≤ 2.5 x upper limit of normal 
− 
creatinine 
≤ 1.5 mg/dL, or  
− 
creatinine clearance 
≥ 30 mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal. 
 
3.1.6 The effects of both radiation therapy and the chemotherapy agents used in this trial are 
known to be teratogenic. Therefore, 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 participation plus 30 days 
from the last date of study drug administration.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.  
 
3.1.7 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
Participants who fulfill any of the following criteria will be excluded from the study: 
 
3.2.1 Evidence of metastatic disease as determined by chest CT scan, abdomen/pelvis CT scan 
(or MRI with gadolinium and/or manganese) within six weeks of study entry. Distant 
nodal disease is allowed if it is in the radiation port.  
 
3.2.2 Any prior chemotherapy, targeted/biologic therapy, or radiation for treatment of the 
participant’s gastric or GE junction cancer. 
 

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3.2.3 Receipt of chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C) prior to entering the study or those who have not recovered from adverse 
events due to agents administered more than 4 weeks earlier. 
 
3.2.4 Treatment of other invasive carcinomas within the last five years with 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. 
 
3.2.5 Receipt of any other investigational agents within 4 weeks preceding the start of study 
treatment. 
 
3.2.6 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/or cardiac arrhythmias not well 
controlled with medication) or myocardial infarction within the last 12 months, or 
ongoing infection as manifested by fever.  
 
3.2.7 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 drug intake.  
 
3.2.8 Pregnant women are excluded from this study because radiation therapy and the 
chemotherapy agents to be used have the potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with these agents, breastfeeding should be 
discontinued while the mother is receiving protocol therapy.  
 
3.2.9 Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, 
without complete recovery. 
 
3.2.10 No concurrent administration of cimetidine (as it can decrease the clearance of 5-FU). 
Another H2-blocker or proton pump inhibitor may be substituted before study entry. 
 
3.2.11 Known, existing uncontrolled coagulopathy.  
 
3.2.12 Prior systemic fluoropyrimidine therapy (unless given in an adjuvant setting and at least 
six months earlier). Prior topical fluoropyrimidine use is allowed.  
 
3.2.13 Known hypersensitivity to 5-fluorouracil or known DPD deficiency.  
 
3.2.14 History of allergic reaction(s) attributed to compounds of similar chemical or biologic 
composition to 5-fluorouracil, irinotecan, or oxaliplatin.  
 
3.3 
Inclusion of Women and Minorities 
 
We do not expect the eligibility criteria to over- or under-represent women, minorities, or under-

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represented populations.  
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 
5. TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis and will include administration of the 
FOLFIRINOX regimen (with dose modifications for those 65 years old or older) followed by 
proton or photon radiation therapy concurrent with paclitaxel and carboplatin.  
 
Expected toxicities and potential risks as well as dose modifications for FOLFIRINOX and 
ChemoRadiation 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.  
 
5.1 
Pre-Treatment Criteria 
 
Prior to study enrollment, participants must undergo the following evaluations: 
 
• Chest CT and abdominal-pelvic CT (or MRI) with intravenous contrast within 42 days of 
enrollment. 
• Physical exam within 14 days of enrollment 

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• Lab studies (CBC with diff, Na, K, BUN, Cr, Glucose, Calcium, Albumin, AST, ALT, 
Total bilirubin, Alkaline phosphatase, and a urine or serum HCG for women of 
childbearing potential) within 14 days of enrollment 
 
Evaluations obtained to confirm study eligibility may be used as pre-treatment evaluations 
provided that they are done within the above timeframes.  
 
Staging laparoscopy is NOT required prior to study treatment because participants will receive 
systemic chemotherapy at doses equivalent to that received by patients who have documented 
Stage IV disease. 
 
The mutational analysis (SNaPSHOT panel) requires a paraffin-embedded block or ten unstained 
slides from the untreated biopsy specimen that were obtained at the time of endoscopy or 
diagnostic biopsy. Participants without sufficient material for SNaPSHOT will NOT be excluded 
from the study as this constitutes a secondary, exploratory aim of the study.  
 
5.2 
Agent Administration 
 
 
A cycle will be two weeks (14 days) long, with FOLFIRINOX administered on days 1-3. 
Participants will receive up to 8 two-week cycles (for a total of 16 weeks) of FOLFIRINOX 
chemotherapy. Cycle adjustments of +7 / -1 days may be made at the discretion of the treating 
physician. A break in therapy of up to one week for restaging after 4 cycles is allowed.  
 
The order of FOLFIRINOX administration is as follows:  
1. Oxaliplatin  
2. Leucovorin (may be given concurrently with Oxaliplatin or following Oxaliplatin) 
3. Irinotecan 
4. 5-Fluorouracil 
 
Paclitaxel and Carboplatin will be given concurrently with radiation therapy weekly (+/- 1 day). 
 
 All treatments should be administered according to institutional standard of care. All dose 
adjustments should be made as outlined in section 6.2.  Additional dose modifications can be 
made at the discretion of the treating medical oncologist but the reason for these modifications 
must be documented in the medical record. 
 
5.2.1 Oxaliplatin 
 
Oxaliplatin will be administered as a dose of 85 mg/m2 by intravenous infusion over 120 
minutes except for patients with an initial platelet count between 75,000 and 100,000 who will 
be treated at an Oxaliplatin dose of 65 mg/m2. Infusion time may be prolonged (up to 6 hours) in 
patients experiencing pharyngolaryngeal dysesthesia. Patients requiring oxaliplatin 
desensitization may continue on study as long as the institution has procedures in place for 
desensitization. Oxaliplatin should be administered on day 1 of each cycle, followed by or 
concurrent with leucovorin and prior to irinotecan.  
 

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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. 
 
5.2.2 Leucovorin 
 
For all patients, Leucovorin (400 mg/m2) will be diluted with 5% dextrose and administered by 
IV infusion over 2 hours. It may either be given after oxaliplatin, or concurrently. If given 
concurrently, use separate containers with a Y-type administration set. There are no adjustments 
of leucovorin.  Even if the bolus 5-FU dose is not given, the leucovorin dose should be 
administered. 
 
5.2.3 Irinotecan 
 
For patients less than 65 years old, Irinotecan will be initially administered as an initial dose of 
180 mg/m2 by intravenous infusion over 90 minutes. For patients aged 65 years or older, the 
Irinotecan will initially be administered as an initial dose of 150 mg/m2 by intravenous infusion 
over 90 minutes.  
 
5.2.4 5-Fluorouracil 
 
For patients less than 65 years old, 5-FU will be initially administered as a bolus dose of 400 
mg/m2 IV push per institutional standard on day one, followed by a 1200 mg/m2/day dose by 
continuous infusion via an ambulatory infusion pump for the subsequent 46 hours. For patients 
65 years or older, the bolus 5-FU will not be given. For patients who have a platelet count 
between 75,000 and 100,000 at the time of registration, the 5-FU bolus should be initially 
administered as a bolus of 200 mg/m2 (DL-1).5-FU administration will occur after irinotecan. 5-
FU is not a vesicant or irritant.  
 
