A Study of Neoadjuvant FOLFIRINOX and FDR-Gemcitabine With Concurrent IMRT in Patients

Gemcitabine has been the cornerstone of systemic therapy for pancreas cancer over this past
decade. Recently, a combination of 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX)
was reported to have significant efficacy in advanced pancreatic cancer. Preclinical data
suggests synergy between irinotecan and 5FU as well as between oxaliplatin and 5FU. Results
of a phase II trial in advanced disease were reported in 2005 demonstrating a 26% confirmed
response rate and median overall survival of 10.2 months. A follow-up phase III trial
comparing FOLFIRINOX with gemcitabine for patients <75 years of age with advanced pancreatic
cancer was presented at ASCO 2010 revealing improvement in PFS (6.4 vs 3.3 months, p=<.0001)
and improved disease control rate (CR+PR+SD) (70.2% vs 50.9%, p=.0003). The most notable
result was an impressive improvement in median overall survival with FOLFIRINOX compared to
gemcitabine (11.1vs 6.8 months, p-value = <.0001, HR=.57). The main toxicity was grade 3/4
neutropenia (45.7% vs 18.7%, p=.0001) and increased risk of febrile neutropenia (5.4% vs
0.6%, p=.009)31.

Inclusion Criteria:

- Patients must have cytologic or histologic confirmation of carcinoma arising in the
pancreas.

- Patients must be deemed to have borderline resectable disease with no radiologic
evidence of distant metastatic disease prior to registration.

- Specifically, patients must have at least one designation of borderline resectable and
no designation of unresectable disease.

- Patients must have a life expectancy of at least 12 weeks, a Zubrod performance status
of < 1 and be willing and medically able to undergo surgical resection.

- Patients must have adequate organ function defined as follows: absolute neutrophil
count of > 1500/mm3, platelets > 100,000/mm3, serum Cr < 1.5 mg/dl, total bilirubin <
2.0 mg/dl with relief of biliary obstruction if present (PTC tube or endobiliary
stent).

- Patients must be free of other active systemic malignancy, ongoing infection, or any
other serious uncontrolled, concomitant systemic disorders or psychiatric condition
that would interfere with the safe delivery of protocol therapy.

- Patients of reproductive potential must agree to use an effective contraceptive method
during participation in this trial due to the unacceptable teratogenic toxicity of
abdominal radiation and cytotoxic chemotherapy.

- Patients must be aware of the investigational nature of the therapy and provide
written informed consent.

Exclusion Criteria:

- Patients with neuroendocrine tumors are excluded.

- Active systemic malignancy, ongoing infection, or any other serious uncontrolled,
concomitant systemic disorders or psychiatric condition that would interfere with the
safe delivery of protocol therapy.

- Patients with preexisting peripheral neuropathy > grade 2 are ineligible

- Pregnant or nursing women are ineligible.

- Patients must have no history of previous chemotherapy for pancreatic cancer or any
abdominal radiation therapy.

- Patients may not have used any investigational agent within 4 weeks prior to
enrollment into the study.