Absorption, metabolism, excretion, and the determination of absolute bioavailability
of Niraparib in subjects with cancer

The rationale for the study is described in the protocol:

Niraparib is an orally active poly (adenosine diphosphate [ADP]-ribose)
polymerase
(PARP)-1 and -2 inhibitor with nanomolar potency that is being developed for
tumors with
defects in the homologous recombination (HR) deoxyribonucleic acid (DNA) repair
pathway or
that are driven by PARP-mediated transcription factors.
The potential benefit of niraparib treatment for patients with cancer is tumor
regression.
This is an open-label study with 2 parts, including an extension study
following completion of
Parts 1 or 2, that is being conducted in approximately 12 subjects (6 subjects
in Part 1; 6 subjects
in Part 2) with cancer to examine the absorption, metabolism, excretion, and
absolute
bioavailability of niraparib.
This study will be performed because the oral bioavailability of niraparib has
been determined in rats and dogs, but has yet to be determined in human
subjects, including those with cancer.
This study will be the first-in-human administration of the IV formulation of
niraparib. Data from the nonclinical studies did not demonstrate any safety
issues that would preclude testing of IV niraparib in humans, and a microdose
(100 µg) of niraparib is being administered in the current study.

Objectives:
Primary:
• To determine the absolute bioavailability of niraparib by using an
intravenous (IV) niraparib
microdose of 100 µg (containing approximately 1 µCi of [14C]-niraparib) in
subjects with cancer.
Secondary:
• To characterize the absorption, metabolism, and excretion of [14C]-niraparib
administered as a
single, 300-mg oral dose (containing approximately 100 µCi of [14C]-niraparib)
to subjects with
cancer.
• To evaluate the safety and tolerability of niraparib in subjects with cancer.

The current study is a phase I, single-center, non-randomised, open label study
with two parts including an extension study after completing part 1 or part 2,
which will be performed with 12 subjects (6 in part 1; 6 in part 2) with cancer
to determine the Absorption, Metabolism, Excretion, and the Determination of
Absolute Bioavailability of Niraparib

Refer to section Intervention for detailed information.

This is an open-label study with 2 parts, plus an extension study following
completion of Part 1 or 2, to be conducted in subjects with cancer at a single
study center in conformance with Good Clinical Practice (GCP).
Part 1: The Screening Visit will occur within the 3 weeks prior to study drug
administration. Clinical laboratory assessments must occur within 72 hours
prior to study drug administration. Subjects have the option of reporting to
and/or staying t at the study center on Day -1 for the fasting period. Subjects
not staying at the study center on Day -1 must report to the study center at
least 2 hours prior to study drug administration. After an overnight fast of at
least 10 hours, subjects will receive a single, 300 mg (3 × 100-mg capsules)
oral dose of niraparib (unlabeled active pharmaceutical ingredient) on Day 1.
Two hours after the oral dose, subjects will receive a 15-minute IV infusion of
100 µg niraparib, containing approximately 1 µCi of radioactivity. Subjects
will continue fasting until 2 hours after the start of the IV infusion, at
which time a light meal will be served. A physician will be present for study
drug administration and will remain on site for 5 hours after oral study drug
administration. All subjects will be confined to the study center and under
appropriate medical supervision from Day 1 to the morning of Day 4, and
subjects will undergo safety assessments and pharmacokinetic (PK) blood
sampling during the confinement period. No strenuous physical activity will be
permitted during the confinement period. Subjects will return to the study
center on Days 5, 7, 9, 11, 13, 15, and 22 for safety assessments and PK blood
sampling.
Part 2: The Screening Visit will occur within the 3 weeks prior to study drug
administration. Clinical laboratory assessments must occur within 72 hours
prior to study drug administration. Subjects have the option of reporting to
and/or staying overnight at the study center on Day -1 for the fasting period.
Subjects not staying at the study center on Day -1 must report to the study
center at least 2 hours prior to study drug administration. After an overnight
fast of at least 10 hours, subjects will receive a single, 300 mg oral dose of
niraparib, containing approximately 100 µCi of radioactivity (3 × 100-mg
capsules, labeled active pharmaceutical ingredient [3 x 33.3 µCi of
radioactivity]), on Day 1. Subjects will continue fasting until 4 hours after
administration of study drug, at which time a light meal will be served. A
physician will be present for study drug administration and will remain on site
for 5 hours after study drug administration. All subjects will be confined to
the study center and under appropriate medical supervision from Day 1 to the
morning of Day 10, and subjects will undergo safety assessments, PK and
metabolite profile blood sampling, and collection of urine and fecal samples
during the confinement period. No strenuous physical activity will be permitted
during the confinement period. Subjects will return to the study center on Days
11, 15, and 22 for safety assessments and PK and metabolite profile blood
sampling. Participation in Part 2 of the study may extend beyond Day 22 based
on the amount of radioactivity recovered.
Extension Study: On the same day that subjects complete Part 1 or 2 of the
study, subjects may be eligible to participate in the extension study following
re-review of the entry criteria and completion of the screening assessments.
Note that if a subject becomes non-evaluable for PK during Part 1 or Part 2,
the subject may be considered for the extension study without continuing
through Day 22 of Part 1 or Part 2, as long as that subject still meets all
inclusion/exclusion criteria. If laboratory values are outside of the range
specified in the inclusion criteria, the subject may continue to participate in
the study at the discretion of the Sponsor and Investigator with consideration
for a reduced dose as described in Table 6. The Screening Visit should occur
within 7 days after the End of Part 1 or Part 2. Assessments performed at the
End of Part 1 or Part 2 that are completed within 7 days of Screening do not
need to be repeated at Screening (with the exception of complete blood count
[CBC] and coagulation/blood chemistry tests, which must be performed within 72
hours prior to first extension study dose). The Cycle 1/Day 1 Visit can also
occur on the same day as the Screening Visit and the End of Part 1 or 2 Visit.
At the Cycle 1/Day 1 Visit, subjects will receive study drug (300 mg [3 × 100
mg capsules, unlabeled active pharmaceutical ingredient] of niraparib) once a
day (QD) and will undergo safety assessments. No fasting period is required
during the extension study. Subjects will return to the study center during
Cycle 1 on Days 8, 15, and 22 to undergo safety assessments. Subjects will
return on the first day of every treatment cycle (28 [±3] days) to receive
study drug and for safety assessments, and an Eastern Cooperative Oncology
Group (ECOG) performance status assessment. Visits will continue approximately
every 4 weeks until treatment discontinuation. Dose interruption and/or
reduction may be implemented at any time for any grade toxicity considered
intolerable by the subject (Section 7.4 ). Dose interruptions or reductions
will not affect the timing and completion of study assessments. Subjects will
continue in the extension study until the subject meets 1 of the withdrawal
criteria (Section 8.4), or until the subject can be transitioned to the
roll-over study (if eligible, see below). At end of treatment (EOT), safety
assessments, and an ECOG performance status assessment will be completed. No
new capsules will be dispensed at EOT.
Roll-over Study (all eligible subjects): Subjects who have completed the main
objectives of Part 1 or Part 2 may be eligible to enroll in a roll-over study
when the protocol becomes available.

