An open-label, single center study to determine the absorption, distribution, metabolism, and excretion (ADME) of a single oral dose of [14C]LDE225 (74 kBq) to healthy male subjects

LDE225 is a new investigational compound that may eventually be used for the
treatment of malignant tumors. LDE225 inhibits the activity of Smo that is
involved in the development of a wide range of malignancies. LDE225 is not
registered as a drug but has been given to humans before.

Primary:
To evaluate the extent of absorption of unchanged drug and total radioactivity
from available blood and plasma exposure, urinary, and fecal excretion data
To determine the mass balance, routes of excretion and extent of metabolism in
humans
To determine the pharmacokinetic parameters of total radioactivity, LDE225,
LGE899, and any other major metabolites as feasible

Secundary:
To generate metabolite profiles in plasma, urine and feces using accelerator
mass spectrometry, to identify the major metabolites, and to elucidate the
major metabolic pathways
To evaluate the systemic exposure to the major metabolites in plasma and
excreta, as feasible using reference standards and metabolite profiles
To evaluate the safety and tolerability of a single oral dose of 800 mg LDE225
plus tracer amount of 14C-radioactivity (74 KBq) to healthy male volunteers

This ADME study aims to provide understanding of absorption, pharmacokinetics,
distribution, metabolism and elimination
of 800 mg of LDE225+tracer amount of 14C (74 kBq) after a single oral dose in
healthy male subjects.

Procedures and assessments:
Screening and follow-up: physical examination, vital signs (weight, body
temperature, blood pressure), pulse rate, clinical laboratory (serum chemistry,
haematology and urinalysis), and ECG
Only at screening: demography, medical history, prior and concomitant
medication, HBsAg, anti HCV, anti-HIV *, alcohol and drug screen, body height
Repeated at entry op Day -1: alcohol and drug screen, physical examination,
vital signs (weight, body temperature, blood pressure), pulse rate, clinical
laboratory (serum chemistry, haematology and urinalysis), ECG

Blood samples:
For PK LDE225, total radioactivity and metabolite profiles: pre-dose and until
85 days post-dose, with a possible extension up to Day 183 post-dose, maximally
Pharmacogenetics: On Day -1

Urine collection:
For PK LDE225, total radioactivity and metabolite profiles: Day 1-22 and during
the 24 hr visits (Day 28-85 with a possible extension up to Day 183 maximally)

Feces collection:
For PK LDE225, total radioactivity and metabolite profiles: Day 1-22 and during
the 24 hr visits (Day 28-85 with a possible extension up to Day 183 maximally)

Vomitus collection:
For total radioactivity: up to 72 hrs post-dose.

One oral dose of 800 mg LDE225 plus tracer amount of radioactivity (74 kBq)
made up of 16 50 mg capsules.

The most important adverse events of LDE225 reported in previous clinical
studies were: nausea, decreased sense of taste, decreased appetite, fatigue,
vomiting, muscle pain, loss of hair, decreased weight, diarrhea, headache, lack
or loss of strength and energy, inflammation of the muscle, and pain in
extremity.

In this study radio labeled LDE225 will be used. The amount of radioactivity in
this dose will be 74 KBq (KBq = kiloBecquerel, this is a unit to express the
amount of radioactivity in the study drug). The average environmental
background radiation burden in The Netherlands is approximately 2 mSv per year
(mSv = miliSievert, this is the unit which indicates the burden on the human
body thus the effect on the human body of the amount of radioactivity
administered). The additional radiation burden in this study due to the
administration of 74 KBq 14C-labeled LDE225 is calculated to be negligible
(that is, less than the natural background radiation in one month).

Registration of adverse effects: During the entire investigation all adverse
effects will be documented.

Blood draw, indwelling canula: During this study approximately 700 ml of blood
will be drawn. It is anticipated that on Day -1 an indwelling canula will be
inserted for most of the blood sampling on Day 1 and 2. On the other days
during this study, blood will be drawn by direct puncture of the vein.

Collection of urine: A pre-dose urine sample of approximately 100 ml will be
collected at anytime before administration of LDE225 on either Day -1 or Day 1.
Further 24-hour urine samples will be collected on Day 1 until Day 22 and on
the 24-hour visits (Day 28-85 with a possible extension up to Day 183,
maximally).

Collection of feces: One stool sample will be collected at any time before
administration of LDE225 (within 48 hours prior to dosing). Further all feces
will be collected completely on Day 1 until Day 22 and on the 24-hour visits
(Day 28-85 with a possible extension up to Day 183, maximally)

Collection of vomitus: If a participant vomits within 72 hours following LDE225
dosing, the vomitus will be collected and analyzed to confirm the level of
radioactivity.

Heart trace (ECG*s): ECG*s will be made regularly.

Blood sample for DNA tests: On Day -1 a blood sample will be taken for possible
DNA tests.