Part 1In Part 1 of the study, no study compound will be administered, but a bone marrow aspiration and a blood sample will be taken to evaluate an assay that will be used for Part 2 and Part 3 of the study. Because no nirogacestat is given, we can…
ID
Source
Brief title
Condition
- Other condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Health condition
multiple myeloma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
•To evaluate the pharmacodynamics (PD) of nirogacestat on BCMA
• To evaluate the serum nirogacestat exposure-response relationship to
membrane-bound BCMA (mbBCMA) and soluble BCMA (sBCMA) kinetics after single
dose administration of nirogacestat
Secondary outcome
• To evaluate the pharmacokinetics of serum nirogacestat after single and
multiple dose administration of nirogacestat
• To evaluate the safety and tolerability of single and multiple dose
nirogacestat in healthy male participants
Background summary
Nirogacestat is a new compound that may potentially be used for the treatment
of a specific type of bone marrow cancer, which is called multiple myeloma.
Multiple myeloma tumor cells carry a protein on their cell surface. This
protein is called *B-cell maturation antigen* or BCMA. BCMA is not only present
on multiple myeloma tumor cells but is also present on normal B-cells. BCMA
plays an important role in the survival and multiplication of the myeloma tumor
cells and normal B-cells. BCMA can be either bound to the cell surface or can
be secreted by the cell as a soluble protein. BCMA can be used as a target for
specific anti-cancer drugs. The anti-cancer drugs will be more effective if the
BCMA is bound to the cell surface and not secreted as a soluble protein.
Nirogacestat will prevent that BCMA is secreted from the cells so that BCMA
remains on the cell surface. In this way, anti-cancer drugs will become more
effective when these agents are combined with nirogacestat.
Study objective
Part 1
In Part 1 of the study, no study compound will be administered, but a bone
marrow aspiration and a blood sample will be taken to evaluate an assay that
will be used for Part 2 and Part 3 of the study. Because no nirogacestat is
given, we can use these samples as a type of blank measurement (baseline) which
we can compare to samples from participants who did receive the study compound.
The test evaluated in this part of the study is a flow cytometry assay, which
is a technique used in general to determine which different types of cells and
how many cells are present in for example blood samples. This type of essay is
even precise enough to measure differences in the amount of proteins bound to
the cells. The degree of binding of certain proteins (BMCA) to specific cell
types (B-cells) is a measure of the effectiveness of the study compound
Part 2 and 3
In Parts 2 and 3 of this study, we will investigate how safe the new compound
nirogacestat is and how well it is tolerated when it is used by healthy
participants.
We also investigate how quickly and to what extent nirogacestat is absorbed,
transported, and eliminated from the body. In addition, we look at the effect
of nirogacestat on B-cells, which is a type of white blood cell.
We also look at the effect of genetic information on the body*s response to
nirogacestat. This part of the study is mandatory.
Nirogacestat has been used by humans before. In addition, it has been
extensively tested in the laboratory and on animals.
Part 4
In Part 1 of the study, no nirogacestat, also referred to as the study
compound, was administered. A bone marrow sample and a
blood sample were taken to develop an assay used in the evaluation of these
samples. As no nirogacestat was given in Part 1, we
used these samples as controls to establish a baseline for information we
obtain from the assay. This assay was then used during
Part 2 and Part 3 of the study, where participants were given nirogacestat,
which allowed us to compare the information from
control samples to samples from participants who did receive the study
compound. In Part 4, bone marrow samples and blood
samples will be taken from participants who were not administered study
compound. These samples will be handled and
processed differently and evaluated using the same assay in Parts 1-3. The
purpose of Part 4 is to evaluate if different handling
and processing of the samples has an effect on the information we obtain from
the assay.
Study design
Part 1
Screening -> Day -35 up to Day -2 prior to Day 1
Arrival -> Day -1
In-house stay -> Day -1 up to Day 1
Departure -> Day 1 (at least 1 hour after the bone marrow aspirate)
During Part 1 of the study, no study compound will be given.
Part 2
Screening -> Day -35 up to Day -3 prior to the Day of (first) dosing
Arrival -> Day -2
In-house stay -> Day -2 up to Day 2 or 3 as explained below
Departure -> Day 2 (if bone marrow aspirate on Day 1 or Day 2), or Day 3 (if
bone marrow aspirate on Day 3)
Follow-up (per phone call) -> Between Day 31 and Day 33
Subjects will receive nirogacestat as oral tablets with 240 milliliters (mL) of
(tap) water.
Part 3
Screening -> Day -35 up to Day 3 prior to the Day of (first) dosing
Arrival -> Day -2
In-house stay -> Day -2 up to Day 2 or 3 as explained below
Departure -> In case of single dose: Day 2 after completion of the final safety
assessments and sample collection
-> In case of multiple doses: Day 3 after completion of the final safety
assessments and sample collection.
Follow-up (per phone call) -> In case of single dose: Between Day 31 and Day 33
-> In case of multiple doses: Between Day 32 and Day 34
Subjects will receive nirogacestat as oral tablets with 240 milliliters (mL) of
(tap) water.
Part 4
Screening -> Day -35 up to Day -2 prior to Day 1
Arrival -> Day -1
In-house stay -> Day -1 up to Day 2
Departure -> Day 2 (at least 1 hour after the bone marrow aspirate)
During Part 4 of the study, no study compound will be given.
Intervention
Part 1
During Part 1 of the study, no study compound will be given.
Part 2
Subjects will receive a single oral dose with 150 mg nirogacestat (3 tablets of
50 mg each) on Day 1.
Part 3
The dose and the number of doses subjects will receive will be based on the
outcome of Part 2 of the study. They will be informed about the dose they will
receive on the day they will enter the research center.