5.2.5 Paclitaxel 
 
Paclitaxel will be given concurrent with radiation therapy. It may be administered before or after 
radiation. Paclitaxel 50 mg/m2 will be administered as an IV infusion over 30-60 minutes, 
weekly (+/- 1 day). Paclitaxel dose does not need to be recalculated for weight changes ≤ 10% of 
the participant’s total body weight. Paclitaxel will be administered via an infusion control device 
(pump) using non-PVC tubing and connectors. Nothing else is to be infused through the line 
through which paclitaxel is administered.  
 
Prior to the first dosage of paclitaxel, participants will be premedicated with dexamethasone 20 
mg (or an equivalent agent) orally the night before and 20 mg either orally or intravenously on 
the morning of paclitaxel administration. On the morning of the first paclitaxel administration: if 
dexamethasone is given intravenously, administer 30 minutes prior to paclitaxel administration; 
if dexamethasone is given orally, administer 1-3 hours prior to paclitaxel administration. Also 
prior to the first dosage of paclitaxel, patients will be premedicated with diphenhydramine, 50 
mg intravenously, and famotidine (or other H2 blocker), 20 mg intravenously. If no allergic 

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reactions occur, then subsequent dosages of premedications with dexamethasone, 
diphenhydramine, and H2 blockers may be reduced at the investigator’s discretion.  
 
Patients must be attended by medical personnel for the first 15 minutes of infusion and then have 
blood pressure checked every 15 minutes for 1 hour, then as needed. Medications for acute 
management of anaphylaxis should be readily available in the location where the patient is being 
treated.  
 
All dose adjustments are to be made at the discretion of the treating medical oncologist. 
 
5.2.6 Carboplatin 
 
Carboplatin will be given concurrent with radiation therapy. It may be administered before or 
after radiation on a dosing day. Carboplatin dose will be area under the curve (AUC) = 2 over 
one hour, weekly (+/- 1 day). The dose of carboplatin is calculated as follows (using the Calvert 
formula based on creatinine clearance): 
 
Total dose (mg) = Target AUC (in mg/mL per min) x (Estimated GFR + 25) 
 
The GFR should not exceed 125 ml/min. If the calculated GFR based on the Calvert formula is 
greater than 125 ml/min, a GFR of 125 ml/min should be used. The maximum carboplatin dose 
for an AUC = 2 should not exceed 300 mg. 
 
Carboplatin reacts with aluminum to form a precipitate and cause a loss of potency. Therefore, 
needles or intravenous sets that contain aluminum may not be used with this agent. Carboplatin 
will be administered after paclitaxel. Patients will receive appropriate antiemetics and 
supplemental hydration as per institutional standard. 
 
All dose adjustments are to be made at the discretion of the treating medical oncologist. 
 
5.3 
Radiation Therapy 
 
5.3.1 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 nodal coverage outlined below.  
 
Total dose will be prescribed to the 95 to 100% isodose line based on coverage. The prescribed 
dose to the PTV is 4500 cGy delivered in 180 cGy/day over 25 fractions. For GE junction 
tumors, a 540 cGy boost may be included to the GTV + 1 cm. A dose painted boost to involved 
vasculature is permitted to a total dose of 30 Gy.  Radiation treatment assignment will be based 
on resource availability at the time of radiation planning. 
 
Patients will be simulated supine. Intravenous and oral contrast will be administered per standard 
department protocol.  4-D CT simulation will be obtained for treatment planning to ascertain the 

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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. For participants 
with diffuse-type gastric cancer, where the GTV cannot be visualized, the entire stomach will be 
identified as the GTV. Areas of involved adenopathy should be carefully depicted and their 
geographic relationship to the primary lesion should be accurately defined on planning images.  
 
When the GTV can be clearly identified, the clinical target volume (CTV) will include a 
longitudinal mucosal margin that extends 3.5-4 cm proximally and distally to the GTV. When 
the GTV cannot be identified, the entire stomach will need to be treated.  
 
All grossly involved lymph nodes should have a 5 mm CTV expansion. The following nodal 
volumes should be covered: 
 
Nodal Coverage (all tumors) 
Celiac nodes 
Gastrohepatic nodes 
 
GE junction tumors and cardia tumors: 
Paraesophageal nodes 4 cm proximal to the GTV 
Splenic nodes may be considered 
Distal tumors: 
Porta hepatis 
Peripancreatic nodes may be considered 
 
The Planning Target Volume (PTV) will be customized based on 4D CT scan. Generally, 0.5 cm 
expansion will be used, except for superiorly/inferiorly where 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.   
 
5.3.2 Treatment 
 
Radiation treatment will begin within 4 weeks after the completion of FOLFIRINOX.  
 
All radiation treatment will be given 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. 
 
Radiation treatment may start on any day that the center is functioning. If the proton center is 

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unexpectedly not functioning for 1 or 2 days, these fractions may be made up the following 
week. However, if the proton center is not functioning for longer than 2 days, patients may 
receive photon radiation for the remaining fractions. If radiation therapy start is delayed 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. 
 
Treatments will be delivered 5 days/week excluding hospital holidays or closed for other 
emergencies.  Patients are encouraged to not eat for 4 hours prior to treatment, and not drink for 
two hours prior to treatment.  For protons, passively scattered protons and pencil beam protons 
are both permitted.  For photons, 3D photons and IMRT are both permitted. 
 
5.3.3 Target Dose Constraints 
 
The prescribed dose to the PTV is 4500 cGy delivered in 180 cGy/day over 25 fractions. For GE 
junction tumors, a 540 cGy boost may be included to the GTV + 1 cm. 
 
The dose to 99% of the PTV must be at least 93% of the prescribed dose, and a contiguous 
volume of no more than 2cc inside the PTV may exceed 20% of the prescribed dose.  
 
Calculations will take into account the effects of tissue heterogeneity. Planning will be 
performed using an approved dose calculation algorithm. Approved algorithms include 
convolution superposition, collapsed cone convolution, and Monte Carlo. 
 
5.3.4 Normal Tissue Dose Constraints 
 
The normal structures to be contoured will depend on the level of the esophagus involved, but 
can include left and right lungs, heart, brachial plexus, left and right kidneys, liver, small 
intestine, and spinal cord. The dose to normal tissues must be kept within parameters described 
below: 
1. Lungs 
a. V20Gy ≤ 20% 
b. and V30Gy ≤ 15% 
c. and V40Gy ≤ 10% 
d. V10Gy ≤ 40%  
2. Cord 
a. Max ≤ 4500 cGy  
3. Bowel 
a.  Max bowel dose < Max PTV dose  
b. 
and D05 ≤ 4500 cGy 
4. Heart 
a.  V30Gy ≤ 30% (closer to 20% preferred) 

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b. 
Mean < 3000 cGy 
5. Left Kidney, Right Kidney (evaluate each one separately): 
No more than 33% of the volume can receive 1800 cGy 
6. Liver 
a. 
V20Gy ≤ 30 %  
b. V30Gy ≤ 20  
c. Mean <2500 cGy 
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.  For protons, passively scattered protons and pencil beam protons are both permitted. 
For photons, 3D photons and IMRT are both permitted. 
 
