A 3-Part, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate Safety and Efficacy of Avapritinib (BLU-285), a Selective KIT Mutation-Targeted Tyrosine Kinase Inhibitor, in Indolent and Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy

Systemic mastocytosis (SM) is a rare, clonal mast cell (MC) neoplasm primarily
driven by the KIT D816V mutation, and is characterized by the uncontrolled
proliferation and activation of MCs, often present as aggregates in skin, bone
marrow (BM), spleen, liver, gastrointestinal (GI) tract and other organs. This
leads to 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 quality of life (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, steroids, and anti-IgE
antibodies. Available cytoreductive therapies, such as cladribine and
midostaurin, which can reduce disease burden, have significant side effects and
are used only for the small minority (5%) of patients with advanced disease,
which confers reduced survival outcomes. The prevalence of SM is estimated at
approximately 1 in 10,000 patients.
Ninety-five percent of SM patients are considered to have non-advanced SM
(non-AdvSM), which primarily includes the World Health Organization (WHO)
variant of indolent SM (ISM) as well as a small number of patients with
smoldering SM (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. Less than 5% of patients with ISM show disease
progression to severe forms of SM. SSM patients have more disease burden and
organ involvement and 9% ultimately progress to AdvSM.
Five percent of SM patients have AdvSM, which includes the WHO variants of
aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN) and
mast cell leukemia (MCL). In addition to MC activation symptoms due to organ
involvement, AdvSM patients have compromised organ function and/or aggressive
pathologic features, both associated with poor overall survival. Almost 20% of
patients with AdvSM eventually transform to acute myeloid leukemia. The KIT
D816V mutation is the driver of disease in 95% of patients, regardless of SM
subtype. Avapritinib was developed to very potently and selectively target KIT
D816V, with a biochemical 50% inhibitory concentration (IC50) of 0.23 nM.
Avapritinib has demonstrated potent activity against in vitro and in vivo KIT
D816V models. In chronic toxicology and safety pharmacology studies in rats and
dogs assessing active low doses of avapritinib, no adverse effects were
observed.
In the open-label, Phase 1, BLU-285-2101 study, avapritinib at doses of 30 mg
to 400 mg once daily (QD) demonstrated significant reductions in MC burden,
improved baseline patient symptoms, and had a well-tolerated side-effect
profile for patients with AdvSM.
Due to these preliminary results, the double-blinded placebo-controlled, Phase
2 BLU-285-2203 clinical trial was initiated to study the safety and efficacy of
avapritinib in reducing symptoms and MC burden in patients with ISM with lower
doses of avapritinib.
Patients were initially enrolled into Part 1 of the study, which was conducted
to identify the recommended Phase 2 dose (RP2D) with the appropriate
benefit-risk for patients with ISM. Due to superior tolerability and equivalent
efficacy of symptom reduction by C7D1, the 25-mg QD dose was selected as the
RP2D for Part 2 (see Part 1 results and Selection of Recommend Phase 2 Dose,
below).
After determination of RP2D, Part 2 will open to enrollment, which is being
conducted to determine the efficacy of avapritinib in reducing symptoms
(compared with placebo) in conjunction with best supportive care (BSC). The
primary endpoint of Part 2 is the main change in Total Symptom Score (TSS) of
the ISM Symptom Assessment Form (ISM-SAF) from baseline to Cycle 7 Day 1
(C7D1). After completion of Parts 1 or 2, patients have the opportunity to
receive avapritinib in an open-label extension cohort (Part 3), to further
characterize the safety and efficacy of long-term treatment.

This study has been transitioned to CTIS with ID 2024-512585-34-00 check the CTIS register for the current data.

Primary:
Part 1
• To determine the RP2D of avapritinib in patients with ISM for use in Part 2
and Part 3 of the study.

Part 2
• To determine main change in ISM-SAF TSS from baseline to C7D1, compared to
placebo.

Part 3
• To assess the long-term safety and efficacy of avapritinib in ISM patients.

