PurIST Classification-Guided Adaptive Neoadjuvant Chemotherapy by RNA Expression Profiling of EUS Aspiration Samples

Inclusion Criteria (for Screening)

1. Have suspicion of pancreas adenocarcinoma and plan for endoscopic biopsy.

2. Plan for endoscopic biopsy or agreeable to an additional EUS/FNA for researchpurposes, otherwise plan to obtain archival tissue for PurlST testing.

Inclusion Criteria (for Treatment)

1. Be 18 years of age or older.

2. Be able to understand and provide written informed consent or have a legallyauthorized representative (LAR).

3. Have documentation of histologically confirmed adenocarcinoma.

4. Have an Eastern Cooperative Group (ECOG) performance status < 2.

5. Have clinical stage consistent with resectable, borderline resectable adenocarcinomaof the pancreas, based on CT or MRI findings.

6. Have adequate organ and bone marrow function, as defined by

• total leukocytes >3 x103/μL.

• absolute neutrophil count (ANC) >1.5x 103/μL.

• hemoglobin >9 g/dL.

• platelets >100 x 10e3/μL.

• creatinine clearance >60 mL/min or creatinine <1.5 mg/dL.

• bilirubin: may be enrolled with an elevated total bilirubin providing currentelevated total bilirubin is shown to be in decline following a stent placementand is judged low enough to safely to begin their assigned chemotherapy regimenby the treating medical oncologist

• aspartate transaminases (AST/SGOT) and alanine transaminases (ALT/SGPT) <3 xupper limit of normal (ULN). At two weeks from biliary decompression, if thesubject's serum AST/ALT remains greater 3x ULN, but has demonstrated aprogressive decline, the subject may be enrolled into the trial and appropriatemodification and dose adjustments will be made to the assigned regimen.Eligibility of subjects whose AST/ALT remain elevated 3x ULN, withoutdemonstrating a downward trend, will be determined at the discretion of thetrial PIs.

7. Female patients must be postmenopausal (absence of menses for > 1 year), surgicallysterile or have a negative pregnancy test and use at least one form of contraceptionfor four weeks prior to Day 1 of the study, during study treatment and during thefirst four months after study treatment is discontinued. Male patients must besurgically sterile or use barrier contraception during the study and for four monthsafter the last dose of any study drug.

Definitions of Clinical Stages of PC Resectable PC

To include:

• No evidence of extrapancreatic disease.

• No evidence of tumor-arterial abutment (celiac, SMA [superior mesenteric artery] orHA [hepatic artery]).

• If tumor-induced narrowing of the SMV [superior mesenteric vein], PV [portal vein]or SMV-PV [superior mesenteric-portal vein] confluence is present, it must be < 50%of the diameter of the vessel.

• CA 19-9 < 5000.

Borderline Resectable PC

To include at least one of the following:

• Tumor abutment <180⁰ of the SMA or celiac axis.

• Tumor abutment or encasement (>180⁰) of a short segment of the HA.

• > 50% narrowing of SMV, PV or SMPV.

• Short-segment occlusion of the SMV, PV or SMV-PV with a suitable anatomy forreconstruction.

• CT or MRI findings suspicious for, but not diagnostic of, metastatic disease (basedon multidisciplinary assessment).

• Radiographically suspicious or biopsy-proven N1 disease (regional lymph nodesinvolved) from prereferral biopsy or EUS-guided FNA.

• CA 19-9 >5000 when bilirubin is < 2 mg/dL or >2 mg/dL and declining.

Locally Advanced Type A PC

To include at least one of the following:

• Between 180⁰-270⁰ encasement of SMA or

• > 180⁰ encasement of the celiac artery without extension to aorta and amenable toceliac resection or

• >180⁰ encasement of the hepatic artery with extension to the celiac artery andamenable to vascular reconstruction

Exclusion Criteria:

1. Has received chemotherapy and/or radiation within three years prior to studyenrollment.

2. Has any previous history of another malignancy (other than cured basal or squamouscell carcinoma of the skin or cured in situ carcinoma of the cervix or localizedprostate cancer with normal prostate specific antigen) within three years of studyenrollment.

3. Uncontrolled comorbidities including, but not limited to, ongoing or active seriousinfection, symptomatic congestive heart failure, unstable angina, unstable cardiacarrhythmias, psychiatric illness, excessive obesity (BMI >55) or situations thatwould limit compliance with the study requirements or the ability to willingly givewritten informed consent.

4. Known HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

5. Pregnant or breastfeeding patients or any patient with childbearing potential notusing contraception four weeks prior to treatment.