Most common side effects experienced by patients taking niraparib:

The following side effects were experienced by 10% or more patients who took
niraparib as a single drug therapy:

• Decrease in blood cells (red blood cells) that carry oxygen; this may make
the subject feel tired or short of breath (*)
• Decrease in blood cells (white cells) that fight infection; this may decrease
the subject*s ability to fight infections (*)
• Decrease in blood cells (platelets) that help stop bleeding; this may
increase the subject*s risk of bleeding (*)
• Loose/liquid stools (diarrhea)
• Infrequent hard stools (constipation)
• Feeling sick to the stomach (nausea)
• Vomiting
• Feeling tired, lack of energy (fatigue)
• Feeling not hungry; decreased appetite (anorexia)
• Decreased kidney function as measure by increase in creatinine levels (blood
markers of kidney function) in the blood

The following side effects were experienced by 5% < 10% of patients who took
niraparib as a single drug therapy:

• Shortness of breath
• Low level of salt in the blood that may cause the subject to feel tired,
confused, or experience headache or muscle cramps
• Disturbances in the electrical activity of the heart; this may be a
lengthening of time between heart beats and/or an abnormal heart beat that is
either faster or slower than normal
• Sleeplessness, trouble sleeping (insomnia)
• Headache
• Hair loss
• Irritation and redness of the lining of the mouth (stomatitis)
(*) The levels of each type of blood cell (red and white) and the cells
responsible to help stop bleeding in the subject*s body will be closely
monitored during the study. Patients must tell the doctor if they take any
medicine to prevent blood clotting. If the subject experiences unusual
bruising of the skin, bleeding of the gums or nose, the subject should tell
his/her doctor.

Most Common Serious side effects experienced by patients taking niraparib that
have required immediate medical intervention

The following side effects most commonly resulted in the need for immediate
medical intervention:

• Decrease in blood cells (platelets) that help stop bleeding and may increase
the risk of bleeding
• Decrease in blood cells (red blood cells) that carry oxygen which may the
subject feel tired or short of breath
• Decrease in blood cells (white cells) that fight infection; this may decrease
the subject*s ability to fight infections


Potential for new blood cancer (pre-leukemia, leukemia):
Leukemia can be caused by repeated chemotherapies the subject may have already
taken for the subject*s cancer. If the subject has experienced pre-leukemia or
leukemia before entering this study, the subject is at increased risk for
developing leukemia again.

Risk to fetus/newborn:
Niraparib may have adverse effects on a fetus in utero. Furthermore, it is not
known if niraparib has transient adverse effects on the composition of sperm.
Patients may not receive niraparib in the study if they are pregnant, planning
to become pregnant, or nursing a child. Patients must agree to use
contraception for 90 days after the last dose of niraparib and must inform the
investigator immediately if they or their partner become pregnant.