A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study of BLU-263 in Indolent Systemic Mastocytosis

SM is a rare, clonal mast cell neoplasm driven by the KIT D816V mutation in up
to ~95% of cases. This mutation leads to the uncontrolled proliferation and
activation of mast cells, often present as aggregates in skin, BM, spleen,
liver, GI tract, and other organs. SM can be associated with debilitating and
potentially life-threatening symptoms, including unpredictable anaphylaxis,
maculopapular skin lesions, pruritis, diarrhea, cognitive impairment, fatigue,
and bone pain. These symptoms have a severely negative impact on the QoL of
patients physically, emotionally, and psychosocially. Patient*s symptoms are
typically managed with significant polypharmacy with symptomatic therapies such
as antihistamines, H2-blockers, proton-pump inhibitors, cromolyn,
corticosteroids, and anti-IgE antibodies.

The prevalence of SM is estimated at approximately 1 in 10,000 people.
Ninety-five percent of patients with SM are considered to have non-AdvSM, which
includes the WHO variant of ISM as well as a small number of patients with SSM.
Patients with non-AdvSM suffer long-term and may worsen over time with no
approved treatments to reduce their burden of disease or impact their disease
course. Approximately 5% of patients with ISM show disease progression to
severe forms of SM associated with poor overall survival. Avapritinib, a
selective KITD816V inhibitor, was approved for use in adult patients with ISM
in the US in May 2023 and in the EU for patients with moderate to severe
symptoms who are inadequately managed by current symptomatic treatment in
November 2023. However, further therapies targeted at improving both the
underlying disease driver and disease-related symptoms are lacking. SSM is
defined by the presence of at least 2 B-findings, resulting from high mast cell
burden, and no Cfindings (organ dysfunction). B-findings include pronounced
mast cell burden (>30% in BM biopsy, high KIT D816V VAF, high serum tryptase),
signs of myeloproliferation or myelodysplasia without clear evidence of an AHN,
and organomegaly. SSM diagnosis also includes no signs of aggressive disease or
an AHN. The clinical course in SSM is often characterized by slow progression
and patients may remain stable for years or may progress into a more advanced
variant (ASM, MCL or SM with an AHN). Patients with SSM progress to AdvSM or
transform to leukemia in approximately 9% of cases and have a worse survival
compared to ISM patients.

mMCAS is a rare clonal mast cell disease defined by the presence of the KIT
D816V mutation. Like SM, mMCAS is classified as a primary mast cell disorder,
with an inherent genetic defect in the mast cells or their progenitors. With
mMCAS, Baseline tryptase levels are often normal but can increase during
symptomatic episodes. Clinical presentation includes episodic symptoms of mast
cell degranulation, such as flushing, lightheadedness, abdominal cramping,
nausea, and diarrhea. Severe episodes of syncope and anaphylaxis have been
associated with mMCAS. Monoclonal mast cell activation syndrome does not fit
the WHO criteria for SM; however, 1 or 2 minor criteria may be present (eg,
c-KIT mutation or CD25 expression on BM analysis). Some of these patients can
be found to have systemic mastocytosis on future biopsies. Spontaneous
resolution of mMCAS or systemic mastocytosis has not been described to date.
Similar to the patients with ISM, mMCAS patients have limited treatment options
that often times offer minimal control of their disease and related symptoms.
There are no approved therapies for mMCAS patients that reduce burden of
disease or alter the disease course. Many mMCAS patients continue to have
substantial burden of disease despite significant polypharmacy with symptomatic
therapies that are primarily directed at mitigating the release or effects of
mast cell mediators.

Elenestinib (BLU-263) is a potent, selective, small molecule inhibitor of the
KIT exon 17 mutant enzyme, KIT D816V. Its potency is demonstrated in vitro in
both the biochemical (dissociation constant, Kd = 0.24 nM) and cellular
(half-maximal inhibitory concentration, [IC50] = 4.3 nM) settings. Elenestinib
has a high degree of selectivity for KIT D816V when compared against other
kinases, transmembrane or soluble receptors, ion channels, transporters, and
other enzymes. The calculated Kp,uu (AUC 0-inf, brain dialysate/unbound AUC
0-inf, plasma) was 0.06, suggesting limited brain penetration potential for
elenestinib.

