Part 1 - Single Ascending Dose (SAD):Primary objective:• To evaluate the safety and tolerability of single oral doses of THB001 in healthy subjects.Secondary objectives:• To characterize the plasma pharmacokinetic (PK) profile of single oral doses…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
allergic mediated diseases
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1, Part 2 and Part 3
• Safety and tolerability parameters include: physical examination, AEs,
clinical laboratory values, vital signs and ECGs (3-lead telemetry and 12-lead
ECGs).
Secondary outcome
Part 1 and Part 2
• PK parameters for THB001 include: Cmax, tmax, t1/2, AUC0-t, AUC0-inf, CL/F
and Vz/F.
Part 1 and Part 3
Mean hourly heart rate analysis including change from baseline and placebo
corrected change from baseline (if applicable) for each subject, heart rate
nadir and time to heart rate nadir. Optional analysis of cardiodynamic
parameters including precision QT analysis may be performed.
Part 3
• PK parameters for THB001 include: Cmax, tmax, t1/2, AUC0-t, AUC0-tau,
AUC0-inf, CL/F (Day 1 only), Vz/F (Day 1 only), Cmin, Cmin,ss, CLss/F, Vss/F,
Cssavg, and AR.
Background summary
Mast cells play a central role in the pathology of allergic-mediated diseases,
providing a strong rationale that depletion of mast cells can benefit patients
diagnosed with allergic mucosal and cutaneous disorders in which mast cell
degranulation plays a role in onset and progression. As a novel therapeutic
approach, mast cell depletion should inhibit multiple mediators of symptoms of
allergic diseases that have inadequate responses to single agents that target
only individual mediators of mast cells or whose off-target toxicity profiles
limit their use.
Mast cell activation, proliferation, and survival depend on the KIT receptor.
Studies have shown that KIT mutations and kinase inhibition of mutant KIT have
profound effects on mast cells. Therefore, KIT is a pharmacologically and
genetically validated target to drive mast cell depletion.
THB001 is highly selective for KIT and therefore mast cell proliferation and
survival. The exquisite selectivity of THB001 was demonstrated in animals by
limited*to*no off*target toxicity and a defined on-target toxicity with a
reasonable therapeutic window. THB001 is expected to have robust mast cell
depletion and a favorable safety profile that supports clinical investigation.
Study objective
Part 1 - Single Ascending Dose (SAD):
Primary objective:
• To evaluate the safety and tolerability of single oral doses of THB001 in
healthy subjects.
Secondary objectives:
• To characterize the plasma pharmacokinetic (PK) profile of single oral doses
of THB001 in healthy subjects.
• To assess the effect of THB001 on ECG parameters (PR, QRS, QTcF and Heart
Rate).
Part 2 - Food Effect (FE):
Primary objective:
• To evaluate the safety and tolerability of a single oral dose of THB001 in
fasted and fed state in healthy subjects.
Secondary objectives:
• To characterize the plasma PK profile of a single oral dose of THB001 in
fasted and fed state in healthy subjects.
Part 3 - Multiple Ascending Dose (MAD):
Primary objective:
• To evaluate the safety and tolerability of multiple oral doses of THB001 in
healthy subjects.
Secondary objectives:
• To characterize the plasma and urine PK profile of multiple oral doses of
THB001 in healthy subjects.
• To assess the effect of THB001 on ECG parameters (PR, QRS, QTcF and Heart
Rate).
Study design
This study is a randomized, placebo-controlled, Phase 1 study in three parts:
single ascending doses (Part 1, double-blind), food effect (Part 2,
open-label), and multiple ascending doses (Part 3, double-blind).
The study will be monitored by a Safety Review Committee (SRC). The intent of
the SRC is to ensure that treatment does not pose undue risk to subjects.
Safety, tolerability and available PK and/or PD data will be assessed by the
SRC between each cohort in Part 1 and Part 3 and prior to initiation of Part 2
and Part 3.
Study burden and risks
Since the study is being executed in healthy volunteers, there are no
anticipated benefits of the IMP. Please see the IB for further information.
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Listed location countries
Age
Inclusion criteria
1. Subjects must understand the nature of the study and must provide signed and
dated written informed consent in accordance with local regulations before the
conduct of any study-related procedures.
2. Healthy as determined by the Investigator, based on a medical evaluation
including medical history, physical examination, laboratory tests and ECG
recording. A subject with a clinical abnormality or laboratory parameters
outside the reference range for the population being studied may be included
only if, in the opinion of the Investigator, the finding is (a) unlikely to
introduce additional risk to the subject, (b) will not interfere with study
procedures or confound study results, and (c) is not otherwise exclusionary
(see Exclusion Criteria).
3. In Part 1 and 2, men and women aged 18-65 years (inclusive) at the time of
Screening will be enrolled, and in Part 3 vasectomized men and women aged 18-65
years (inclusive) at the time of Screening will be enrolled.
4. Women of child-bearing potential must agree not to attempt to become
pregnant and to use a highly effective form of hormonal (excluding oral
contraceptives) or non-hormonal birth control, which entails the use of a
non-hormonal intra-uterine device/system in combination with a barrier method
(e.g. condom, diaphragm, cervical cap with spermicide) or abstinence during the
study and for 90 days after the (last) study drug administration.
Postmenopausal women must have had >=12 months of spontaneous amenorrhea (with
documented follicle-stimulating hormone (FSH) >=30 mIU/mL). Surgically sterile
women are defined as those who have had a hysterectomy, bilateral ovariectomy,
or bilateral tubal ligation. Women who are surgically sterile must provide
documentation of the procedure by an operative report or by ultrasound. All
women must have a negative pregnancy test result on Day -1 before (first)
administration of study medication.
Exclusion criteria
1. A positive urine drug screen/alcohol breath test at Screening or Day -1 of
the (first) treatment period.
2. A positive Hepatitis B surface antigen or positive Hepatitis C antibody
result at Screening.
3. A positive test for human immunodeficiency virus (HIV) antibody at Screening.
4. Alanine aminotransferase, aspartate aminotransferase, or total bilirubin
levels greater than the upper limit of normal (ULN) at Screening or Day -1 of
the (first) treatment period. One test result up to 1.25 x the ULN is allowed.
One retest at Screening and on Day -1 of the (first) treatment period is
allowed. Subjects with Gilbert*s Syndrome are permitted to have total bilirubin
values outside the 1.25 x the ULN, as judged by the Investigator, as long as
the AST and ALT are within normal limits (WNL).
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000164-29-NL |
| CCMO | NL76587.056.21 |
| OMON | NL-OMON21075 |