An open-label, non-randomized, single-center, Phase I trial to investigate the mass balance and the metabolite profile of cilengitide in five healthy subjects

Cilengitide is a new investigational compound that may eventually be used for
the treatment of cancer. The compound reduces a part of the angiogenesis (the
growth of new blood vessels) limiting the growth of tumors. Cilengitide is not
registered as a drug but has been given to humans before.

Primary:
- To evaluate the mass balance of total 14C radioactivity, i.e. PK parameters
of cilengitide and potential metabolites,
- To quantify the route(s) of excretion in urine (14C and cilengitide) and
feces (14C),
- To profile potential metabolites of 14C-cilengitide in plasma, and
- To assess and compare the pharmacokinetic (PK) profiles of cilengitide and
total radioactivity in plasma, after a single dose of 2.2 MBq 14C-cilengitide
administered together with a single dose of 2000 mg of unlabeled cilengitide in
healthy subjects by a 1-hour intravenous (i.v.) infusion.

Secondary:
-To assess the safety and tolerability of cilengitide in healthy subjects.
-To assess the metabolite profile in urine and in feces.
-To structurally identify potential relevant metabolite(s).
-To determine blood/plasma ratio of total 14C radioactivity.

Exploratory:
- To determine the influence of genetic variants in genes potentially involved
in the pharmacokinetics of cilengitide.

The purpose of the study is to investigate how quickly and to what extent
cilengitide is distributed, metabolized (broken down) and eliminated from the
body (this is called pharmacokinetics). The compound to be administered will
be labeled with 14-Carbon (14C) and is thus radioactive. This enables the
investigator to trace the compound in blood, urine and feces. The safety and
tolerability of the compound will also be evaluated.

Screening and follow-up:
clinical laboratory, full physical examination, ECG; at eligibility screening:
medical history, drug screen, HBsAg, anti-HBc, anti HCV, anti-HIV 1/2

Observation period:
one period in clinic from -18 h up to 96 h after start of drug administration
with possible extension to 144 h, 192 h, 240 h. Additional ambulatory visits
possible on Days 13 and 15.

Blood sampling:
Plasma samples for determination of total radioactivity will be taken at
pre-dose, 0.5 h after SOI (Start Of Infusion), 1 h (at EOI (End Of Infusion)),
2 h, 4 h, 6 h, 12 h and 24 h, after SOI, and every further 12 h after SOI until
96 hours after administration, and, if necessary every 24 h until
End-of-Hospitalization as defined above. Whole Blood samples for determination
of total radioactivity will be taken at 0.5 h, 1 h (at EOI), 2 h, 4 h, 6 h, and
12 h after SOI. Plasma samples for determination of cilengitide will be taken
at pre-dose, 0.5 h after SOI, 1 h (at EOI), 2 h, 4 h, 6 h, 12 h, and 24 h after
SOI.
Plasma samples for metabolite profiling will be taken at pre-dose, 1 h (at
EOI), 2 h, 4 h, 6 h, 12 h, 24 h, and 96 h after SOI.

Urine sampling:
Urine samples will be collected before dosing (-12 to 0 h) and at 0-4 h, 4-8,
8-12, 12-24 h after SOI. Collection will continue in further 12-hour intervals
until 96 h after SOI and in 24-hour intervals until End-of-Hospitalization as
defined above.

Feces sampling:
Feces samples will be taken before dosing and every 24 hours after SOI until
End-of-Hospitalization as defined above. If release criteria are not met at
End-of-Hospitalization, subject will be asked to continue collecting urine and
feces at home and hand in the samples every 2nd day.

Safety assessments:
AEs, CM, from inclusion until follow-up, 12-lead ECG, vital signs, clinical
laboratory, at screening, pre-dose, and 1 h, 5 h, 24 h, and 48 h after start of
infusion and at discharge on Day 5, if the stay is prolonged at Day 7 and 9
when relevant, physical examination at screening, end of hospitalization and
follow-up.

One intravenous infusion of 2000 mg 14C labeled cilengitide in 250 ml over 60
minutes

The additional radiation burden in this study due to the administration of 2.2
MBq 14C-labeled cilengitide is calculated to be approximately 0.5- 0.7 mSv.
This is approximately 25 % of the average annual radiation burden and can be
compared with two return flights to Australia.

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

Blood draw, indwelling canula: During this study less than 500 ml of blood will
be drawn. It is anticipated that an indwelling canula will be used on Day 1 and
regular blood draws will be drawn by direct puncture of the vein. It is
anticipated that a maximum of 19 punctures will be done with a volume of 8.2 mL
each.

IV dosing: For the iv administration you will have an indwelling canula
inserted specifically for this purpose in addition to the indwelling canula
used for blood sampling on Day 1. Thus you will have a canula inserted in both
arms during dosing. The canula for the infusion will be removed immediately
after dosing.

Collection of urine and feces: Urine and feces will be collected until 96 hours
after administration of cilengitide (thus until Day 5) with a possible maximum
extension to Day 11 (240 hours).

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

Blood sample for DNA tests: For general information on DNA tests, please refer
to section 4.6 of the information booklet. On Day 1 a blood sample of 6 mL will
be taken for DNA tests. Participation in this part of the study is mandatory
and double coding will be used. This means that the blood samples will be given
a first code assigned to you at the start of the Main Study (your coded trial
subject number). Specific Sponsor personnel will assign a second code
(double-coding) to these blood samples, only they will have the link between
the two codes. The laboratory analyzing your blood will only use your second
code and will not have access to the first code or the link to the first code.