LDE225 in Patients With Advanced or Metastatic Hepatocellular Carcinoma and Child-Pugh A/B7 Cirrhosis

This is an open-label, single institution, Phase I, 3+3 dose escalation study of LDE225 in
patients with advanced or metastatic hepatocellular carcinoma and Child-Pugh A Cirrhosis who
are intolerant to sorafenib. The investigational treatment cycle (21 days) will consist of
daily oral LDE225.

Dose escalation will be performed in serial patient cohorts. Up to six patients can be
studied at each dose level. Safety and clinical data will be tabulated and the decision to
open the next cohort level will be the responsibility of the principal investigator. Dose
escalation will be based on the dose-limiting toxicities encountered through Day 42 of
investigational treatment.

Patients will be dosed on a flat scale of daily dosing of LDE225 prescribed by the dose
cohort.

Inclusion Criteria:

- Age 18 years or older

- Pathological confirmation of advanced or metastatic HCC

- HCC not amenable to surgical resection, liver transplantation, chemoembolization, or
ablation therapy

- Patients with Child-Pugh A and Child-Pugh B7 (if due to low albumin but not elevated
INR or bilirubin) cirrhosis are allowed.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- At least one measurable site of disease (as defined by Response Evaluation Criteria in
Solid Tumors)

- Patients with adequate bone marrow, liver and renal function

- Inability to tolerate first-line treatment with sorafenib

- Patient amenable to liver tumor biopsy

Exclusion Criteria:

- Child-Pugh B or Child-Pugh C cirrhosis

- Patients with known Gilbert's Syndrome

- Ongoing alcohol use or abuse defined as > an average of 2 alcoholic beverages daily

- Patients who have had major surgery within 4 weeks of initiation of study medication

- Patients with known brain metastases

- Patients with concurrent uncontrolled medical conditions that may interfere with their
participation in the study

- Patients with known human immunodeficiency virus (HIV) or acquired immunodeficiency
syndrome (AIDS)-related illness

- Patients with Hepatitis B and/or Hepatitis C infection are excluded if they are on any
of the following viral suppressive agents: boceprevir (Victrelis), ribavirin (Rebetol,
Ribatab, Ribasphere), telaprevir (Incivek)

- Patients unable to take oral drugs or with lack of physical integrity of the upper
gastrointestinal tract or known malabsorption syndromes

- Patients who have previously been treated with systemic LDE225 or with other Hh
pathway inhibitors

- Patients who have neuromuscular disorders or are on concomitant treatment with drugs
that are recognized to cause rhabdomyolysis

- Patients who are planning on embarking on a new strenuous exercise regimen after
initiation of study treatment

- Patients who have taken part in an experimental drug study within 4 weeks of
initiating study treatment with LDE225

- Patients who are receiving other anti-neoplastic therapy concurrently or within 2
weeks of starting study treatment with LDE225

- Patients who are receiving any anti-coagulation or anti-platelet therapy

- Patients who are receiving treatment with medications known to be strong inhibitors or
inducers of cytochrome P450 3A4 (CYP3A4/5) or drugs metabolized by cytochrome P450 2B6
(CYP2B6) or cytochrome P450 2C9 (CYP2C9) that have narrow therapeutic index, and that
cannot be discontinued before starting study treatment with LDE225

- Impaired cardiac function or clinically significant heart disease

- Patients with contraindications for MRI and/or MRI contrast agents

- Pregnant or nursing (lactating) women

- Women of child-bearing potential must use highly effective contraception during the
study and through 6 months after the final dose of study treatment

- Sexually active males who are unwilling to use a condom during intercourse while
taking drug and for 6 months after stopping investigational medications and agree not
to father a child in this period