5.4 
Other Modalities and Procedures 
 
5.4.1 Surgery 
 
Surgery will be performed five weeks after chemoradiation. Patients who do not proceed to 
surgery will remain in active follow up.   
 
5.4.2 Pathology 
 
Processing the specimen and pathology will be reported according to the AJCC Cancer Staging 
Manual, 6th Edition.  Recorded on permanent section will be: tumor size, degree of 
differentiation (well, moderate, poor), lymph node status, and margin status.   
 
5.4.3 Chemotherapy 
 
Patients may receive adjuvant chemotherapy after surgery at the discretion of the treating 
investigator. Adjuvant chemotherapy is not considered part of protocol treatment. If there is no 
evidence of metastatic progression in the pre-operative and intra-operative assessment, then four 
additional months of therapy with the FOLFIRINOX regimen will be the recommended 
standard.  
 
If adjuvant chemotherapy is administered, at minimum, administration of FOLFIRINOX therapy 
will be contingent on participant meeting original inclusion criteria (lab parameters and 
performance status). Physicians may opt to provide FOLFOX or FOLFIRI in the postoperative 
setting, with the full FOLFIRINOX regimen administered only when the patient can tolerate this 
therapy. If there is evidence of progression, patients will be withdrawn from the study and, as per 
NCCN guidelines, proceed to second-line therapy. Appropriate dose reductions and 
modifications can be made at the discretion of the treating physician. 
 

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5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Prophylactic administration of G-CSF (Neulasta) should be completed per institutional 
guidelines with each cycle of FOLFIRINOX at the discretion of the treating provider, due to the 
high rate of neutropenia typically experienced by patients receiving this regimen. G-CSF should 
be administered 24-48 hours after discontinuation of infusional 5-fluorouracil. 
 
Participants should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, anti-emetics, etc. when appropriate. Erythropoietin is allowed.  
 
No other cytotoxic therapy or radiotherapy may be used during therapy. 
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), 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 protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
5.7 
Duration of Follow Up 
 
Study participants will be in active follow-up after completion of neoadjuvant treatment until 5 
years post surgery, except in the case of documented progression, at which time they will be 
followed for survival only. Participants who do not undergo surgery will be followed for 5 years 
post completion of neoadjuvent treatment. Participants removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the event.  
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 

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The reason for taking a participant off study and the date the participant was removed must be 
documented in the case report form (CRF). 
 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made using the following recommendations. The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
When 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.  
 
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 Regimen 
 
Expected hematologic adverse events associated with the FOLFIRINOX regimen include 
neutropenia, febrile neutropenia, anemia, and thrombocytopenia. 
 
Anticipated non-hematologic adverse events associated with the FOLFIRINOX regimen include 
fatigue, nausea, diarrhea, peripheral neuropathy, elevated ALT, vomiting, alopecia (grade 2) and 
infection without neutropenia.   
 
6.1.2 5-FU 
 
In addition to the above, 5-FU is also known to cause poor appetite, taste changes, stomatitis 
(usually 5-8 days after treatment initiation), loss of nails, hyperpigmentation, photosensitivity, 
maculopapular rash, palmar-plantar erythrodysethesias (in many patients receiving continuous 
infusion), cerebral ataxia (rare), myocardial infarction, angina, asymptomatic S-T changes, 
excessive lacrimation and, rarely, tear duct stenosis.  
 

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6.1.3 Oxaliplatin 
 
The most commonly observed oxaliplatin toxicities include neurotoxicity, GI toxicity, and 
myelosuppression. 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, 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 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 to minimize neurotoxicity of oxaliplatin (e.g. 
carbamazepine, Mg+, Ca++). Calcium and magnesium infusions appear to be beneficial in 
preventing neurotoxicity. Generalized pain, cough and headache have been observed.  
 
Gastrointestinal toxicities include nausea, vomiting (oxaliplatin is moderately emetogenic), 
constipation 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 hepatomegaly, 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 patients indicated histological 

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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. 
 
6.1.4 Irinotecan 
 
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, 
weight loss, insomnia, headache, chills, skin rash, flatulence, flushing of the face during infusion 
and anemia. Dehydration has occurred as a consequence of diarrhea, particularly when 
associated with severe vomiting. Patients may have an acute syndrome of 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. Occasionally, 
abnormalities of hepatic enzymes, or thrombocytopenia have been observed.  
 
6.1.5 Radiation Therapy 
 
The most common toxicities of radiation therapy are fatigue, nausea, abdominal pain, diarrhea, 
indigestion, vomiting, weight loss, lymphocytopenia, and anorexia. Other toxicities may include 
radiation fibrosis if surgery is delayed too long, skin redness and irritation, esophagitis, gastritis, 
pneumonitis, elevated liver function tests, skin damage, GI bleed and bowel perforation.  
 
Much less common toxicities could include liver damage, kidney damage, and late secondary 
malignancies. 
 
6.1.6 Paclitaxel  
 
The most common toxicities of paclitaxel include myelosuppression, nausea, diarrhea, vomiting, 
abdominal pain, peripheral neuropathy, severe anaphylactic reactions, alopecia, fatigue, 
arthralgia, myalgia, infiltration (induration, tenderness, rarely ulceration), irritation to the 
injection site, mucositis.  
 
6.1.7 Carboplatin 
 
Myelosuppression is a common toxicity with carboplatin. Thrombocytopenia, neutropenia, 
leukopenia, and anemia are common but typically resolve by day 28 when carboplatin is given as 
a single agent. 
 
Hypersensitivity to carboplatin has been reported in 2% of patients. Symptoms include rash, 
urticariaThe reactions can be managed with standard epinephrine, corticosteroid, and 
antihistamine therapy.  

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Peripheral neuropathies have been observed in 4% of patients, with mild paresthesia being the 
most common. Nausea and vomiting are common but usually resolve within 24 hours and also 
respond to anti-emetics. Other gastrointestinal events include diarrhea and constipation. Pain, 
asthenia, and alopecia, taste changes, abnormal magnesium levels, infection and central 
neurotoxicityhave also been reported.  
6.2 
Dose Modifications for Toxicities 
 
6.2.1 FOLFIRINOX Dose Modifications 
 
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. Only those agents specified in the sections 
below should be dose-reduced.  
 
Participants who require multiple dose reductions during a cycle for grade 2 toxicity may, at the 
discretion of the treating physician, begin the following cycle at one dose level higher than the 
current dose reduction. If dose reduction beyond dose level -3 is required for any agent, that 
agent will be discontinued.  
 
 
 
 
 
 
 
 
Leucovorin dose is always 400 mg/m2, IV, given prior to the infusion of 5-FU. If any infusion of 
5-FU is to be skipped, leucovorin will also be skipped. Initial doses may be reduced, if 
necessary, at treating physician’s discretion.  
 
