LDE225 is a new medicine that blocks the Hedgehog (Hh) pathway. The Hh pathway is a cascade of molecular events that control cell growth and have been linked with the development of many human cancers, including pancreatic cancer. Information from research studies suggests that LDE225 in combination with FOLFIRINOX may help to stop the growth of cancer cells. In this research study, the investigators are looking to determine the maximum dose of LDE225 in combination that can be given safely to patients with locally advanced or metastatic pancreatic cancer.

Study medication will be given in cycles of 14 days. Subjects will keep a study drug diary for each treatment cycle. LDE225 capsules will be taken by mouth in the morning every day of each cycle.

On days 1-2 of each cycle, subjects will take LDE225 at the clinic followed by FOLFIRINOX intravenous infusion (through a vein).

Subjects will come to the clinic weekly for the first 5 weeks, then every other week (Week 7, 9, 11, etc.) and receive the following procedures:

Review of current medications and any side effects Physical exam Performance Status Blood tests (2 teaspoons of blood) Assessment of tumor (repeated every 8 weeks) ECG at week 3 and 5

Subjects will also have pharmacokinetic (PK) blood samples taken. PK samples are used to find out the amount of study medication in the blood. Each PK sample is about 1/2 teaspoon of blood. Subjects will have PK samples taken on:

Day 1 of Cycles 1, 2, 3, 4, 6, and 7 before the dose of LDE225 Day 1 of Cycle 5 - drawn before the first dose of LDE225 and at 1, 2, 3, 4, 5, and 6 hours Day 2 of Cycle 5: One PK blood sample

Inclusion Criteria:

• Histologically or cytologically confirmed locally advanced or metastatic pancreatic adenocarcinoma
• Previously untreated locally advanced or metastatic pancreatic adenocarcinoma. Pts newly diagnosed with metastatic recurrence after adjuvant therapy for resected disease are eligible, if completion of adjuvant therapy was > 8 months ago
• Measurable disease
• Adequate organ and marrow function
• Able to take oral drugs

Exclusion Criteria:

• Concurrent active primary or metastatic cancer other than superficial squamous cell or basal cell skin cancer
• Pregnant or breastfeeding
• Receiving any other standard or investigation anticancer agents, with the exception of hormonal therapy
• Prior chemoradiation to the primary pancreatic tumor unless there is a measurable distant site of disease
• Known CNS metastases
• History of hypersensitivity reactions to any components of the treatment regimen
• Known malabsorption syndromes
• Neuromuscular disorders
• Receiving other anti-neoplastic therapy concurrently
• Requires warfarin/Coumadin for therapeutic coagulation
• Receiving treatment with medications known to be moderate and strong inhibitors or inducers of CYP3A4/5
• Uncontrolled diarrhea
• Peripheral neuropathy > grade 1 due to any cause
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia other than chronic atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements
• HIV positive