This study is designed to determine the RD and assess the safety and efficacy
of elenestinib in patients with ISM, SSM, or mMCAS whose symptoms are not
adequately controlled by BSC. There are 5 parts to the study and 2 open-label
PK groups:

• Part 1 of the study contains 3 dose groups and a placebo group to determine
the RD of elenestinib
for patients with ISM.
• Part 2 of the study will assess if elenestinib treatment in addition to the
BSC improves outcomes
in patients with ISM compared to placebo + BSC.
• Part 3 of the study is an open-label extension to further characterize
long-term safety and efficacy
of elenestinib.
• Part S will explore elenestinib treatment + BSC in patients with SSM in an
open-label design.
• Part M will explore elenestinib treatment + BSC in patients with mMCAS in an
open-label
design.

A PK group of up to 20 patients may be enrolled prior to and/or in parallel to
Part 1. An additional PK group of approximately 60 patients may also be
enrolled prior to Part 2. Both PK groups are to better characterize PK, safety,
and efficacy of elenestinib in patients with ISM. Patients in each PK group may
have a wider range of TSSs than the randomized portions of the study or have
selected comorbidities or co-medications with potential to impact elenestinib
PK.

This study has been transitioned to CTIS with ID 2024-516728-32-00 check the CTIS register for the current data.

To determine RD of elenestinib
To assess if treatment with elenestinib improves outcomes compared to placebo +
BSC, as assessed using the ISM-SAF
To assess the long-term safety and tolerability of treatment with elenestinib
To assess the long-term efficacy of treatment with elenestinib

This is a randomized, double-blind, placebo-controlled, Phase 2/3 study
comparing the efficacy and safety of elenestinib + BSC with placebo + BSC in
patients with ISM, SSM, or mMCAS whose symptoms are not adequately controlled
by BSC. In Part 1, the RD of elenestinib will be identified in
patients with ISM who have an ISM-SAF TSS >= 28. In Part 2, patients with ISM,
regardless of ISMSAF TSS, will be randomly assigned to the RD of elenestinib
identified in Part 1 + BSC or to matching placebo + BSC. In Part 3, patients
who have completed Part 1 or Part 2 of the study will participate in a
long-term extension, receiving open-label elenestinib at the RD + BSC. In Part
S, patients with SSM will receive 100 mg of open-label elenestinib + BSC. In
Part M, patients with mMCAS will receive the RD of open-label elenestinib + BSC.

Screening (All Parts)
After provision of written informed consent, patients will be evaluated for
eligibility during the Screening period.

In Part 1 and PK groups, after consent is provided, the ISM-SAF should be
completed daily to determine the 14-day average eligibility TSS. No other
Screening assessments can be performed during the 14-day Eligibility TSS
period. The patient will continue to complete the ISM-SAF throughout the
Screening period. Once the Eligibility TSS is determined; other Screening
assessments may begin. Baseline TSS should be calculated prior to C1D1.
Patients in Part 2 will complete the ISM-SAF daily through Screening to
determine a Baseline score, but inclusion in the study is not dependent upon a
particular TSS. No other Screening assessments can be performed during the
14-day Eligibility and Baseline TSS period. Note: C1D1 must be delayed until a
valid 14-day average Baseline TSS has been obtained for Part 1 and Part 2.

In Part S and Part M, after informed consent is provided, patients will begin
completing the ISM-SAF, the MC-QoL, and all other Screening procedures
simultaneously. Screening should last no longer than 8 weeks (56 days), except
with written permission of the Sponsor. Randomization in Part 1 and Part 2 will
occur after patients are deemed eligible to participate following
Screening. Please refer to Section 8.10.1 for more details on the Screening
Period.