If a patient has undergone biliary stent placement prior to enrollment, the following treatment 
guidelines will apply for Cycles 1 and 2. If ALT and AST are elevated at 2.5 x the upper limit of 
normal or higher at time of study enrollment, but demonstrate two consecutive down-trending 
values, the patient should begin treatment without Irinotecan, or with dose-reduced Irinotecan if 
clinically indicated. The agents 5-FU and Oxaliplatin may be given during Cycle 1 with 
Irinotecan incorporated as 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, with 
Irinotecan incorporated as laboratory values permit. If total bilirubin is elevated between the 
upper limit of normal and 2.0 mg/dl at time of enrollment, the patient may receive full dose 5-FU 
and Oxaliplatin, with dose-reduced Irinotecan. Irinotecan may be increased to full dose in the 
first or second cycle if laboratory values permit. 
 
Agent*  
  
Oxaliplatin  
 
5-FU Bolus  
 
5-FU Infusion 
(per 46-48 hours) 
Irinotecan 
Initial Dose 
85 mg/m2  
 
400 mg/m2  
 
2400 mg/m2  
180 mg/m2 
Level –1 
65 mg/m2  
 
320 mg/m2  
 
1920 mg/m2  
150 mg/m2 
Level –2  
 
50 mg/m2  
 
270 mg/m2  
 
1600 mg/m2 
120 mg/m2 
Level –3 
40 mg/m2 
230 mg/m2 
1360 mg/m2  
100 mg/m2 

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6.2.1.1 
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.)  
 
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 
@permanent 
DL-1 
Hold until 
ANC 
>=1500, 
resume 
without 
dose 
reduction 
Neutropenia G3-4, 
Febrile 
neutropenia 
(ANC 1000-500, 
<500) 
HOLD 
ALL 
THERAPY, 
Supportive 
care and 
antibiotics 
per 
institutional 
guidelines 
Hold until 
ANC >=1500, 
resume @ 
permanent DL-
1 level once 
resolved 
Hold until 
ANC >=1500, 
resume @ 
permanent DL-
1 level once 
resolved 
Hold until 
ANC 
>=1500, 
resume @ 
permanent 
DL-2 level 
once 
resolved 
Hold until 
ANC 
>=1500, 
resume @ 
permanent 
DL-1 level 
once 
resolved 
Thrombocytopenia 
(PLT <100K – 
75K) 
Treat with 
DR 
Oxaliplatin 
Treat at 
permanent DL 
-1 
No reduction 
Treat at 
permanent 
DL-1 
No 
reduction 
Thrombocytopenia 
G2 
(75K – 50K) 
HOLD 
ALL 
THERAPY 
Hold until 
resolved to 
>75K, resume 
at permanent 
DL-1 
Hold until 
resolved to 
>75K, no 
reduction 
Hold until 
resolved to 
>75K, No 
reduction 
Hold until 
resolved to 
>75K, No 
reduction 
Thrombocytopenia 
G3-4 
(50K – 25K, 
<25K) 
HOLD 
ALL 
THERAPY 
Hold until 
resolved to 
>75K.  Resume 
@ permanent 
DL-1 if 
resolved in 1 
week, 
permanent DL 
-2 if >1 week 
Hold until 
resolved to 
>75K.  Resume 
@ permanent 
DL-1. 
Hold until 
resolved to 
>75K 
Resume @ 
permanent 
DL-1. 
Hold until 
resolved to 
>75K 
Resume @ 
permanent 
DL-1. 

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to resolve 
 
6.2.1.2 
Non-hematologic 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.). 
 
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): For grade 2 diarrhea, reduce 5-FU and irinotecan one dose level 
for the next cycle, and for all cycles thereafter. Oxaliplatin is not dose reduced.  For grade 3 or 4 
diarrhea, eliminate bolus 5-FU and dose reduce 5-FU and irinotecan by one dose level for the 
next cycle and for all cycles thereafter.  
 
The following dose modifications are based on the grade of mucositis seen for any day after Day 
1 in any cycle. For grade 2 mucositis, reduce 5-FU one dose level for the remainder of the cycle 
and for all cycles thereafter. For grade 3 and 4 mucositis, eliminate bolus 5-FU for the next 
cycle and all cycles thereafter. Dose-reduce infusional 5-FU and irinotecan by one dose level for 
the next cycle and all cycles thereafter.  
 
The following dose modifications are based on the grade of nausea and vomiting occurring 
during a cycle (i.e., after Day 1 in any cycle). For grade 3 or 4 nausea or vomiting despite 
maximal antiemetic therapy, reduce all agents in the FOLFIRINOX regimen by one dose level 
for the next cycle and for all cycles thereafter.  
 
Oxaliplatin may cause sensory neuropathies. Use this Scale for 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, reduce oxaliplatin by one dose level 
for the next cycle and for all subsequent cycles. For grade 3 neurotoxicity that resolves to grade 
2 between treatments, reduce oxaliplatin by one dose level for the next cycle and for all 

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subsequent cycles. 
 
For recurrent grade 3 neurotoxicity resolving to grade 2 between treatments, 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. Participants should continue to receive other protocol therapy. 
 
For grade 3 neurotoxicity persisting between treatments, discontinue oxaliplatin. Participants 
should continue to receive other protocol therapy. For grade 4 neurotoxicity, discontinue 
oxaliplatin. Participants should continue to receive other protocol therapy. 
 
For pharyngo-laryngeal dysesthesia, increase the duration of oxaliplatin infusion to 6 hours for 
all subsequent treatments.  
 
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. 
 
For all other grade 3 non-hematologic toxicities, decrease each drug by one dose level for the 
next cycle.   
 
For all other grade 4 non-hematologic toxicities, discontinue the FOLFIRINOX chemotherapy. 
 
6.2.2 Radiation Therapy 
 
Radiation therapy will be held for Grade 3 or 4 nausea that is not well-controlled with anti-
emetic support, until nausea resolves to Grade 2 or less. It will then be resumed at same dose.  
 
Radiation therapy will be held for ANC < 500 mcL or Platelets < 50,000 mcL. Resume radiation 
therapy when ANC > 500 and Platelets > 50,000.  
 
6.2.3 Paclitaxel and Carboplatin 
 
Dose reductions of paclitaxel and carboplatin are permanent. 
 
Dose levels for paclitaxel are as follows: 
Weekly Paclitaxel 
Dose 
50 mg/m2 
Dose Level -1 
40 mg/m2 
Dose Level -2 
30 mg/m2 
Dose Level -3 
20 mg/m2 
There will be no dose level reductions below a weekly dose of 20 mg/m2 
 
Dose levels for carboplatin are as follows: 

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Weekly Carboplatin 
Dose 
AUC = 2 
Dose Level -1 
AUC = 1.5 
Dose Level -2 
AUC = 1.0 
Dose Level -3 
AUC = 0.5 
There will be no dose level reductions below a weekly dose AUC = 0.5. 
 
6.2.4 Hematologic Toxicities 
 
The dose of paclitaxel and carboplatin will be modified according to blood counts within 72 
hours of the day of treatment as shown in the table below. 
 
