Gemcitabine + Nab-paclitaxel With LDE-225 (Hedgehog Inhibitor) as Neoadjuvant Therapy for Pancreatic Adenocarcinoma

The investigators propose treating 6-12 patients during the phase 1 portion and 40 patients
in the phase 2 stage.

Phase 1 Stage:

1. Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in
combination with escalating doses of LDE-225. After completion of neoadjuvant therapy, the
subjects will receive combined chemotherapy and radiation. Then subjects who are eligible for
resection will go ahead with surgery. Following resection, subjects will complete two
additional cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 in combination with
LDE-225.

Phase 2 Stage: In the Phase 2 stage the patients will be randomized to receive gemcitabine
and nab-paclitaxel with or without the hedgehog inhibitor LDE225:

1. Arm A: Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m on days 1, 8
and 15 in combination with LDE-225 at the recommended phase 2 dose.

2. Arm B: Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m on days 1, 8
and 15.

After completion of neoadjuvant therapy, the subjects will receive combined chemotherapy and
radiation. Then subjects who are eligible for resection will go ahead with surgery. Following
resection, subjects will complete two additional cycles of the pre-surgical therapy.

Several correlative laboratory studies will be conducted during the course of this study.
They were designed around the goals of providing us with a better understanding of how the
stroma-tumor interaction and the intra-tumoral drug levels of gemcitabine are affected with
the use of LDE-225. Two additional biopsies are required to participate in this study.

Inclusion Criteria:

.Histologically or cytologically confirmed adenocarcinoma of the pancreas.

- Must have borderline resectable pancreatic adenocarcinoma

- Measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension

- No previous radiotherapy, surgery, chemotherapy or investigational drug therapy.

- Age >18 years .Life expectancy of greater than 1 month.

- ECOG performance status 0 or 1

- Adequate organ and marrow function .Asymptomatic for jaundice and ascites. Pain
symptoms should be stable.

- Negative serum pregnancy test

- Sexually active males should agree to use a barrier form of contraception, even if
they have had a vasectomy, during the study and for 6 months after stopping LDE225.
Males should not donate sperm during treatment, and for up to six months after last
dose. Sexually active females of child bearing potential agree to using highly
effective contraception during study and for 20 months after final dose of LDE225.

.Agree not to donate blood products for 12 months after stopping LDE225. .Willing to have
two biopsies while on treatment for correlative studies.

Exclusion Criteria:

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to LDE225 or other agents used in the study.

- Patients taking medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

- Uncontrolled illness including, but not limited to, ongoing or active infection
requiring IV antibiotics, symptomatic congestive heart failure not controlled with
medication, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.

- Pregnant women are excluded

- Patient has undergone a major surgery, other than diagnostic surgery within four weeks
prior to starting treatment on this study.

- Patients who are receiving treatment with medications known to be moderate and strong
inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have
narrow therapeutic index, and that cannot be discontinued before starting treatment
with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued at
least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting
treatment with LDE225. .Patients with neuromuscular disorders. .Patients with impaired
cardiac function.