Borderline Pancreas Study: FOLFIRINOX +SBRT

The study investigators hypothesize that neoadjuvant FOLFIRINOX can be safely and
efficaciously delivered using a sequential regimen with SBRT as an alternative to standard
neoadjuvant chemoradiotherapy. Standard of care neoadjuvant treatment typically requires
about six weeks of treatment with sub-systemic dosing of chemotherapy. The feasibility of the
sequential delivery of the FOLFIRINOX followed by SBRT will be evaluated by capturing the
prevalence of grade 3 toxicity and the treatment delay rate.

In our study, SBRT is planned sequentially to follow cycle 4 of chemotherapy treatment,
provided toxicity has resolved to grade 2 or less. Thus, allowing for resolution of
chemotherapy toxicity prior to initiation of radiation therapy. This interval and the fact
that there is no concurrent delivery of chemo-RT, based on previously discussed experiences,
including approaches where SBRT safely follows other intense chemotherapy regimens (see
Polistina et al and Chuong [35,36]) makes this study feasible without establishing toxicity
profile.

The proposed regimen of 4 cycles of FOLFIRINOX followed by 30 Gy/5 fractions using SBRT will
be safely tolerated and will improve resectability rates in borderline resectable PDAC
patients. In addition, this regimen will not compromise the ability to achieve a successful
Whipple resection.

This regimen will improve the local control rate and overall disease free survival in this
patient population. The investigators further hypothesize that early administration of
FOLFIRNOX will provide optimal systemic therapy to control clinically occult micrometastases.

Inclusion Criteria:

- ≥ 18 years at diagnosis.

- Biopsy proven pancreatic adenocarcinoma.

- Borderline resectable per NCCN criteria (No distant metastases, venous involvement of
the portal vein/SMV, demonstrating tumor abutment and narrowing of the lumen,
encasement of the portal vein/SMV without encasement of the nearby arteries, or
short-segment venous occlusion resulting from either tumor thrombus or encasement but
with suitable vessel proximal or distal to this area of vessel involvement, allowing
for safe resection and reconstruction; gastroduodenal artery encasement up to the
hepatic artery with either short segment encasement or direct abutment of the hepatic
artery, without extension to the celiac axis; tumor abutment of the SMA not to exceed
180 degrees of the circumference of the vessel wall.).

- Radiologically measurable or clinically evaluable disease.

- Pancreas protocol CT and/or MRI if required for further clarification of disease
tissue planes within 4 weeks of registration.

- ECOG PS of 0-2.

- Able to get a Whipple resection per surgeon assessment performed within 4 weeks of
registration.

- The following laboratory values obtained ≤ 28 days prior to registration:

- Absolute neutrophil count (ANC) ≥ 1,500/mm3.

- Platelet count ≥ 100,000/mm3.

- Hemoglobin > 8.0 g/dL.

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN).

- SGOT (AST) ≤ 2 x ULN.

- SGPT (ALT) ≤ 2 x ULN.

- Creatinine ≤ 1.5 x ULN.

- CA 19-9 level (to establish baseline).

- A negative pregnancy test within 7 days prior to registration for women of
childbearing potential. In addition, male and female participants must commit to
adequate contraception while on study.

- Able to provide written informed consent.

- Willing to return for all required study assessments.

- Neurological assessment for pre-existing peripheral neuropathy.

- Documentation of pre-existing hearing deficits.

Exclusion Criteria:

- Any pancreatic adenocarcinoma that does not meet criteria for borderline resectable
disease.

- Prior history of abdominal radiation therapy.

- History of autoimmune disease such as scleroderma, lupus, and inflammatory bowel
disease.

- Patients with tumor-caused symptomatic bowel obstruction.

- Chemotherapy (including hormonal therapy) within the past 5 years from date of
registration.

- Other invasive malignancies within the past 5 years from date of registration.

- Pregnant or nursing women or women of childbearing age that are unwilling to employ
adequate contraception.

- Other co-morbid conditions which, based on the judgment of the physicians obtaining
informed consent, would make the patient inappropriate for this study.