Treatment Day Blood Counts 
Modification 
ANC 
 
Platelet Count 
≥ 1,000 mcL 
AND 
> 75,000 mcL 
Full dosage paclitaxel and carboplatin. 
500-999 mcL 
OR 
50,000-75,000 mcL 
Hold carboplatin and paclitaxel. Recheck 
CBC weekly. When ANC > 1,000 and Plt > 
75,000, resume paclitaxel at 1 dose level 
reduction and carboplatin at 1 dose level 
reduction. 
< 500 mcL 
OR 
< 50,000 mcL 
Hold carboplatin, paclitaxel; Recheck CBC 
weekly. When ANC >1,000 and Plt > 75,000 
resume paclitaxel and carboplatin and reduce 
both by 1 dose level. 
 
Participants who experience 4 episodes of ANC < 500 or Platelets < 50, 000 may complete 
radiation but will not receive additional carboplatin or paclitaxel.  
 
6.2.5 Non-hematologic Toxicities 
 
Nonhematologic adverse events that require dose reduction of paclitaxel or carboplatin include 
treatment-related diarrhea, mucositis, esophagitis, gastritis, nausea/vomiting/dehydration despite 
adequate treatment with anti-emetic therapy, and treatment-related pulmonary toxicity. The dose 
of paclitaxel and carboplatin will be modified for these non-hematologic events as shown in the 
table below. 
 
Toxicity 
Grade 
Agent 
Modification 

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1st Episode 
Grade 3 or 4  
≥ grade 3 
Carboplatin 
Paclitaxel 
 
Hold until ≤ grade 2; resume, dose, 
reducing carboplatin by 1 dose level 
and paclitaxel by 1 dose level 
2nd Episode 
 
≥ grade 3 
Carboplatin 
Paclitaxel 
 
Hold until ≤ grade 2; resume dose, 
reducing carboplatin by 1 dose level 
and paclitaxel by 1 dose level 
3rd Episode 
≥ grade 3 
Carboplatin 
Paclitaxel 
 
Discontinue carboplatin and paclitaxel.  
Paclitaxel 
infusion-related 
reaction  
≥ grade 4 
Paclitaxel 
 
Discontinue paclitaxel. Carboplatin and 
radiation may be continued. 
Carboplatin 
infusion-related 
reaction  
≥ grade 4 
Carboplatin 
 
Discontinue carboplatin. Paclitaxel and 
radiation may be continued. 
 
7. ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
Participants will be evaluated for adverse events at the post-operative visit. Adverse events that 
occur during prolonged hospitalizations due to surgery will not be recorded unless deemed 
necessary by the Principal Investigator.  
 
 
 
All serious adverse events (SAE) 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 7.1.2, as well as the following: 
 
• 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 that are unexpected or not specifically 
listed in the protocol as not requiring 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. 
 

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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 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, neutropenia, and low lymphocyte count.  
 
7.1.3 Expectedness 
 
Adverse events can be expected or unexpected  
 
7.1.3.1 
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. Refer to 
Section 6.1 for a listing of expected adverse events associated with the study agent(s). 
 
7.1.3.2 
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. 
 

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7.1.4 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. 
 
7.2 
Expedited Serious Adverse Event Reporting 
 
Investigators must report to the overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment 
on the local institutional SAE form.  
 
Investigative sites within DF/HCC will report SAEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.3 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the IRB, 
FDA, etc.) must also be reported in routine study data submissions. All Adverse Events that 
occur through 30 days after the last dose of study drug will be recorded in the protocol-specific 
case report forms.  
 
Only Grade 3 and higher adverse events will be input into the case report forms. Furthermore, 
only the highest grade for each individual toxicity will be recorded. If treatment attribution 
changes, a new toxicity will be logged.  
 
Additionally, participants will be evaluated for adverse events at the post-operative visit. 
Adverse events that occur during prolonged hospitalizations due to surgery will not be recorded 
unless deemed necessary by the Principal Investigator.  
 
7.4 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the agents administered in this 
study can be found in Section 6.1. 

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8.1 
5-Flurouracil (5-FU, fluorouracil, “Adrucil”) 
 
Please refer to the package insert for complete product information. 
 
8.1.1 Form 
 
5-FU is available as a 50mg/mL solution for injection in 10mL, 20mL, 50mL, and 100mL vials.  
 
8.1.2 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 
pump, manufacturer of drug, concentration and diluent. Please refer to appropriate reference 
sources for additional information.  
 
8.1.3 Compatibility 
 
5-FU should not be mixed in the same solution with most parenteral antiemetics. 
Leucovorin enhances the cytotoxicity of 5-FU by forming a more stable tertiary complex with 
thymidylate synthase. Concomitant administration 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.  
 
8.1.4 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of 5-FU in a self-
contained and protective environment.  
 
8.1.5 Availability 
 
5-FU is commercially available.  
 
8.1.6 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. 
 
8.2 
Oxaliplatin (Eloxatin) 
 
Full information regarding oxaliplatin is available on the package insert.  

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8.2.1 Form 
 
Oxaliplatin is an aqueous solution in vials containing 50mg in 100mg at a concentration of 
5mg/mL.  
 
8.2.2 Storage and Stability 
 
Vials of Oxaliplatin do not contain any preservatives and they are intended for single use. 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. 
 
8.2.3 Compatibility 
 
Oxaplatin is unstable in the presence of chloride or alkaline solutions. Do NOT mix or 
administer oxaliplatin with saline or chloride-containing solutions. Do NOT administer other 
drugs or solutions in the same infusion line.  
 
8.2.4 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of Oxaliplatin in 
a self-contained and protective environment.  
 
8.2.5 Availability 
 
Oxaliplatin is commercially available.  
 
8.2.6 Preparation 
 
The calculated dose of oxaliplatin should be diluted for infusion with 250mL to 500mL 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. 
 
8.3 
Irinotecan (CPT-11, Camptosar) 
 
Full information regarding Irinotecan is available on the package insert.  
 
8.3.1 Form 
 
Irinotecan is available as a 20 mg/mL solution in 2mL and 5mL vials.  
 
8.3.2 Storage and Stability  
 
Intact vials should be stored at controlled room temperature 59° to 86° F (15° to 30° C) and 

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protected from light. Solutions diluted in D5W are reported to be stable for 48 hours under 
refrigeration and when protected from light. Irinotecan solutions should not be frozen as the drug 
may precipitate. 
 
8.3.3 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal Irinotecan in a 
self-contained and protective environment.  
 
8.3.4 Availability 
 
Irinotecan is commercially available.  
 
8.3.5 Preparation 
 
 
Irinotecan is diluted in 5% dextrose (D5W) 500mL to a final concentration of 0.12-1.1 mg/mL.  
 
8.4 
Leucovorin 
 
Please refer to the package insert for complete Leucovorin product information. 
 
8.4.1 Form 
 
Leucovorin is available in 50mg, 100mg, 350mg vials for reconstitution. 
 
8.4.2 Storage and Stability 
 
Intact vials should be stored at room temperature and protected from light. Solutions 
reconstituted with Bacteriostatic Water for Injection (BWI) are stable for at least 7 days at room 
temperature.  
 
