In this study, we will investigate how safe the new compound AB521 is and how well it is tolerated when it is used by healthy participants. We will also investigate how quickly and to what extent AB521 is absorbed and eliminated from the body. In…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Renal cell carcinoma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To assess the safety and tolerability of AB521 after single- and multiple
oral doses.
- To characterize the PK profile of AB521 after single- and multiple oral
doses.
Secondary outcome
- To evaluate the effect of multiple oral doses of AB521 on the PK of midazolam
when midazolam is administered as a single dose
Exploratory:
- To assess the potential PD effects of AB521
- To characterize AB521 excretion in urine
- To characterize potential metabolite(s) of AB521 in plasma and urine
Background summary
AB521 is a new compound that may potentially be used for the treatment of
cancer. Cells of solid tumors (tumors that don't contain any liquid or cysts)
are frequently exposed to low oxygen conditions. In order to survive in these
conditions, tumor cells make use of specific proteins, including *Hypoxia-
Inducible Factor-2α* (HIF-2α). AB521 has been shown to be able to inhibit the
HIF-2α protein. Treatment with AB521 is expected to prevent the growth and
spread of these tumor cells.
*For part 3 only:
This study evaluates how AB521 affects the body, in particular the enzymes in
the liver that are important in the breakdown of other medication such as
midazolam. Laboratory studies have shown that this may be the case. Midazolam
is a substance processed by enzymes in the liver and is recommended by the
European Medicines Agency (the agency that approves drugs for use in Europe) to
study the effects on these enzymes. This could alter the amount of midazolam in
the body when given at the same time as AB521.*
Study objective
In this study, we will investigate how safe the new compound AB521 is and how
well it is tolerated when it is used by healthy participants. We will also
investigate how quickly and to what extent AB521 is absorbed and eliminated
from the body. In addition, we will look at the effect of AB521 on a certain
blood marker.
AB521 has been administered to 32 healthy participant in Part 1 of this study.
It has also been tested in the laboratory and on animals. AB521 will be tested
at various dose levels.
We will compare the effects of AB521 with the effects of a placebo. A placebo
is a compound without any active ingredient.
*For part 3 only:
Furthermore, we will evaluate a possible interaction between AB521 and
midazolam. We will do this by investigating the effect of AB521 on the
pharmacokinetics of midazolam. Both these compounds will be administered in
this study.
Midazolam is a sedative and sleep-inducing agent that is registered as a sleep
aid for oral administration and as a short-acting sedative before or during a
medical examination or surgery for other forms of administration. The dose of
midazolam used in the current study is well below the dose levels achieved for
these purposes.*
Study design
For part 1:
It is necessary that the volunteer stays in the research center for 1 period of
9 days (8 nights). This will be followed by 3 short visits to the research
center, including a follow-up visit at the end of the study. These short visits
will take place on Day 10, Day 13, and between Day 21 and Day 28.
Day 1 is the day when the volunteer receives the study compound. The volunteer
is expected at the research center 2 days before the day of administration of
the study compound (Day -2). He/she will leave the research center on Day 7 of
the study.
The volunteer will be given AB521 or placebo as oral capsules with 240
milliliters (mL) of (tap) water.
Whether the volunteer will receive AB521 or placebo will be determined by
chance. Per group, 6 participants will receive AB521 and 2 participants will
receive placebo.
For part 2:
It is necessary that the volunteer stays in the research center for 1 period of
10 days (9 nights). This will be followed by 3 short visits to the research
center and a follow-up visit at the end of the study. These short visits will
take place on Day 11, Day 14, and day 17.
Day 1 is the first day that the volunteer receives the study compound. The
volunteer is expected at the research center 2 days before the day of
administration of the study compound. The volunteer will leave the research
center on Day 8 of the study.
The volunteer will be given AB521 or placebo as oral capsules with 240
milliliters (mL) of (tap) water.
Whether the volunteer will receive AB521 or placebo will be determined by
chance. Per group, 6 participants will receive AB521 and 2 participants will
receive placebo.
For part 3:
It is necessary that the volunteer stays in the research center for 1 period of
10 days (9 nights). This will be followed by 1 short visit to the research
center and a follow-up visit at the end of the study. This short visit will
take place on Day 13.
Day 1 is the first day that the volunteer receives the study compound. The
volunteer is expected at the research center 2 days before the day of
administration of the study compound. The volunteer will leave the research
center on Day 9 of the study.
The volunteer will be given AB521 or placebo as oral capsules with 240
milliliters (mL) of (tap) water. The volunteer will also receive midazolam as a
drink containing 2 mg compound.
Intervention
Part 1:
The volunteer will be given AB521 or placebo as oral capsules with 240
milliliters (mL) of (tap) water.