Part 1
In Part 1 of the study, approximately 40 evaluable patients with ISM with TSS >=
28 will be equally randomized (1:1:1:1 ratio) to 1 of 3 doses of
elenestinib+BSC or to placebo. Randomization will be stratified based on
centrally measured serum tryptase levels at screening (< 20 ng/mL versus >= 20
ng/mL ) with approximately 7 patients with serum tryptase levels >= 20 ng/ml in
each group. The 3 dose levels (25 mg, 50 mg, or 100 mg) of elenestinib+BSC and
placebo will be tested in parallel. Patients, study staff, and the Sponsor will
be blinded to treatment assignment; however, select personnel, primarily
functioning in safety reporting, clinical pharmacology, and conduct of the IDMC
will be unblinded throughout the study. Elenestinib will be administered
orally, once daily (QD) continuously. Patients will be assessed weekly for the
first 4 weeks for safety, laboratory monitoring, and QoL assessments.
Pharmacokinetic sampling will be performed in all patients. The
pharmacokinetics data may be unblinded after the completion of intensive PK
collections (C1D1 and C1D15) of all patients. The ISM-SAF will be completed
daily. After completion of 12 weeks of treatment, BM and skin biopsy will be
repeated for mast cell quantification by the Central Pathology Laboratory and
skin photographs (optional) may be taken in patients with baseline mastocytosis
in skin. The RD will be determined based on the efficacy, safety, and PK data
at each dose level from Part 1 and the PK groups. The major efficacy criterion
for selection of the RD will be the dose of elenestinib that produces the
maximum reduction in TSS, as assessed using the ISM-SAF at 12 weeks of
treatment (Week 13) compared with Baseline. Other measures of efficacy (eg,
change in serum tryptase)
will also be taken into consideration. Once assessments after 12 weeks of
treatment (Week 13) are completed, and the interim placebo crossover dose is
determined, all patients will be unblinded and continue treatment in Part 1
until RD is determined. Patients randomized to elenestinib will remain in Part
1 on their current dose; dose modifications are permitted (criteria for dose
modification are outlined in Section 7.3.1). Patients receiving placebo in Part
1 will receive elenestinib at the interim placebo cross-over dose. This interim
placebo cross-over dose may be different than the RD for Parts 2, Part 3, and
Part M. Once RD is determined, all patients will roll over into Part 3 at the
RD. Please refer to Section 4.3.1 for details on the interim placebo cross-over
dose.


Part 2
In Part 2, of the study, approximately 303 patients with ISM will be enrolled
(at least 204 evaluable patients with TSS >= 28 and up to 99 patients with TSS <
28). Once the targeted sample size in Part 2 for patients with TSS >= 28 has
been met, enrollment of patients with TSS < 28 may stop even if the number of
patients in the TSS < 28 group is less than 99. Patients will be randomly
assigned to treatment at a 2:1 ratio to receive the RD of elenestinib + BSC or
matching placebo + BSC, respectively. Randomization will be stratified based on
TSS score (< 28 and > 28) and on centrally measured serum tryptase levels at
Screening (< 20 ng/mL versus >= 20 ng/mL). In addition, enrollment of patients
with < 20 ng/mL serum tryptase will be capped at approximately 20% for patients
with TSS >= 28 and approximately 20% for patients with TSS <28. Elenestinib and
placebo dosing will be administered orally, QD, continuously. Patients will be
assessed through 24 weeks of treatment (Week 25) for safety, laboratory
monitoring, and QoL assessments. Sparse PK sampling will be performed in all
patients. For patients with mastocytosis in skin who opt to do so, skin
photographs will be taken every 12 weeks. The ISM-SAF should be completed
daily. After completion of 24 weeks of treatment, the ISM-SAF, BM, and skin
biopsy will be repeated for mast cell quantification by the Central Pathology
Laboratory and skin photographs (optional) may be taken in patients with
baseline mastocytosis in skin. Each patient completing the assessment after 24
weeks of treatment (Week 25) will roll over into the Part 3 long-term extension
to receive the RD of elenestinib QD in an open-label fashion. The Week 25
assessments will be the Baseline for Part 3. After all patients in Part 2 roll
over into Part 3, all Part 2 treatment assignments will be unblinded. At this
point the primary endpoint of proportion of patients with a >=30% reduction in
TSS from Baseline to after 25 weeks of treatment (Week 25) and other efficacy
endpoints will be analyzed.

Part 3
After all Part 1 patients have completed Part 1 and the RD has been determined
or as each patient in Part 2 completes their study assessments after 24 weeks
of treatment (Week 25), patients will roll over to Part 3. All patients will
receive open-label treatment with the RD of elenestinib.
In Part 3, Part 1 patients who received elenestinib will have study visits
every 4 weeks until Week 25, then every 8 weeks until Week 49. After Week 49,
patients will have study visits every 12 weeks for a total treatment duration
of up to approximately 4 years, inclusive of Part 1. Part 1 patients who
received placebo may have weekly visits until Week 5 in Part 3 at the
discretion of the Investigator.
In Part 3, patients rolling over from Part 2 will have weekly visits until Week
5 and will then follow the same schedule as Part 1 patients according to the
SoA in Table 4.
Additional ad hoc study visits may occur based on the Investigator*s clinical
judgement.
The ISM-SAF will be completed daily for patients in Part 1 and Part 2, and Q

In Part 1 of the study, approximately 40 patients with ISM with TSS >= 28 will
be equally randomized (1:1:1:1 ratio) to 1 of 3 doses of elenestinib +BSC or
to placebo +BSC.

