Single center, open-label, non-randomized, non-placebo-controlled study to investigate the metabolism, excretion pattern, mass balance, safety, tolerability and pharmacokinetics after single administration of 200 mg [14C]rogaratinib (oral solution) in healthy male subjects

Rogaratinib is a new compound that may eventually be used for the treatment of
tumors. Fibroblast growth factors (FGF) and fibroblast growth factor receptors
(FGFR) are specific proteins that play an important role in cell proliferation,
survival and migration. Rogaratinib is an inhibitor of FGFR1, 2, 3 and 4. In
this way, rogaratinib may be used as a treatment of tumors. Rogaratinib is in
development and it is not registered as a drug but has been given to humans
before.

The purpose of this study is to investigate how quickly and to what extent
rogaratinib is absorbed, distributed, metabolized (broken down) and eliminated
from the body (this is called pharmacokinetics). Rogaratinib will be labelled
with 14 Carbon (14C) and is thus radioactive (also called radiolabeled). In
this way rogaratinib can be traced in blood, urine and feces. It will also be
investigated how safe rogaratinib is and how well it is tolerated when it is
administered to healthy male volunteers.

A study to investigate the absorption, distribution, metabolism and excretion
(ADME) of rogaratinib in healthy male volunteers. Rogaratinib is a new compound
developed for the treatment of tumors

The volunteer will receive a single dose of 200 mg/3.7 MBq radiolabeled
rogaratinib as an oral solution. Thereafter the volunteer is also required to
drink an additional amount of 100 mL of non-sparkling water.

The study will consist of 1 period during which the volunteerr will stay in the
PRA research center at the Martini Hospital location for up to 16 days (15
nights): from Day -1 up to Day 15.

Day 1 is the day of administration of the study compound. The volunteer is
expected at the research center at 14:00 h in the afternoon prior to the day of
administration of the study compound (on Day -1).

The duration of the stay in the research center will depend on the amount of
radioactivity left in urine and feces at the end of the study (Day 15). The
amount of radioactivity in urine and feces will be measured daily from Day 1
onwards. If, from Day 8 onwards, the radioactivity levels in urine and feces
are below the pre-defined levels, the volunteer will be allowed to leave the
research center at an earlier day. From Day 8, this will be communicated with
the volunteer on a daily and per person basis. If the radioactivity levels are
still above the pre defined levels on Day 15, the volunteer will be required to
come back to the research center after 7 days for a stay of 2 days (1 night).
For this overnight stay, the volunteer is expected at the research center at
11:00 h in the morning and will leave the research center after 24 hours. If
necessary, this procedure will then be repeated every 7 days until the
radioactivity levels are below the pre-defined levels. For a maximum of 4 times
the volunteer will visit the research center for a stay of 2 days (1 night).

The volunteer will receive a single dose of 200 mg/3.7 MBq radiolabeled
rogaratinib as an oral solution. Thereafter you are also required to drink an
additional amount of 100 mL of non-sparkling
water.

Administration of a single dose of 200 mg of rogaratinib is not expected to
cause any clinically relevant side effects, however they cannot be entirely
excluded.

The side effects that are described in the following information have been
observed after administration of multiple and higher doses of rogaratinib
either in animal studies (which can be transposed to humans only to a limited
extent), or in the 2 clinical studies in human subjects (studies 16443 and
16958) in which 118 patients with cancer have been treated to date.

In the animal studies, it was observed that the use of rogaratinib may cause
abnormal calcium deposits in soft tissues of the body (for example in the
lungs, stomach, trachea (breathing tube), skin and cartilage). This is known as
soft tissue mineralization and this represents the most important potential
risk associated with the use of rogaratinib.

Although soft tissue mineralization has not been observed in any patient
treated with rogaratinib, it is known that the risk of this increases with
abnormally high phosphate and abnormally high calcium in the blood. Therefore,
the responsible doctor will monitor the levels of phosphate and calcium in
volunteers blood and the overall health whilst you are receiving rogaratinib.

If the volunteers blood phosphate level is above normal, it might be necessary
to take blood samples more often than once a week, for as long as the phosphate
in the blood remains high. The responsible doctor can also give the volunteer
other medicine called *phosphate binders* to reduce the blood phosphate level.
This would reduce the risk of soft tissue mineralization.