Part 2:
If the volunteer participates in group 1 it will receive on day 1 to 7 AB521 15
mg or placebo once daily
If the volunteer participates in group 2 it will receive on day 1 to 7 AB521 50
mg or placebo once daily
Part 3:
The volunteer will receive AB521 from day 2-7, dose between 15 mg and 50 mg
based on Part 2.
The volunteer will receive AB521 on day 8, dose between 15 mg and 50 mg based
on Part 2.
The volunteer will receive Midazolam on day 1 and day 8, dose 2 mg once daily.
Study burden and risks
Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
cannula can sometimes lead to inflammation, swelling, hardening of the vein,
blood clotting, and bleeding in the environment of the puncture site. In some
individuals, a blood draw can sometimes cause pallor, nausea, seating, low
heart rate, or drop in blood pressure with dizziness or fainting.
In total, we will take about 215 mL (Part 1), 221 mL (Part 2) or 161 mL (Part
3) of blood from the volunteer. This amount does not cause any problems in
adults. To compare: a blood donation involves 500 mL of blood being taken each
time.
Heart tracing (holter monitoring)
To make a heart tracing, electrodes will be placed on the arms, chest and legs.
To monitor your heart rate, electrodes will be placed on the chest and abdomen.
Prolonged use (3 day period) of these electrodes can cause skin irritation.
Coronavirus test
Samples for the coronavirus test will be taken from the back of the nose and
throat using swabs. Taking the samples only takes a few seconds, but can cause
discomfort and can give an unpleasant feeling. Taking a sample from the back of
the throat may cause the volunteer to gag. When the sample is taken from the
back of the nose, the volunteer may experience a stinging sensation and the
eyes may become watery.
Fasting
If the volunteer has to fast for a prolonged time during the study, this may
lead to symptoms such as dizziness, headache, stomach upset, or fainting.
Point Eden Way 3928
Hayward 94545
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Point Eden Way 3928
Hayward 94545
US
Listed location countries
Age
Inclusion criteria
1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in
this protocol.
2. Participant must be at least 18 to 55 years of age inclusive, at the time of
signing the informed consent.
3. Participants who are healthy volunteers (in the opinion of the investigator)
as determined by pre-study medical history, physical examination, vital signs,
and 12-lead ECG.
4. Participants must have clinical laboratory tests within the reference range
for age and gender at screening and baseline.
5. Screening and randomization hemoglobin for males and females is as follows:
a) SAD: male and female hemoglobin level >= 12.5 g/dL (7.7 mmol/L)
b) MAD and DDI: male hemoglobin level >= 14.2 g/dL (8.8 mmol/L) and female
hemoglobin level >= 12.5 g/dL (7.7 mmol/L).
Further criteria apply
Exclusion criteria
1. Has any (acute or chronic [including SARS-CoV-2 infection]) medical or
psychiatric condition that, in the opinion of the investigator, could
jeopardize or would compromise the study participant*s ability to participate
in this study.
2. Has history or presence of cardiovascular, respiratory, hepatic, renal,
gastrointestinal, endocrinological, hematological, cerebrovascular,
neurological, or other major disorders capable of significantly altering the
absorption, metabolism, or elimination of IMP; constituting a risk when taking
the study intervention; or interfering with the interpretation of data in the
opinion of the investigator.
3. Abnormal blood pressure (BP) or pulse measurements at the Screening Visit or
Day -2/-1 (Admission) in a supine position after 5 minutes of rest as follows:
mean systolic BP >= 139 mm Hg or mean diastolic BP >= 89 mm Hg; mean pulse < 40
bpm or > 100 bpm. Study participants with a BP within normal range but who, in
the opinion of the investigator, have a high risk for cardiovascular accident
based on, eg, family history, smoking, BMI, or lipid spectrum can be excluded.
Results that are outside the specified ranges and are deemed clinically
non-significant will be allowed at the discretion of the investigator, after
discussion with the Sponsor Medical Monitor (or designee). If a study
participant has a test result outside the normal range that is deemed
potentially clinically significant, repeat of the investigation may be allowed
once at the discretion of the investigator, after discussion with the Sponsor
Medical Monitor (or designee).
4. The following liver enzyme test results:
a) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin,
or alkaline phosphatase (ALP) >1.0× upper limit of normal (ULN).
• Tests that result in ALT, AST, bilirubin, or ALP up to 25% above the
exclusion limit may be repeated once for confirmation.
b) Current or chronic history of liver disease or known hepatic or biliary
abnormalities (with the exception of asymptomatic gallstones).
5. Has 12-lead ECG with changes considered to be clinically significant (eg,
QTcF > 450 msec for males and > 470 msec for females, left bundle branch block,
or evidence of myocardial ischemia) at the Screening Visit or Day -2/-1
(Admission).
Further criteria apply
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-003856-17-NL |
| CCMO | NL79307.056.21 |