Thte effect of acid reducing agents on the single dose pharmacokinetics of PQR309 and the absolute bioavailability, safety and tolerability of PQR309 following oral and intravenous administration in healthy subjects.

PQR309 is a new investigational compound that may eventually be used for the
treatment of cancer patients. The phosphoinositide 3-kinase
(PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is an intracellular
signaling pathway important in regulating the cell cycle. Therefore, it is
directly related to cell proliferation and cancer. PI3K and mTOR are proteins
that can be inhibited by PQR309, which may result in an inhibition of tumor
growth. PQR309 is not registered as a drug, but has been given to cancer
patients before. The other compound that will be given in this study is
ranitidine which is an approved drug and already available in the market under
several dosages and formulations. Ranitidine is an acid
reducing agent and is prescribed for the treatment of gastric and duodenal
ulcers.

The study will be performed in 3 groups, Group 1, 2 and 3. Group 1 will be
performed in 12 healthy non smoking male volunteers. Group 2 will be performed
in 12 healthy non smoking male volunteers and Group 3 will be performed in 14
healthy smoking male volunteers.

The actual study will consist of 3 treatment periods during which the
volunteers will stay in the clinical research center in Groningen. The time
interval between the different treatment periods is between 14 and 21 days. All
volunteers will need to come to the clinical research center on Day -5 of
Period 1, because on this day the order of all treatments will be randomly
assigned to all volunteers (also called randomization). Dependent on the
randomization of the treatments, they will need to come to the clinical
research center for an ambulatory visit on Day -5 of 2 of the 3 periods or all
3 periods.During the study the volunteers will take ranitidine at home. They
will receive instructions for home dosing and a diary in which they need to
record the time of each administration of ranitidine. They will be contacted
daily to check the administration of ranitidine.
The post-study screening will take place 21 - 28 days after administration of
the study compound in Period 3. The appointment for the post-study screening
will be made with you during the study. The participation to the entire study,
from pre-study screening until the post-study screening, will
be maximally 8 weeks.

Group 1:
Treatment A: 80 mg PQR309 once
Treatment B: 300 mg ranitidine once a day for 4 days, 300 mg ranitidine once,
80 mg PQR309 once
Treatment C: 150 mg ranitidine twicel, per day for 4 days, 80 mg PQR309 once,
150 mg ranitidine once

Group 2:
Treatment D: 80 mg PQR309 once (capsul) and 100 mg caffein once
Treatment E: 20 mg PQR309 oncel (iv) and 100 mg caffein once
Treatment F: 300 mg ranitidine once per day for 4 days.80 mg PQR309 once
(capsule), 300 mg ranitidine once

Group 3:
Treatment G: 80 mg PQR309 once (capsul) and 100 mg caffein once
Treatment H: 20 mg PQR309 once (iv) and 100 mg caffein once
Treatment I: 100 mg fluvoxamine once per day for 6 days, 80 mg PQR309 once
(capsul), 100 mg caffein once,
100 mg fluvoxamine oncel, 100 mg fluvoxaminen once per day for 12 days, 50 mg
fluvoxamine once a day for 2 days.

During the study various examinations are carried out that can be experienced
more or less stressful. Blood sampling, indwelling canula, heart tracing.