A phase II, randomized double-blind study of efficacy and safety of two dose levels of LDE225 in patients with locally advanced or metastatic basal cell carcinoma

Skin cancers are the most common malignancy in Europe, Australia and North
America. Basal-cell carcinomas (BCC) account for about 80%, and the incidence
rises in younger individuals. The worldwide incidence is increasing by 10% per
year. It is estimated that 1 in 3 Caucasians will develop BCC in their
life-time. Common causes for BCC are genetic predisposition and exposure to
ultraviolet radiation.
Although in most cases, BCC is not typically life-threatening, it is associated
with considerable morbidity: BCC or its necessary treatment (mainly surgical
excision and/or radiotherapy) can destroy the skin and surrounding structures,
causing severe disfigurement. In 90 to 95 % of the cases BCC is completely
cured. However recurrent, more aggressive, infiltrated or rare cases of
metastatic spread BCC are difficult to treat. There are currently no effective
systemic treatment options for these patients.
Almost all BCCs are dependent on aberrant Hedgehog (Hh) signaling for growth
and survival. Smoothened (Smo) is a receptor molecule that positively regulates
the Hedgehog (Hh) signal transduction pathway. Normally, the activity of Smo is
sufficiently repressed.
The inhibition of the Hh signaling pathway as a therapeutic approach has
increasingly become an area of extensive research, with several different
compounds currently been tested in labs and clinics. LDE225 is a potent
selective and orally bioavailable Smo antagonist from a novel structural class.
On the basis of the available data and the understanding of the role of Hh
signaling in the pathogenesis of BCC, it is anticipated that LDE225 could offer
a viable therapeutic option for this patient population.

The purpose of this phase II study is to assess the efficacy and safety of oral
treatment with two dose levels of LDE225, as measured by objective response
rate (ORR), in patients with locally advanced or metastatic BCC. Additional
assessments include safety, pharmacokinetics, other efficacy endpoints and
pharmacodynamic biomarkers.

This is a multi-center, adaptive, randomized double-blind Phase II study.
Approximately 120 patients will be needed. All enrolled patients will be
initially randomized in a 2:1 fashion to receive LDE225 at either 800 mg or 200
mg on a continuous once daily dosing schedule.
In order to ensure similar patient populations stratification will occur
according to the following prognostic factors:
* Stage of disease (locally advanced or metastatic) and
* For locally advanced BCC further stratification of aggressive or
non-aggressive
Patients will have tumor assessments with the appropriate radiological imaging
modality (CT or MRI) and color clinical photography (where appropriate).
Baseline tumor assessments must be performed * 21 days prior to starting study
treatment. After baseline (screening assessments), further tumor response
evaluations will be performed in week 5, 9 17 and subsequently once every 8
weeks during the first year and once every 12 weeks after the first year until
documented disease progression.
An interim analysis (IA) to assess the safety and efficacy of LDE225 will be
performed when the first 48 randomized patients have been treated for 16 weeks,
discontinued treatment or discontinued the study. The results of this IA
determine whether the remaining positions in each treatment arm will be filled
or that one or 2 treatment arms are dropped due to futility or poor
tolerability.
The primary analysis of study data will be conducted 24 weeks after the last
patient is enrolled. A final analysis of safety and efficacy will be performed
and the study will be unblinded at 78 weeks (18 months) following enrollment of
the last patient. After the final analysis, patients who have not experienced
disease progression and are still obtaining benefit from study treatment will
continue on the study with reduction in the frequency of the visits and
collection of limited efficacy and safety data.
Every effort will be made to obtain archival tumor specimens. 2ml of blood will
be collected for Hh pathway mutation analyses from all patients from whom tumor
sample are provided.
The study will include clinical and histological assessments (for patients with
locally advanced BCCs), assessment of activation of Hh pathway by mutation and
gene expression analysis, PK, hematology and blood chemistry laboratory
assessments, ECG, pregnancy testing and collection of adverse events. Optional
exploratory pharmacogenetic assessments are performed.

All enrolled patients will receive LDE225 at either 800 mg or 200 mg.

LDE225 is currently undergoing phase I evaluation in a first-in-human clinical
trial, to assess the safety, tolerability, PK, PD and potential efficacy of
continuous once daily oral administration in patients with malignant solid
tumors.
As of October 29, 2010, data were available on 76 patients with cancer who have
been treated with LDE225 at different dose levels up to 3000 mg once daily and
750 mg twice daily. Once daily administration of LDE225, up to 800 mg, has been
found to be well tolerated.
CTC grade 3 or 4 Adverse Events occurred at higher doses: increases in plasma
creatine phosphokinase (CK) associated with muscle pain, increased aspartate
amino transferase ,muscular weakness and increased plasma myoglobin. None of
the patients experienced impairment of renal function as a result of toxicity.
Following discontinuation of LDE225 therapy, resolution of these AEs was
observed over a period of up to 4 weeks in 12 patients, and over up to 8 weeks
in the remaining two cases.
Commonly (>10%) reported CTCAE grade 1 or 2 adverse events that are suspected
to be treatment-related include: nausea, vomiting, dysgeusia, decreased
appetite, myalgia, muscle spasms and fatigue. No treatment-related clinically
significant changes in the other safety laboratory data (hematology, and
urinalysis), vital signs or ECGs have been observed for any of the patients
treated in the studies.