In Part 2, of the study, approximately 303 patients with ISM will be enrolled
(approximately 204 patients with TSS >= 28 and up to 99 patients with TSS < 28).
Patients will be randomly assigned to treatment based on a 2:1 ratio to receive
the RD of elenestinib + BSC or matching placebo + BSC, respectively.

After all Part 1 patients have completed Part 1 and the RD has been determined
or as each patient in Part 2 completes their study assessments after 24 weeks
of treatment (Week 25), patients will roll over to Part 3. All patients are
eligible to receive open-label treatment with the RD of elenestinib .

In Part 3, patients who received elenestinib in Parts 1 or 2 will have study
visits every 4 weeks until after 24 weeks of treatment (Week 25), then every 8
weeks until Week 49. After Week 49, patients will have study visits every 12
weeks for a total treatment duration of up to approximately 4 years, inclusive
of Part 1 or Part 2 as applicable.
Patients assigned to placebo during Part 1 or Part 2 who are starting
elenestinib for the first time in Part 3 may have weekly visits until Week 5
at the discretion of the Investigator and will then follow the same schedule in
Part 3 that patients who received elenestinib in Part 1 or Part 2 will follow
as per SoA (Table 4)

In Part S of the study (exploratory), approximately 20 patients with SSM will
receive open-label elenestinib at a dose of 100 mg QD + BSC. Formulation and
administration will be the same as described above for Part 2 but will not
include a placebo arm. An alternative lower dose may be selected by the
Investigator after consultation with the Sponsor. Assessments will be collected
as described in the SoA (Table 5). BM biopsies will be required for PPR
assessment by the Central Pathology Laboratory. Patients will continue to be
treated up to approximately 4 years.

In Part M of the study (exploratory), approximately 20 patients with mMCAS will
receive open-label elenestinib QD + BSC. Dose, formulation, and administration
will be the same as described above for Part 2 but will not include a placebo
arm.

Two PK groups may be enrolled to better evaluate the PK, safety, and efficacy
of elenestinib. SM patients may have GI issues and/or take concomitant
medications that may impact absorption of elenestinib requiring more specific
guidance to optimize dosing. Optional PK group(s) is/are therefore included. An
optional PK group of up to 20 patients may be enrolled prior to and/or in
parallel to Part 1. An additional PK group of up to 20 patients may also be
enrolled prior to Part 2.

Both PK groups will receive elenestinib in an open label fashion. Patients
enrolled in optional PK group prior to and/or parallel to Part 1 will receive
elenestinib 50 mg QD. For patients enrolled in optional PK group prior to Part
2, elenestinib will be administered orally, QD at the RD and will not exceed
doses previously determined to be safe.

POSSIBLE DISCOMFORTS AND RISKS OF BLU-263
During the study, you may have discomforts and possible risks from BLU-263 and
from the study procedures. BLU-263 has been studied in healthy volunteers and
SM patients; however, safety information is considered limited and your
experience may be different. The clinical study with BLU-263 in patients with
Indolent Systemic Mastocytosis (ISM) is still ongoing. Some side effects are
unknown, and there is always the possibility that unknown risks may occur.
Additionally, discomforts and risks may vary from person to person. Everyone
taking part in the study will be watched carefully for side effects; however,
doctors do not know all the discomforts and risks that may happen. There is
always the possibility that unknown risks may occur. These may be mild or
severe, and in some cases may be long-lasting, or may never go away. There may
even be a risk of death. If any discomforts or risks occur, you must tell your
study doctor.
Your doctor may give you medications to help lessen some of the discomforts and
risks. Depending on your side effect to BLU-263 occurs, your doctor may
interrupt or reduce the study drug dose or stop the study drug.