Also, additional ECGs (heart trace) will be taken to monitor the heart function
if volunteers blood calcium level is found to be abnormal. The results from
blood samples and ECGs taken during the study will support the responsible
doctor to determine whether the volunteer is at risk for soft tissue
mineralization or cardiac side effects.

In the clinical studies in human subjects, mostly mild or moderate adverse
events (untoward medical occurrences) were observed in patients during the
treatment with rogaratinib. The very common adverse events (> 10 % of treated
patients) were:
• An abnormally high level of phosphate in the blood
• Gastro-intestinal disorders such as diarrhea, nausea and constipation
• Nail disorders (nail deformity, discoloration and nail loss)
• Decreased appetite
• Feeling tired (fatigue)
• Anemia (decrease in the total amount of red blood cells or hemoglobin in the
blood)
The high phosphate in the blood, the diarrhea and nail disorders are regarded
to be caused by rogaratinib.

Furthermore, a detachment of retinal pigment epithelium (a layer of the
light-sensitive structure in the eye) was found in some patients treated with
rogaratinib. Therefore, eye examinations will be performed prior and after
participation in the study to monitor volunteers eye health.

The data collected in the 118 patients to date, indicates that rogaratinib is
removed from the body via the urine only in small amounts. Therefore, it is not
expected that rogaratinib will significantly accumulate in the body in patients
with impaired kidney function. To date, 2 patients have experienced impairment
of their kidney function, which recovered back to normal within a few days
after sufficient fluid intake. No kidney function impairment re-occurred in
these patients after the treatment with rogaratinib was resumed. Currently, no
difference in behavior of rogaratinib in the body is expected in patients with
mild or moderate kidney impairment versus patients with healthy kidneys. The
responsible doctor will monitor the values reflecting volunteers kidney
function and the overall health continuously with regular blood samples and
urine tests.

As rogaratinib is an experimental drug, it is also possible that more and/or
other side effects may occur in humans that have not been observed before.

While on the study, the volunteer may experience diarrhea or vomiting.
Therefore, oral intake of adequate amount of water is recommended.

The study drug contains lactose as a filler, but in such a small amount that no
side effects are expected in patients with slight or moderate lactose
intolerance. The volunteer should inform the responsible doctor if he is
subject to lactose intolerance. The doctor will then decide if the volunteer
can be treated.

Up to now the results of 135 cancer patients, who received multiple dose
administrations between 50 and 800 mg rogaratinib twice daily have been
reported. In these patients the following complaints and abnormalities have
been recorded: an increase in the concentration of phosphate in the blood,
diarrhea, a decreased appetite, fatigue, nausea, constipation, anemia and dry
mouth. Also, some reports have been made of increases in liver enzyme
activities, decrease of the concentration of sodium in the blood, decrease of
the number of neutrophil cells (a subgroup of the white blood cells) in the
blood, lung infection, urine tract infection, alopecia (hair loss), arthralgia
(joint pain), dysgeusia (distortion of the sense of taste), and stomatitis
(inflammation of the mouth and lips). In 4 patients abnormalities in the retina
have been observed. Because these studies involved patients with often advanced
cancer, it is often not possible whether and in what degree complaints and
abnormalities are related to the study compound or to the underlying disease or
other treatments given. Because the study compound will be given once in the
current study, the chance on above-mentioned or other complaints appears not
high, but can certainly not be excluded.

Tests
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising. In total, we will take about 505 milliliters of blood from
the volunteer. This amount does not cause any problems in adults. To compare: a
blood donation involves 500 milliliters of blood being taken each time.

To monitor volunteers heart rate, electrodes (small, plastic patches) will be
pasted at specific locations on the chest and arms and legs. Prolonged use of
these electrodes can cause skin irritation (rash and itching).

Exposure to radiation
In this study radiolabeled rogaratinib will be used. The amount of
radioactivity in this dose will be approximately 3.7 MBq (MBq = megaBecquerel,
this is a unit to express the amount of radioactivity in the study compound).
The average environmental background radiation burden in The Netherlands is
approximately 2.5 mSv per year (mSv = milliSievert, this unit 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 approximately 3.7 MBq radiolabeled rogaratinib is
calculated to be 0.1 mSv. This is approximately 4% of the average annual
radiation burden in The Netherlands.


Procedures: pain, minor bleeding, bruising, possible infection