Key Secondary Objectives (Part 2 Only):
• To determine the proportion of avapritinib treated patients with ISM with a
>=50% reduction in serum tryptase from baseline to C7D1, compared to placebo.
• To determine the proportion of avapritinib treated patients with ISM with a
>=50% reduction in peripheral blood KIT D816V allele fraction from baseline to
C7D1 or undetectable (<0.02%) for patients with detectable mutation at
baseline, compared to placebo.
• To determine the proportion of avapritinib treated patients with ISM
achieving >=50% reduction in ISM-SAF TSS from baseline to C7D1, compared to
placebo.
• To determine the proportion of avapritinib treated patients with ISM
achieving >=30% reduction in ISM-SAF TSS from baseline to C7D1, compared to
placebo.
• To determine the proportion of avapritinib treated patients with ISM with a
>=50% reduction in bone marrow MCs from baseline to C7D1, or no aggregates for
patients with aggregates at baseline, compared to placebo.

Additional Secondary Objectives:
Part 1 and Part 2
• Assess change in the following measures of MC burden in each treatment cohort
from baseline to C4D1 (Part 1) and C7D1 (Part 2):
o Serum tryptase.
o KIT D816V allele burden in blood.
o BM MCs.
• Assess change in BSC usage for SM symptoms.
• Assess change in GI and skin domains, neurocognitive symptom cluster (brain
fog, headache and dizziness), and individual symptom scores of ISM-SAF.
• Assess change in "lead (most severe) symptom" and *lead (most severe)
domain/symptom cluster* score (ie, individual symptom and domain/symptom
cluster with highest mean score at baseline in each patient) of ISM-SAF.
• Assess changes in other Patient-Reported Outcomes (PROs) and QoL measures
based on the Mastocytosis Quality of Life Questionnaire (MC-QoL), Patient's
Global Impression of Symptom Severity (PGIS), 12-item Short Form Health Survey
(SF-12), Patients' Global Impression of Change (PGIC), and the 5-level EuroQol
5D (EQ-5D-5L) questionnaire.
• Assess the safety and tolerability of avapritinib, as assessed by adverse
events (AEs), vital signs, electrocardiograms (ECGs), and laboratory tests.
• Assess the pharmacokinetics (PK) of avapritinib.
• Correlate avapritinib exposure with safety and efficacy endpoints.

Part 3
• Assess changes in the following measures of MC burden: o Serum tryptase.
o KIT D816V allele burden in blood.
o Bone marrow MCs (optional at approximately 1 year after the biopsy at the end
of Parts 1 and 2).

• Assess change in BSC usage for SM symptoms.
• Assess change in "lead (most severe) symptom" score and *lead (most severe)
domain/symptom cluster* (ie, individual symptom and domain/symptom cluster with
highest mean score at baseline in each patient) of ISM-SAF.
• Assess the proportion of avapritinib treated patients with ISM achieving >=50%
reduction in TSS at 1 year after initiation of avapritinib therapy.
• Assess the proportion of avapritinib treated patients with ISM achieving >=30%
reduction in TSS at 1 year after initiation of avapritinib therapy.
• Assess change in TSS, symptom cluster, domain scores, and individual symptom
scores of ISM-SAF from Part 3 baseline (and Part 1 or Part 2 baseline for
patients on the same dose of avapritinib in both parts of the study) to C4D1,
C7D1, C11D1, and C13D1.
• Assess change in other PROs and QoL measures based on the MC-QoL, PGIS,
SF-12, PGIC, and EQ 5D-5L questionnaires.
• Assess the safety and tolerability of avapritinib, as assessed by AEs, vital
signs, ECGs, and laboratory tests.
Exploratory Objectives:
Parts 1, 2, and 3
• Explore potential correlations between the ISM-SAF and other PRO and QoL
measures and individual measures of MC burden.
• Assess correlation of clinical features (eg. demographics, laboratory tests,
concomitant medications, AEs, concomitant mutations) with activity against ISM.
• Identify potential new biomarkers (DNA, RNA, serum protein) in blood for
pharmacodynamic effects and safety of avapritinib.
• Assess whether avapritinib can affect platelet aggregation as a possible
mechanistic contributor to bleeding events.
• Assess change in bone density by dual x-ray energy assessment (DXA)/bone
densitometry scan (optional, to be performed at the Investigator*s discretion).
• Assess changes in skin lesions by photography in patients with baseline
mastocytosis in skin from baseline to C4D1 (in Part 1) and C7D1 (in Part 2)
• Assess changes in skin lesions by photography in patients with new
mastocytosis in skin from baseline (Part 3) to C7D1 (Part 3).
• Assess changes in MCs in skin biopsies in patients with baseline mastocytosis
in skin.
• Assess change in the frequency of anaphylactic episodes based on epinephrine
use.