8.4.3 Availability 
 
Leucovorin is commercially available. 
 
8.4.4 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. 
 
8.5 
Paclitaxel 
 
Refer to the package insert for additional information.  
 

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8.5.1 Form 
 
Paclitaxel is a poorly soluble plant product from the western yew, Taxus brevifolia. Improved 
solubility requires a mixed solvent system with further dilutions of either 0.9% sodium chloride 
or 5% dextrose in water. All solutions of paclitaxel exhibit a slight haziness directly proportional 
to the concentration of drug and the time elapsed after preparation. 
 
A sterile solution concentrate, 6 mg/ml in 5 ml vials (30 mg/vial) in polyoxyethylated castor oil 
(Cremophor EL) 50% and dehydrated alcohol, USP, 50%. The contents of the vial must be 
diluted just prior to clinical use. 
 
8.5.2 Storage and Stability 
 
Paclitaxel vials should be stored between 20°-25°C (68°-77°F). Properly prepared solutions (0.3 
– 1.2 mg/mL) are physically and chemically stable for 27 hours at ambient temperature (270 C). 
 
8.5.3 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of Paclitaxel in a 
self-contained and protective environment.  
 
8.5.4 Availability 
 
Paclitaxel is commercially available. 
 
8.5.5 Preparation 
 
Paclitaxel will be diluted to a final concentration of 0.3 to 1.2 mg/ml in D5W, USP, in glass or 
polyolefin containers due to leaching of diethylhexphthalate (DEHP) plasticizer from polyvinyl 
chloride (PVC) bags and intravenous tubing by the Cremophor vehicle in which paclitaxel is 
solubilized. Each bag/bottle should be prepared immediately before administration.  
 
NOTE: Formation of a small number of fibers in solution (NOTE: acceptable limits established 
by the USP Particular Matter Test for LVPs) have been observed after preparation of paclitaxel. 
Therefore, in-line filtration is necessary for administration of paclitaxel solutions. In-line 
filtration should be accomplished by incorporating a hydrophilic, microporous filter of pore size 
not greater than 0.22 microns (e.g.: Millex-GV Millipore Products) into the intravenous fluid 
pathway distal to the infusion pump. Although particulate formation does not indicate loss of 
drug potency, solutions exhibiting excessive particulate matter formation should not be used. 
 
8.6 
Carboplatin 
 
Refer to the package insert for additional information.  
 

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• Within two weeks of disease progression (radiologic) 
 
9.1.3 Analyses  
 
Serial blood draws will be analyzed as follows: 
 
Serial monitoring of tumor burden and residual disease by circulating tumor DNA analysis.  
 
Cell free DNA will be isolated from serial plasma aliquots. For each patient, one to two specific 
clonal mutations identified by exome sequencing of tumor tissue (above) will be used to track 
circulating tumor DNA (ctDNA) levels throughout treatment using custom mutation-specific 
droplet digital PCR probes as a personalized measure of tumor burden.  This method will allow 
accurate monitoring of the response of overall tumor burden to treatment and can be correlated 
with radiologic endpoints.  The presence of detectable ctDNA one month after surgery (or at 
subsequent time points) will be evaluated as a means of detecting minimal residual disease post-
operatively and will be correlated with recurrence. 
 
In addition, based on findings from preliminary studies, we propose here to evaluate the changes 
in blood circulating proteins and circulating immune cells throughout the treatment course to 
explore potential associations between the changes in these biomarkers and resistance to 
treatment and survival outcomes. Plasma will be separated from the cellular fraction, aliquoted 
and stored at <–70ºC until the end of the study. At that point, we will evaluate several cytokines 
using multiplex protein array (Meso-Scale Discovery, Inc.) and single analyte ELISA kits (RnD 
Systems) using the CLIA-certified Clinical Correlative Studies Core of the Steele Laboratories. 
Circulating immune cells will be enumerated and phenotyped by flow cytometric analysis in 
fresh samples, using the same Core, and using published protocols. 
 
9.1.4 Potential risks to patients 
 
These studies will involve peripheral blood draw only.  Peripheral blood draws do involve a 
small risk of patient discomfort, bruising, or puncture site infection, but these risks are minimal.  
Furthermore, correlative blood draws will be performed at the same time as patients are having 
routine clinical blood laboratory assessments during study treatment, and thus will not involve 
any additional peripheral venipuncture. 
 
9.2 
Correlative Studies: SNaPshot analysis 
 
Mutational analysis will be performed by tumor SNaPSHOT for the mutations listed in section 
2.4. Paraffin-embedded block or ten unstained slides will be used from the untreated biopsy 
specimen obtained at the time of upper endoscopy or initial diagnostic biopsy.  Analysis will be 
performed as described by Dias-Santagata at the Translational Research Laboratory at MGH. 
 
9.3 
Patient-reported outcomes   
 
QOL (EORTC QLQ-C30, version 3.0 and the EORTC STO22), symptoms (ESAS-r), mood 
(HADS), and nutrition (MNA) will be assessed at time of informed consent prior to neoadjuvant 

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therapy; day 1 of cycles 2, 4, 6, 8 of neoadjuvant chemotherapy; on day 1 and every 2 weeks 
during chemoradiotherapy and during post-op follow up.  
 
9.4 
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. 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
must be done ≤ 6 weeks prior to the start of therapy. In the event that the participant’s condition 
is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of 
the next cycle of therapy. 
 
All pre-study assessments must be performed prior to administration of any study medication, 
unless otherwise noted. All study assessments and medications should be 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. 
 
 
Baseline 
Day 1 of each cycle 
of FOLFIRINOX 
Restaging
During 
ChemoRT 
Post-op 
F/U (11) 
Progression
Informed consent 
X 
 
 
 
 
 
History 
X 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X (8) 
X 
X 
Vital Signs and performance 
status 
X 
 
 
X (8) 
X 
 
Height/Weight 
X 
 
 
X (9) 
 
 
Toxicity Assessment 
 
X 
X 
X (8) 
X 
X 
CBC/plts/diff 
X (2) 
X 
X 
X (10) 
X 
X 
Serum chemistries (1) 
X (2) 
X 
X 
X (10) 
X 
X 
CEA/CA19-9 
X (2) 
X (15) 
X 
X (15) 
X 
 
Creatinine clearance 
calculation (Cockroft Gault) 
X 
X (6) 
 
X (10) 
 
 

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Pregnancy test (3) 
X (2) 
 
 
 
 
 
CT (or MRI) of chest, 
abdomen, pelvis 
X 
 
X (7) 
 
X 
X 
Tumor SNaPshot (4) 
OPTIONAL  
X 
 
 
 
X 
 
Correlative Studies (5) 
OPTIONAL 
X 
X 
X 
X 
X 
X 
Patient-reported outcomes 
(EORTC, ESAS, HADS, 
MNA) 
X 
X (12) 
 
