FOLFIRINOX for Unresectable Locally Advanced and Borderline Resectable Pancreatic Cancer

FOLFIRINOX regimen was recently presented at an international oncology meeting and represents
a new standard in the treatment of metastatic pancreatic cancer for selected patients. With
improved overall survival (OS) and response rates (RR) in the metastatic setting, we
hypothesize that in patients with less tumor burden, this regimen will be safe and well
tolerated, improve OS, progression free survival (PFS), and RR, and improve resectability
rates, as compared to historical data from standard single agent gemcitabine therapy for
unresectable locally advanced (ULA) patients and standard radiation with concurrent 5
fluorouracil (5FU) chemotherapy for borderline resectable (BR) patients. While both ULA and
BR patients will be eligible for the present study, our primary objective concerns ULA
patients, and we plan to enroll 45 patients in this group.

Patients meeting eligibility criteria will be consented and treated with FOLFIRINOX every 2
weeks (1 cycle = 4 weeks = 2 treatments). Patients will undergo repeat imaging (CT or MRI)
every 2 cycles and reassessed for resectability of the tumor. All patients that are not able
to undergo surgical resection, due to insufficient down-staging or patient preference, will
continue on protocol-based therapy until disease progression, unacceptable toxicity, study
withdrawal, or death.

Inclusion Criteria:

- Biopsy confirmed adenocarcinoma of the pancreas.

- Measurable or non-measurable but evaluable (as determined by Response Evaluation
Criteria in Solid Tumors version 1.1 [RECIST 1.1]) unresectable locally advanced (ULA)
or borderline resectable (BR) disease that is not amenable to curative intent therapy.
Baseline CT abdomen and chest (or MRI abdomen) within 28 days prior to initiation of
FOLFIRINOX is required.

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

- No prior chemotherapy or chemoradiotherapy for pancreatic cancer.

- Age ≥ 18 years of age.

- Laboratory requirements at study entry:

- Hemoglobin ≥ 10 g/dL (transfusions are acceptable)

- absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelets ≥ 100 x 109/L

- Creatinine ≤ 1.5 x upper limit of normal (ULN), or creatinine clearance ≥ 50
mL/min (estimated by Cockcroft-Gault or measured)

- Total bilirubin ≤ 1.5 x ULN

- aspartate aminotransferase/Alanine Aminotransferase (AST/ALT) ≤ 3 x ULN

- Gamma-Glutamyl Transferase (GGT) ≤ 5 x ULN

- Life expectancy of at least 6 months.

- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test performed within 14 days prior to initiation of FOLFIRINOX.

- WOCBP and men must agree to use adequate contraception prior to study entry, for the
duration of study participation, and 8 weeks after the end of treatment.

- Before patient registration, written informed consent must be given.

Exclusion Criteria:

- Local recurrence or resectable recurrence of pancreatic cancer.

- Other malignancies within the past 3 years except for adequately treated cervical or
vulvar carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors
(Ta, Tis & T1). Any cancer curatively treated >3 years prior to entry is permitted.

- Hypersensitivity to 5FU, oxaliplatin or other platinum agent, or irinotecan or to
their excipients. Known dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.

- Participation in any investigational drug study within 4 weeks preceding the start of
study treatment. Patients are not permitted to participate in another investigational
drug study while being treated on this protocol.

- Cardiac disease: Congestive heart failure symptoms > class II New York Heart
Association (NYHA). Unstable angina (anginal symptoms at rest) or new onset angina
beginning within the last 3 months. Myocardial infarction within the past 6 months.
Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- History of or suspected Gilbert's Disease (baseline testing not required).

- Baseline peripheral neuropathy/paresthesia grade ≥ 1.

- Active hepatitis B, unless patient has been on stable meds for at least 2 months
(baseline testing not required).

- Active clinically serious infections (> grade 2).

- Any other hemorrhage/bleeding event > CTCAE Grade 3 within the 12 weeks prior to the
first dose FOLFIRINOX.

- Evidence or history of bleeding diathesis or coagulopathy. Note: If therapeutic
anticoagulation required, the investigator is encouraged to switch patient to (or
maintain on) low molecular weight heparin during the trial.

- Major surgery, open biopsy or significant traumatic injury within 8 weeks of first
study drug. A core pancreatic or liver biopsy does not preclude the patient from the
study.

- Unable or unwilling to discontinue use of ketoconazole or St John's wort. Use of
CYP3A4 enzyme-inducing drugs and strong CYP3A4 inhibitors is discouraged, but not
contraindicated.

- Active drug or alcohol abuse.

- Pregnant or lactating women.

- Psychological, familial, sociological or geographical condition potentially hampering
compliance with the study protocol and follow-up schedule; those conditions should be
discussed with the patient before registration in the trial.