Possible Side Effects Observed in Patients with ISM

Based on results from 115 patients, who were dosed at 25 mg, 50 mg, 75 mg and
100 mg, most of the patients were treated up to 35 weeks, the following side
effects have been reported in patients who are receiving BLU-263:

Very common side effects (in at least in 10% of the patients)
• Diarrhoea
• Headache
• Nausea
• Oedema (swelling of lower legs and hands, swollen eyelid)
• Joint pains
• Abdominal Pain
• Lack of energy/ fatigue
• Respiratory infections
• Dizziness
• Flushing
• Muscle pain
Common side effects (between 5% and 10% of the patients)
• Back pain
• Itchy skin
• Changes in laboratory tests, which may indicate injury to the liver or muscle
(e.g.: Blood alkaline phosphate increased)
• Weight increased
• Increased blood pressure
• Vomiting
• Abdominal swelling
• Constipation
• Rash
• Bone pain
• Cough
• Trouble sleeping
• Urinary tract infection
• Hair loss
• Redness of skin
• Inflammation of the stomach and intestines
• General feeling of discomfort, illness or lack of well-being

Most of the reported events were mild or moderately severe.


Possible Side Effects Based on Animal Studies
What happens in animals does not always predict what will happen to people who
take the same drug. Based on studies of high doses in animals, other possible
effects in humans of BLU-263 are:
• Low number of red blood cells and white blood cells.
• Loss of cells in organs that support your body*s immune response (e.g., bone
marrow, lymph nodes, spleen etc.).
• Effects on male reproductive system including shrinkage of testes and
prostate gland.
• Effects on female reproductive system including increased mucus production in
the vagina, bleeding in the ovaries and uterus, and ovarian cysts.
• Bleeding in the brain, and pituitary gland (a gland important in controlling
growth and development and regulating other glands).
• Increase in the size of the heart.
• Clustering of a type of white blood cells in the lungs.
• Abnormal levels of liver enzymes in blood
• A risk of abnormal development of the embryo and fetus if BLU-263 is
administered to a pregnant woman.


RISK TO THE UNBORN CHILD

Female patients: We do not know if the study drug BLU-263 will affect mother*s
milk or an unborn child. Therefore, breast-feeding and pregnant women are not
allowed to take part in the study. Due to unknown risks and potential harm to
the unborn child/ infant, you should not become pregnant or nurse a baby while
on this study. You must have a negative pregnancy test prior to enrolling in
the study.
Unless you cannot have children because of surgery or other medical reasons
(you had an effective tubal ligation, or had the ovaries or the uterus removed;
or you are post-menopausal), you must use a highly effective method of birth
control from the time of signing the informed consent form, and throughout the
entire study drug treatment period, and for 30 days following the last dose of
study drug. Highly effective methods of birth control with low user dependence
include:
• Hormonal birth control pills/oral contraceptives, injectable contraceptives,
contraceptive patches, or contraceptive implants (female patients using this
method must also agree to use a back-up barrier method, preferably a male
condom)
• Intrauterine devices (IUD)
• Intrauterine hormone-releasing system (IUS) (female patients using this
method must also agree to use a back-up barrier method, preferably a male
condom).
• Bilateral tubal occlusion
• Male partner vasectomy or other method of surgical sterilization provided
that the partner is your only sexual partner and a doctor has confirmed that
the sterilization was successful.
• Abstinence of heterosexual intercourse if it is the preferred and usual
lifestyle
The following methods of contraception are not considered highly effective and
are not acceptable:
• Oral hormonal contraceptives that do not inhibit ovulation (progesterone-only
pills, often called *mini pills*)
• Barrier methods including condoms, cervical caps, or diaphragm with or
without spermicide
You must use birth control methods as directed above, unless you completely
avoid having heterosexual intercourse.

Male patients: While BLU-263 does not have direct effects on sperm, you should
not get your partner pregnant during the study drug period due to potential
abnormal development of the embryo and fetus. Even if you are surgically
sterilized (i.e. have had a vasectomy) you must agree to use an appropriate
method of barrier contraception (latex condom with a spermicidal agent) from
the time of signing the informed consent form, and throughout the entire study
drug treatment period, and for 90 days following the last dose of study drug.
Or, you should completely avoid having heterosexual intercourse. Male patients
must agree to not donate sperm from the first dosing until at least 90 days
after the last dosing.
All patients (male or female): If you or your partner becomes pregnant during
this study, you must tell the study doctor immediately. The doctor will advise
you of the possible risks to your unborn child and discuss options for managing
the pregnancy with you. For female patients who become pregnant while on this
study, the study drug will be stopped immediately, and the pregnancy will be
followed until conclusion.