LDE225 With Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan for Untreated Advanced 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