Neoadjuvant Therapy Followed by Stereotactic Body Radiotherapy (SBRT) for Locally Advanced Pancreatic Cancer

We want to find out what effects, good and bad, using chemotherapy combinations modified
FOLFIRINOX (Oxaliplatin, Irinotecan, and fluorouracil) OR gemcitabine plus nab-paclitaxel
(Gem-ABRAXANE) and radiation using Stereotactic Body Radiation Therapy (SBRT) have on the
cancer and to increase the percentage of patients who can have surgery to remove their
disease. SBRT is a short course of high dose precisely delivered radiation. The two
combination chemotherapy routines (mFOLFIRINOX or GEM-ABRAXANE) have been shown in previous
clinical trials to be the most effective FDA approved chemotherapy in wide spread pancreatic
cancers. These chemotherapy drugs will be given before the surgery. Radiation Therapy, using
the 5 ½ week method as well as SBRT has been used as standard of care and found to be
effective to reduce the size of pancreatic cancer, so patients can have surgery.

SBRT uses advance techniques to deliver radiation therapy which minimizes the volume of
normal tissue receiving high dose radiation while maximizing the dose to the tumor. The use
of SBRT spares normal tissue and reduces the side effects of radiation. By being more
precise, and using a higher dose of radiation per treatment, the radiation delivery time can
be decreased to about one week. When this chemotherapy followed by SBRT is combined in this
order, this routine has the potential to treat both the primary disease, as well as to
prevent the early spread of disease. It is hoped that the treatment routines in this study
will increase the percentage of patients who can proceed to have surgery to remove their
tumor.

This combination of chemotherapy drugs, mFOLFIRINOX or GEM-ABRAXANE and the sequence of
chemotherapy followed by SBRT- the shorter course of radiation has not been studied
previously and is considered investigational.

Inclusion Criteria:

- Histologically or cytologically proven adenocarcinoma of the pancreas. Patients with
mixed tumor with predominant adenocarcinoma pathology can be enrolled

- Subjects will be staged according to the 2010 American Joint Committee on Cancer
(AJCC) staging system with pathologic stage T1-4, being eligible; and have a primary
tumor of the pancreas (either pancreatic head, neck, uncinate process, or body/tail)

- The tumor must be deemed as being borderline/unresectable. Final CT confirmation of
surgical staging/eligibility will be at the discretion of the pancreatic surgeon of
the patient

- Disease must be confined to loco-regional site as confirmed by CT imaging and / or
diagnostic staging laparoscopy to avoid occult peritoneal deposits Diagnostic
laparoscopy will be performed only if absolutely required

- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) on
imaging studies CT

- Karnofsky performance status greater than or equal to 70 or Eastern Cooperative
Oncology Group (ECOG) performance of 0-2

- Age > 18

- Estimated life expectance > 12 weeks

- If female patient is of child bearing potential, she must have a negative serum
pregnancy test (βhCG) documented up to 72hrs prior to administration of first study
drug

- Patient has screening blood work performed which includes the following (should be
drawn ≤ 14 days prior to enrollment):

- Absolute neutrophil count (ANC) > 1.5 x 109/L

- Platelet count ≥ 100000/mm3

- Hemoglobin (HgB) ≥ 9g/dL

- Aspartate aminotransferase (AST), Alanine Aminotransferase (ALT)≤ 2.5 x upper limit of
normal (ULN) Total Bilirubin ≤ 1.5 ULN

- Serum Cr within normal limits (WNL)

- Prothrombin Time and International Normalized Ratio (PT/INR) and Partial
Thromboplastin Time (PTT) within normal limits (±15%).

- Disease must be encompassed in a reasonable SBRT "portal" as defined by the treating
radiation oncologist

Exclusion Criteria:

- Ineligible Histology including non-adenocarcinomas, adenosquamous carcinoma, islet
cell carcinomas, cystadenomas, cystadenocarcinomas, carcinoid tumors, duodenal
carcinomas, distal bile duct and ampullary carcinomas

- Patients must not have received prior pancreatic surgery, radiation therapy,
chemotherapy or any investigational therapy for pancreatic cancer

- Patients with tumors extending or invading duodenum or gastric are not eligible

- Evidence of distant metastasis on upright chest x-ray, CT or other staging studies

- Subjects with recurrent disease are not eligible

- Prior radiation therapy to the upper abdomen or liver at the discretion of the
treating radiation oncologist could impair delivery of the prescribed radiation
treatment

- Patients with scleroderma, ulcerative colitis or other systemic conditions deemed
risky for radiation treatment. Therefore, will be excluded.

- Prior chemotherapy

- Subjects in their reproductive age who are breast feeding or have a positive pregnancy
test

- Any co-morbid condition such as but not limited to congestive heart failure, cardiac
arrhythmia or psychiatric illness of sufficient severity to limit full compliance with
the protocol per assessment by the individual treating physician

- Concurrent active infection

- No prior malignancy allowed except cervical cancer in situ, adequately treated basal
cell or squamous cell carcinoma of skin or treated low risk prostate cancer

- Patient with known historical or active infection with HIV, Hepatitis B or Hepatitis C

- Patient who has undergone recent major surgery, other than diagnostic prior to
enrollment

- Patient who has a history of allergy or hypersensitivity to any of the study drugs

- Patients with a history of interstitial lung disease, history of slowly progressive
dyspnea and unproductive cough, sarcoidosis, silicosis, interstitial pulmonary
fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies

- Patients with greater than grade 2 peripheral neuropathy at the time of enrollment are
not eligible