X (13) 
X (14) 
X 
 
(1) Serum chemistries include: Na, K, BUN, Cr, Glucose, Calcium, Albumin, AST, ALT, 
Total bili, Alk Phos 
(2) Pre-study laboratories are to be obtained with 14 days of study entry. 
(3) For women of child-bearing potential 
(4) Tumor SNaPshot will be done once for each participant; either on the pre-treatment 
biopsy specimen (if available) or on the resected tumor specimen.  
(5) Peripheral blood for correlative studies will be obtained with clinical labs at 
pretreatment, Cycle 1 Day 8 of FOLFIRINOX, at restaging visits, after chemoradiation 
therapy (pre-operatively), 1 month after completion of therapy (surgery or neoadjuvent 
treatment) and within two weeks of radiographic progression (these blood draws are 
optional).  
(6) Creatinine clearance to be done on Day 1 of Cycles 1, 3, 5 and 7 of FOLFIRINOX.  
(7) CT/MRI to be done at baseline, after first week of Cycle 4 of FOLFIRINOX, after the 
first week of the last cycle of FOLFIRINOX, 3-4 weeks after chemoradiation. 
(8) To be done weekly during ChemoRT 
(9) Height and weight should be measured at the start of ChemoRT.  
(10) On Days 1, 8 and 15 of ChemoRT.  
(11) Post-op follow up schedule is as follows. For years 1 and 2 follow up will be visit and 
labs at least every 3 months, scans at least every 6 months, For year 3, visit and labs will 
be at least every 3 months and scans will be at least every 12 months. For years 4 and 5 
visit and labs will be at least every 6 months and scans will be at least every 12 months.  
For patients with R0, R1 and R2 resections, the first post-op CT scan, visit and labs are 
3-8 weeks postoperatively. All follow up assessments may be performed +/-21 days of 
the protocol-specified date. Participants who do not undergo surgery will be followed 
per the schedule above for 5 years post completion of neoadjuvant treatment 
(12) Patient-reported outcomes will be assessed on day 1 of cycles 2, 4, 6, and 8. 
(13) Patient-reported outcomes will be assessed on day 1 and every 2 weeks during 
chemoradiotherapy. 
(14) Patient-reported outcomes will be assessed per the post-op follow schedule outlined 
above, 11. 
(15) Tumor markers (CEA and CA19-9) to be assessed on Day 1 of Cycles 2, 4, 6, and 8 of 
FOLFIRINOX; Day 1 and Day 29 of ChemoRT; and 1 month after completion of 
therapy (surgery or neoadjuvant treatment). 

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11. MEASUREMENT OF EFFECT 
 
11.1 
Completion 
 
The primary endpoint is the completion of induction chemotherapy with FOLFIRINOX in 
combination with chemoradiation. 
 
11.2 
Evaluation of Response 
 
11.2.1 Clinical Response  
 
For the purposes of this study, participants should be re-evaluated for response as outlined in 
section 10.   
 
Response to therapy and/or progression after induction chemotherapy with FOLFIRINOX and 
after chemoradiation will be evaluated using the international criteria proposed by the Response 
Evaluation Criteria in Solid Tumors (RECIST) committee (version 1.1) (Eisenhauer 2009). 
Changes in 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.  
 
Objective clinical response is defined as a best overall response of CR or PR according to 
RECIST v1.1. The best overall response is defined as the best response (in the order of CR, PR, 
SD, PD, and not evaluable) among all overall responses recorded from the start of treatment until 
progression (per RECIST v1.1), or the last evaluable disease assessment in the absence of PD 
prior to the initiation of subsequent anticancer therapy or the discontinuation from the study, 
whichever occurs first. The best overall response of CR or PR must be confirmed, which means a 
response of CR/PR is recorded at one visit and confirmed by repeat imaging not less than 4 
weeks after the visit when the response was first observed with no evidence of progression 
between the initial and CR/PR confirmation visit. 
 
11.2.2 Pathological Response 
 
All patients will undergo a full pathological review of their surgical specimen according to the 
AJCC Staging Classification, 6th.  Initial gross evaluation and identification of resection margins 
will be performed jointly by the surgeon and the pathologist.  Pathological complete response 
will be defined as the absence of any viable tumor cells within the pathologic specimen. 
 
11.2.3 Progression-free Survival 
 
Progression-free survival (PFS) is defined as the time from the date of first dosing to the first 
documentation of radiographic disease progression (per RECIST v1.1) or death due to any cause, 
whichever occurs first. Subjects who are alive with no documented progressive disease by the 
data cutoff date for PFS analysis will be censored at the date of their last evaluable disease 
assessment. 

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11.2.4 Overall Survival 
 
Overall survival (OS) is defined as the time from the date of first dosing until death due to any 
cause. If there is no death reported for a subject by the data cut-off date for overall survival 
analysis, OS will be censored at the last known alive date.  
 
11.3 
Toxicity 
 
All participants who receive at least one dose of study treatment will be evaluable for toxicity 
from the time of their first treatment.  
 
Acute and late toxicities will be scored using Common Toxicity Criteria (CTCAE) version 4.03. 
Toxicities will be noted and recorded in protocol-specific case reports from the time of first dose 
of protocol therapy until 5 years after the end of protocol therapy. 
 
11.4 
Definitions 
 
11.4.1 Evaluable for Target Disease response 
 
Only those participants who have measurable disease present at baseline, have received at least 
four cycles of FOLFIRINOX, and have had their disease re-evaluated will be considered 
evaluable for target disease response.  These participants will have their response classified 
according to the definitions stated below. (Note:  Participants who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
11.4.2 Evaluable Non-Target Disease Response.  
 
Participants who have lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions.  
 
11.4.3 Measurable disease 
 
Measurable lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of 10 mm by CT scan 
(irrespective of scanner type) and MRI (no less than double the slice thickness and a minimum of 
10mm). 
 
11.4.4 Non-measurable disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by 

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CT or MRI), and cystic lesions are all considered non-measurable. 
 
Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
11.4.5 Target lesion 
 
The primary tumor is the target lesion.  
 
11.4.6 Non-target lesions 
 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow up.  
 
11.5 
Method for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
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 unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  
 
CT scan. The RECIST guideline has defined measurability of lesions on CT scan based on the 
assumption that CT thickness is 5mm or less. CT scans should be performed with contiguous 
cuts in slice thickness of 5mm or less. Spiral CT should be performed using a 5-mm contiguous 
reconstruction algorithm.  
 
MRI scan. Magnetic resonance imaging of the chest and abdomen is acceptable for measurement 
of lesions provided that the same anatomical plane is used for serial assessments. If possible, the 
same imaging device should be used for serial evaluations.  
 
