The objective of this study is to estimate the R0 resection rate in patients with Resectable Pancreatic Ductal Adenocarcinoma (R-PDAC) as well as those with Resectable Pancreatic Ductal Adenocarcinoma (BR-PDAC) independently in response to neoadjuvant sequential therapy of combination nab-paclitaxel and gemcitabine followed by stereotactic body radiotherapy (SBRT).

Patients in both cohorts will receive a total of 3 cycles of neoadjuvant combination chemotherapy of nab-paclitaxel and gemcitabine, followed by re-staging CT scan, if re-staging CT does not show evidence of metastatic disease. Patients will receive SBRT and definitive surgical resection. Subsequently, patients will receive 3 cycles of adjuvant combination chemotherapy of nab-paclitaxel and gemcitabine. Each cycle of combination chemotherapy will be a total of 4 weeks. Patients will be evaluated for response at completion of the 3 cycles of neoadjuvant combination chemotherapy with CT scans of chest, abdomen and pelvis. Patients will undergo surveillance CT scan at 3-month intervals until evidence of disease progression.

Inclusion Criteria:

1. Histologically confirmed resectable or borderline resectable pancreatic adenocarcinoma.

2. No evidence of distant metastasis representing stage IV metastatic disease.

3. R-PDAC: No evidence of distant metastasis and tumor mass showing no extension to superior mesenteric artery (SMA) and hepatic artery. There must be a clearly defined fat plane between SMA and celiac axis. Patent superior mesenteric vein (SMV/portal vein (PV) with no distortion of venous architecture.

4. BR-PDAC: defined as localized PDAC with 1 or more of the following features: a) an interface between the primary tumor and superior mesenteric vein (SMV)-portal vein (PV) measuring 180o or greater of the circumference of the vein wall, and/or b) short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction and/or c) short-segment interface of any degree between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and arterial reconstruction and/or d) an interface between the tumor and SMA or celiac trunk measuring less than 180o of the circumference of the artery wall.

5. Age > 18 years old

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

7. Patients must have adequate bone marrow function:

   • Platelets >100,000 cells/mm3
   • Hemoglobin > 9.0 g/dL
   • Absolute Neutrophil Count > 1,500 cells/mm3

8. Patients must have adequate liver function:

   • aspartate aminotransferase (AST) and Alanine Aminotransferase (ALT) < 2.5 X upper limit of normal
   • Alkaline phosphatase < 2.5 X upper limit of normal, unless bone metastasis is present in the absence of liver metastasis
   • Total bilirubin < 1.5 mg/dL

9. Patients must have adequate renal function: creatinine <1.5 mg/dL is recommended; however, institutional norms are acceptable. Creatinine within institutional limits of normal or creatinine clearance (CrCl) > 50 mL/min calculated using the Cockcroft-Gault equation.

10. Women of childbearing potential and sexually active males must use an effective contraception method during treatment and for three months after completing treatment.

11. Negative serum or urine β-human chorionic gonadotropin (hCG) pregnancy test at screening for patients of childbearing potential.

12. Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE 4.03).

13. Ability to understand and willingness to sign a written informed consent.

Exclusion Criteria:

1. Patients with locally advanced surgically unresectable PDAC.
2. Patients with evidence of distant metastatic PDAC.
3. Prior chemotherapy or radiation therapy of any kind for treatment of pancreas adenocarcinoma.
4. Prior major surgery within 4 weeks of starting study drug administration.
5. Patient unable or not willing to perform all study related biopsies and blood draws for exploratory endpoints will not be enrolled on study as all study related procedures are mandatory.
6. Concomitant treatment with full dose warfarin (coumadin) is NOT allowed. However, treatment with low molecular weight heparin (LMWH) (such as enoxaparin or dalteparin) or rivaroxaban is allowed. Patients on full dose warfarin (coumadin) must be transitioned to either LMWH or rivaroxaban prior to administration of any study related drugs.
7. Recent or ongoing clinically significant gastrointestinal disorder (e.g., malabsorption, bleeding, inflammation, emesis, diarrhea >grade 1).
8. Patients with clinically significant cardiac disease (New York Heart Association Classification III or IV and cardiac arrhythmias not well controlled with medication), or myocardial infarction within the previous six months.
9. Serious, uncontrolled, concurrent infection(s) requiring antibiotics.
10. Pregnant or breastfeeding women: positive pregnancy test within 7 days of starting treatment.
11. Treatment for other carcinomas within the last five years, except cured non-melanoma skin and treated in-situ cervical cancer.
12. Participation in any investigational drug study within 4 weeks preceding the start of study treatment.
13. Patients with external biliary drains.