The purpose of this study is to determine the maximum tolerated dose of the chemotherapy drugs nab-paclitaxel and gemcitabine when combined with hypofractionated ablative proton therapy for the treatment of locally advanced pancreatic cancer. You will receive proton therapy once a day (Monday - Friday) for 3 weeks. Participants will also receive chemotherapy on each Monday of those three weeks.

The investigators propose a phase I trial to determine the maximum tolerable dose (MTD) and the recommended dose for phase II (RP2D) of concurrent nab-paclitaxel + gemcitabine in combination with ablative IMPT delivered as a fixed dose of 67.5 Gy in 15 fractions daily fractions with 5 fractions per week. In contrast to prior pancreatic cancer studies of chemoradiotherapy which utilized photon RT to treat gross disease and elective lymph nodes (1,2) the proposed study is hypothesized to reduce toxicity risk by limiting highly conformal IMPT to the gross tumor volume. Furthermore, to increase the margin of safety in a manner similar to published data from MDACC (3), the high dose region will be limited to areas at least 5 mm from nearby GI structures (duodenum, small bowel, stomach, etc.). Regions within this area will be treated only to 37.5 Gy in 15 fractions. This dose limitation is also important given that paclitaxel, in addition to increasing systemic efficacy, is a known radiosensitizer (1).

Inclusion Criteria:

1. Cytologic or histologic proof of adenocarcinoma of the pancreas.
2. Nonmetastatic pancreatic cancer. Metastatic disease includes spread to distant (non-regional) lymph nodes, organs, peritoneum and ascites.
3. Unequivocal radiographic findings contraindicating resection including, but not limited to, solid tumor contact with any of the following: 1) the SMA >180º; 2) the celiac axis >180º; 3) the first jejunal superior mesenteric artery (SMA) branch; 4) unreconstructible superior mesenteric vein (SMV)/portal vein due to tumor involvement or occclusion; 5) the most proximal draining jejunal branch into the SMV.
4. ECOG Performance Status 0 or 1.
5. Absolute neutrophil count ≥1,000/mm3
6. Platelet count ≥100,000/mm3
7. Creatinine ≤1.5 × upper limit of normal
8. Calculated creatinine clearance >45 mL/min
9. Total bilirubin ≤2 mg/dL

Exclusion Criteria:

1. Patients with resectable or borderline resectable pancreatic cancer are ineligible.
2. No prior definitive resection of pancreatic cancer.
3. No prior radiation therapy to the abdomen that would overlap fields required in this study. Prior radiotherapy for other disease is allowed.
4. No prior chemotherapy except for FOLFIRINOX, Gem-Abrax, or Gem-Cap. A patient may be registered for the trial while undergoing chemotherapy.
5. Any grade 4 toxicity prior to start of chemoradiotherapy that may be due to induction chemotherapy.
6. Greater than 2 dose reductions during induction chemotherapy.
7. Chronic concomitant treatment with strong inhibitors of CYP3A4. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to the start of study treatment. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.
8. Baseline Grade ≥ 2 neuropathy. Known Gilbert's disease or known homozygosity for UGAT1A1*28 polymorphism.
9. Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 14 days of study entry if they are in childbearing years/premenopausal.
10. Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with gemcitabine and nab-paclitaxel.
11. Non-compliance with induction chemotherapy.