11.5.1 Evaluation of Response by RECIST v. 1.1 
 
11.5.1.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 

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Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.5.1.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression of existing non-target 
lesions will be defined as the overall level of substantial worsening in non-target disease such 
that, even in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. In the absence of measurable disease, change in 
non-measurable disease comparable in magnitude to the increase that would be required to 
declare PD for measurable disease. Unequivocal progression should not normally trump target 
lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.5.1.3 
Appearance of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical location that was not scanned 
at baseline is considered new and will indicate PD. If a new lesion is equivocal (because of small 
size etc.), follow-up evaluation will clarify if it truly represents new disease and if PD is 
confirmed, progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 

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11.5.1.4
Evaluation of Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Evaluation of Overall Response at a Single Timepoint by RECIST V1.1  
 
Target Lesions  
Non-target Lesions  
New Lesions  
Overall Response  
Complete response  
Complete response  
 
No  
Complete response  
No target lesion
a
 
Complete response  
No  
Complete response  
Complete response  
Not evaluable 
b  
No  
Partial response  
Complete response  
Non-complete response/ 
non-progressive disease  
No  
Partial response  
Partial response 
Non-progressive disease 
and not evaluable 
b 
No  
Partial response  
Stable disease 
Non-progressive disease 
and not evaluable 
b  
No  
Stable disease  
Not all evaluated 
Non-progressive disease  
No  
Not evaluable  
No target lesion 
a 
 
Not all evaluated  
No  
Not evaluable  
No target lesion 
a
 
Non-complete response/ 
non-progressive disease 
No 
Non complete 
response/non-
progressive disease 
Progressive disease 
Any 
Yes or No 
Progressive disease 
Any 
Progressive disease 
Yes or No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesion
a
 
Unequivocal progressive 
disease 
Yes or No 
Progressive disease 
No target lesion 
a
 
Any 
Yes 
Progressive disease 
a Defined as no target lesions at baseline 
b Not evaluable is defined as either when no or only a subset of lesion measurements are made 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
Adverse Events Reporting Requirements. 

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12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. 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 Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if 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 with 30 
days of intervention for Phase I or II protocols; for gene therapy 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.  
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
The primary endpoint of the pilot study is completion of induction chemotherapy comprising 8 
cycles of FOLFIRINOX followed by 5 weeks of chemoradiation. A total of 25 patients with 
locally advanced gastric or gastroesophageal junction cancer will be enrolled and treated. If at 
least 18 of them were to complete the treatment plan specified in the protocol (5.2-5.3), it will be 
considered as feasible in the management of resectable and borderline resectable tumors. The 
decision rule is associated with 89% power for declaring success if FOLFIRINOX in 
combination with chemoradiation were associated with an underlying completion rate of 80%. In 
contrast, the probability of type 1 error is only 15% if 60% of patients were truly able to 
complete the intended therapy. 

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13.2 
Sample Size, Accrual Rate and Study Duration  
The accrual duration is projected to be about 2 years to enroll a total of 25 patients with locally 
advanced gastric or gastroesophageal junction cancer. The follow-up schedule will extend up to 
5 years post-operatively for late effects, progression, survival and patient-reported outcomes. 
 
13.3 
Stratification Factors  
No stratification of patient enrollment. 
13.4 
Interim Monitoring Plan 
Not applicable. 
13.5 
Analysis of Primary Endpoint  
The completion rate of chemotherapy in combination with chemoradiation will be estimated with 
a 95% confidence interval of maximal width +/-20% based on the exact binomial distribution. 
13.6 
Analysis of Secondary Endpoints 
 
• Toxicity associated with neoadjuvant FOLFIRINOX and chemoradiation will be 
summarized by category and grade according to the CTCAE version 4.0 (7.1). 
• Clinical response will be assessed using RECIST criteria (11.2.1) after 4 and 8 cycles of 
FOLFIRINOX as well as 3-4 weeks following chemoradiation. The rate of objective 
clinical response to induction FOLFIRINOX and chemoradiation will be reported as the 
proportion of eligible patients starting protocol therapy who achieve a complete or partial 
response as the best overall response.  
• Pathologic response will determined by a full pathological review of the surgical 
specimen according to the AJCC classification (11.2.2). The rate of pathologic complete 
response at surgery following FOLFIRINOX and chemoradiation will be reported as the 
proportion of eligible patients who start protocol therapy. The denominator will include 
patients who are not resected due to discontinuation of chemotherapy or chemoradiation, 
disease progression or early death. 
• Progression-free survival (PFS) is defined as the duration from the first date of protocol 
therapy to the earliest date of disease progression per RECIST criteria or death due to any 
cause. PFS time will be censored at the date of last follow-up for patients still alive with 
no documentation of progressive disease. The PFS rate will be estimated using the 
Kaplan-Meier method with 95% confidence intervals based on the complementary log-
log transformation. 
• Overall survival (OS) is defined as the duration from the first date of protocol therapy to 
the date of death due to any cause and will be censored at the date of last follow-up for 
patients still alive. The OS rate will be estimated using the Kaplan-Meier method with 
95% confidence intervals based on the complementary log-log transformation 

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• To investigate the relationship between tissue, cell and plasma biomarkers and response 
rate in patients with gastric and GE junction cancers treated with neoadjuvant 
FOLFIRINOX and chemoradiation. 
• 
Mutational analysis will be available from the routine testing of patients with GI patients 
that includes KRAS and the majority of activating mutations. Association of specific 
genotype and clinical response to chemotherapy and chemoradiation will be analyzed 
using Fisher’s exact test. 
• 
Peripheral blood will be collected at serial timepoints (9.1.3) between baseline and one 
month post-operatively and also at disease progression. ctDNA levels of one or two 
specific clonal mutations identified by exome sequencing of tumor tissue will be used as 
a personalized measure of tumor burden and correlated with clinical response. The 
detectable level of post-operative ctDNA will be evaluated as a measure of minimal 
residual disease to determine the association with progression following surgery. Plasma 
proteins, ctyokines and circulating immune cells at baseline as well as changes during 
and after treatment will be analyzed as biomarkers of response and resistance. ctDNA and 
biomarker data will be analyzed primarily using standard methods for graphical and 
descriptive statistics to identify potential trends and associations. Analyses will be 
exploratory and hypothesis-generating due to the optional biospecimen collection. 
• Patient-reported outcomes will be reported using descriptive statistics to summarize QOL 
(EORTC QLQ-C30 and STO22), symptom burden (ESAS-r), mood (HADS), and 
nutrition (MNA) at each timepoint. Changes in QOL and symptom burden during 
neoadjuvant therapy may be analyzed by repeated measures ANOVA. The HADS 
subscales will be used with a cutoff of 7 to estimate the proportion of patients with 
depressive and anxiety symptoms at each timepoint. The MNA tool to estimate the 
proportion of patients with abnormal nutritional status. The dichotomous outcomes may 
be analyzed by McNemar’s test to assess changes between paired timepoints. 
• Health care utilization will be assessed using descriptive statistics to summarize hospital 
admissions, intensive care unit stays, emergency department visits and palliative care use 
during the course of protocol participation. Patient subgroups may be compared using 
standard for two-sample methods, such as the Wilcoxon rank-sum test and Fisher’s exact 
test. 
 
13.7 
Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
 
All enrolled patients who receive any protocol therapy will be evaluated for toxicity from 
the time the first dose is administered. 
 
13.7.2 Evaluation of the Primary Endpoint 
 
All enrolled patients who receive any protocol therapy will be evaluable for analysis of 
the completion rate, including those who do not proceed to chemoradiation due to early 
progression or toxicity.  
 

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14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. 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 Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.