The dose(s) could be as follows:
• a single dose of between 50 mg (1 tablet of 50 mg) to 300 mg (6 tablets of 50
mg) nirogacestat, or
• multiple doses of 100 mg twice daily (2 tablets of 50 mg in the morning and
in the evening) for 1 or 2 days (maximum of 4 doses of nirogacestat). The
highest nirogacestat doses given in previous studies are: 330 mg nirogacestat
twice daily for 21 days in patients, 95 mg once daily for 14 days in healthy
participants and 150 mg once in healthy participants.
Part 4
During Part 4 of the study, no study compound will be given.
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 (bruising) of the puncture
site. In some individuals, a blood draw can sometimes cause pallor, nausea,
sweating, low heart rate, or drop in blood pressure with dizziness or fainting.
In total, we will take about 26 (in part 1), 113 (in part 2) and 173 (in part
3) milliliters (mL) of blood from screening to follow-up. This amount does not
cause any problems in adults. To compare: a blood donation involves 500 mL of
blood being taken each time at once. If the investigator thinks it is necessary
for the safety of a participant, extra samples might be taken for possible
additional testing. If this happens, the total amount of blood drawn may be
more than the amount indicated above.
Heart tracing
To make a heart tracing, electrodes will be placed on arms, chest and legs.
Prolonged use of these electrodes can cause skin irritation (rash and itching).
Bone marrow sampling with local anesthetics (lidocaine injection)
The procedure will be performed by a hematologist and will be as follows:
They will lie on their side (usually the left side) and the doctor first
applies a local anesthetic to the back of the pelvis, where the
puncture will then take place. The application of anesthetic (lidocaine
injection) may hurt for a short period of time, because the
outside of the bone has to be anesthetized. Disinfecting the puncture site may
feel cold. When the anesthesia has taken effect, the
doctor will puncture the bone marrow cavity with the puncture needle. Through
this needle, the doctor can aspirate a small amount
of bone marrow cells with a syringe. Aspirating bone marrow cells only takes a
few seconds but can radiate painfully to the leg.
Usually the removal of the bone marrow cells is almost painless, although
despite the anesthetic the procedure may still hurt a lot.
If it does hurt, it is important to mention this (during the puncturing of the
bone), so extra anesthetic may be applied. The collection
of the bone marrow may be painful or uncomfortable (unpleasant), but the pain
should not last long (at the most 10 seconds), and
they will always be warned in advance.
It is expected that the whole procedure (including anesthesia, sample
collection, etc.) takes about 20 minutes. A plaster with gauze
will be applied at the puncture site. Thereafter they will have to lie on their
back for a while (usually about half an hour), to apply
pressure to the puncture hole using their own weight. After it has been checked
that any bleeding has stopped, they are allowed to
get up and resume their activities. They cannot take a shower on the evening of
the puncture, so that the *wound* can recover.
After 24 hours, the plaster with gauze may be removed.
After the sampling, the site may be sore, just like a large bruise, may hinder
movement for the first few hours, and fever and/or
blood loss from the puncture site may occur. If there is still pain afterwards,
they can discuss with the study doctor whether they
may use paracetamol. The second bone marrow sampling will be taken from the
same area as the first sample.
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Listed location countries
Age
Inclusion criteria
2. Participant understands the study procedures, is willing to comply with all
study requirements and restrictions and agrees to participate in the study by
providing written informed consent as described in Appendix 1, prior to any
study-related procedures being performed.
3. Participant is a male between 18 and 55 years of age (inclusive) at the time
of informed consent.
4. Participant has a body mass index (BMI) >= 18 kg/m2 and <= 32 kg/m2
(inclusive) at Screening and a total body weight > 50 kg.
5. Participant is considered to be medically healthy, as determined by a
responsible and experienced investigator, based on a clinical evaluation
(including medical history, physical examination, clinical laboratory tests,
vital sign measurements and a 12-lead ECG) performed as directed in the SoA
(Section 1.3), Section 1.2.1; and the results of clinical chemistry, and
hematology carried out at Screening and Day -1 (Parts 1 and 4) or Day -2 (Parts
2 and 3).
Exclusion criteria
1. Participant has a history or presence of oncologic, cardiovascular,
pulmonary, hepatic, renal, hematological, gastrointestinal, ocular, endocrine,
immunologic, dermatologic, musculoskeletal, neurological, psychiatric or other
disease or condition or the laboratory test abnormality that in the
investigator*s judgment poses a significant risk to the safety
of the participant or the achievement of study objectives.
2. Participant has a medical history or abnormal findings at Screening or Day
-1 (Parts 1 and 4) or Day -2 (Parts 2 and 3) that the investigator judges may
put at risk achieving the objectives of the study or protecting the safety of
the participant.
3. Participant has an acute illness with symptom or treatment that has started
or persisted within 14 days prior to study treatment administration unless mild
in severity and enrollment is approved by both Investigator and Sponsor*s
medical monitor.
4. Participant has clinically significant infections (e.g., HBV, HCV, HIV)
within 90 days prior to Day 1, as judged by the investigator, or evidence of
any infection with the past 14 days prior to Day 1.
5. Participant has blood pressure (BP) that is greater than or equal to 140 mm
Hg systolic or 90 mm Hg diastolic following at least 5 minutes of rest at
Screening or Day -1 (Parts 1 and 4) or Day -2 (Parts 2 and 3). Additionally, BP
that is less than 90 mm Hg systolic or 45 mmHg diastolic following at least 5
minutes of rest at Screening or Day -1 (Parts 1 and 4) or Day -2 (Parts 2 and
3).
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 | EUCTR2022-000386-40-NL |
| CCMO | NL80762.056.22 |