OPEN LABEL PHASE I STUDY TO INVESTIGATE THE EFFECT OF MULTIPLE DOSES OF KETOCONAZOLE ON THE SINGLE-DOSE PHARMACOKINETICS OF TASQUINIMOD IN HEALTHY SUBJECTS

Tasquinimod is a new, investigational compound that may eventually be used for
the treatment of prostate cancer. In addition, Tasquinimod may be used for
other indications in the future.
Ketoconazole is a registered drug for the treatment of infections caused by
fungus or yeast that are not responding to local treatment. Ketoconazole
inhibits the enzyme CYP3A4. Tasquinimod is broken down by this enzyme.
Inhibition of the activity of CYP3A4 by ketoconazole may result in not breaking
down of tasquinimod, leading to increased tasquinimod blood concentrations.
This study will possibly clarify the potential effect of ketoconazole on the
concentrations of tasquinimod in the body.

Primary:
- To assess the effect of multiple doses of ketoconazole on the single-dose
pharmacokinetics (PK) of tasquinimod.

Secondary:
- To assess the safety and tolerability of multiple doses of ketoconazole with
single doses of tasquinimod.

Design
This is an open-label, 2-period, fixed sequence, crossover, drug interaction
study in healthy volunteers. Subjects will receive a single dose of tasquinimod
alone on Day 1 of Period 1, followed by an assessment/washout period of at
least 7 days. On Days 1 to 13 of Period 2, subjects will receive daily doses of
ketoconazole in combination with a single dose of tasquinimod on Day 4.

Treatments
12 healthy male or female subjects will receive treatments in 2 periods as
follows:
Period 1: single per oral dose of 0.5 mg tasquinimod administered on Day 1
followed by 7 days of assessment and washout.
Period 2: multiple per oral doses of 400 mg ketoconazole, administered once
daily on Days 1-13, and given in combination with a single per oral dose of 0.5
mg tasquinimod on Day 4 (tasquinimod administered immediately after the
ketoconazole dose)

Procedures and assessments
Screening:
medical history, demographic data (including body weight and height), clinical
laboratory (including clinical chemistry, haematology and urinalysis), alcohol
and drug screen, pregnancy test (females only), hepatitis B surface antigen
(HBsAg), anti-hepatitis C virus (HCV) and anti-human immunodeficiency virus
(HIV) *, vital signs (including supine and standing systolic and diastolic
blood pressure, pulse rate, respiratory rate and body temperature measured with
an ear thermometer), 12 lead electrocardiogram (ECG), physical examination,
adverse events (AEs) from the signing of the informed consent form (ICF) and
previous and concomitant medication

Follow-up:
clinical laboratory (including clinical chemistry, haematology and urinalysis),
vital signs (including supine systolic and diastolic blood pressure, pulse
rate, respiratory rate and body temperature), 12-lead ECG, physical
examination, pregnancy test (females only), AEs and concomitant medication

Each admission (Day -1 in each period):
drug and alcohol screen, pregnancy test (females only), clinical laboratory
(including
clinical chemistry, haematology and urinalysis), vital signs (including supine
systolic and diastolic blood pressure, pulse rate, respiratory rate and body
temperature), 12-lead ECG, AEs and concomitant medication

Observation period: 2 periods in the clinic
Period 1: from the afternoon on Day -1 until the morning of Day 3, daily
outpatient visit on Days 5 and 7 (Day 7 of Period 1 is the same day as Day -1
of Period 2)
Period 2: from the afternoon on Day -1 until the morning of Day 14 (a follow-up
visit will occur 7 to 10 days after the Day 13 dose of ketoconazole)

Blood sampling:
for PK of tasquinimod in plasma: at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12,
24, 36, 48, 96, and 144/168 hours after administration of tasquinimod on Day 1
of Period 1 and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72,
96, 120, 144, 168, 192, 216 and 240 hours after administration of tasquinimod
on Day 4 of Period 2
for PK of ketoconazole in plasma: at pre-dose on Days 1, 2, 4, 5, 7 and 10 of
Period 2

Safety assessments:
AEs recorded from the signing of the ICF until completion of the follow up
visit; clinical laboratory (including clinical chemistry, haematology and
urinalysis) and 12-lead ECG at screening, Day -1 of each period, 4 hours
post-dose on Days 1 and 3 of Period 1 and Days 1, 3, 4 and 6 of Period 2, and
at follow-up; vital signs (including supine systolic and diastolic blood
pressure, pulse rate, respiratory rate and body temperature measured with an
ear thermometer) at screening, Day -1 of each period, once daily within 2 and 4
hours after any dosing on in-clinic days (but in the morning around 11 am on
Days 2 and 3 of Period 1 and Day 14 of Period 2 when there is no dosing), and
at follow-up; physical examination at screening and at follow-up.

Active substance: tasquinimod
Activity: anti-angiogenic
Strength: 0.5 mg
Dosage form: per oral capsule

Active substance: ketoconazole
Activity: antimycotic
Indication: mycotic infections
Strength: 200 mg/tablet; a dose of 400 mg will be administered
Dosage form: per oral tablets

Risks
Procedures:
Pain, light bleeding, heamotoma, possibly an infection

Medication:
Tasquinimod: muscle or joint pain, tiredness, dizziness and headache.

Ketoconazole:
The most common adverse effects of ketoconazole are nausea, vomiting, bloating,
reduced appetite, diarrhea and abdominal pain. Sometimes adverse effects such
as, headache, dizziness, photophobia, rash, itching and allergic reactions can
occur. Finally, transient changes of certain laboratory blood values can occur
(liver enzymes).