This is a Phase 2, randomized, double-blind, placebo-controlled study comparing
the efficacy and safety of avapritinib + BSC with placebo + BSC in patients
with ISM whose symptoms are not adequately controlled by BSC.
In Part 1, the optimal dose of avapritinib (RP2D) will be identified in
patients with ISM. In Part 2, patients with ISM will be randomly assigned to
the RP2D of avapritinib identified in Part 1 + BSC, or to matching placebo +
BSC. In Part 3, patients who have completed treatment in Part 1 or Part 2 of
the study may participate in a long-term extension, receiving avapritinib at
the RP2D + BSC.
Screening
After provision of written informed consent, patients will be evaluated for
eligibility during the Screening period. In both Part 1 and Part 2, immediately
after informed consent is obtained, patients will begin daily symptom reporting
with the ISM-SAF questionnaire, using a hand-held device. The Investigators
may, at their discretion, optimize BSC medications, which may take up to 4
weeks, but if already optimized, may proceed directly to the 14-day TSS
eligibility assessment period.
Doses and schedules of BSC for SM symptom management will need to be stable for
at least 14 days (which may have begun prior to signing of the informed consent
form [ICF]) before the beginning of the ISM-SAF TSS eligibility period. The
patient should not be experiencing an acute flare of symptoms beyond their
typical baseline symptoms. As soon as BSC is optimized, the investigator will
initiate the eligibility TSS calculation over a 14-day period to determine
symptom eligibility. Patients not meeting the symptom severity threshold will
be deemed screen failures and will not be eligible for study participation.
Patients meeting the threshold for symptom severity will continue completing
the ISM-SAF daily without interruption through screening and study
participation if deemed eligible.
After ISM-SAF symptom eligibility is confirmed, the screening assessment and
central review period may begin, which may last up to 8 weeks. Patients meeting
the threshold for symptom severity will continue completing the ISM-SAF daily
without interruption into Part 3. Screening procedures will include the
following: BM biopsy (an archival sample obtained within the preceding 24 weeks
or a fresh sample) and skin biopsy of lesional and non-lesional skin (in
patients with mastocytosis in skin) will be performed and sent to the Central
Pathology Laboratory for confirmation of SM diagnosis and quantification of
MCs. Patients with mastocytosis in skin may have skin photographs taken
(optional, patients may choose not to undergo skin photography at any time).
Additional procedures will include MRI or computed tomography scan of the
brain; bone densitometry; serum tryptase, KIT D816V mutation testing; routine
laboratory testing; ECG; and physical examination.
All screening procedures should be completed within a 4-week period, followed
by central review and approval for enrollment, which may take up to an
additional 4 weeks. Patients who fail screening due to objective criteria (ie,
pathology, laboratory, other diagnostic tests) may be re-screened. Once
screening procedures are completed and the patient determined to meet
eligibility criteria, a 14-day baseline TSS calculation will be initiated to
establish baseline TSS scores. Dosing will occur no later than 8 weeks (56
days) after the confirmation of TSS eligibility, except with written permission
of the Sponsor. Patients who fail screening due to objective criteria (ie,
pathology, laboratory, other diagnostic tests) may be re-screened if the
objective criteria subsequently meet the eligibility criteria.
At the completion of the 14-day baseline TSS calculation, the patient will be
randomly assigned to treatment and begin dosing.
Part 1
In Part 1 of the study, approximately 40 patients will be randomly assigned to
1 of 3 doses of avapritinib or to placebo. Each dose-level cohort and placebo
group in Part 1 will be composed of 10 patients. The 3 dose levels of
avapritinib will be tested in parallel: 25, 50, and 100 mg. Patients, study
staff, and the Sponsor will be blinded to treatment assignment; however, select
personnel, primarily functioning in safety reporting and conduct of the
independent data monitoring committee (IDMC) will be unblinded throughout the
study.
Avapritinib will be administered orally, once daily (QD) in continuous 28-day
cycles. Patients will be assessed weekly for the first 4 weeks (until the RP2D
is determined) for safety, laboratory monitoring, and QoL assessments.
Intensive PK sampling will be performed in all patients. The ISM-SAF will be
completed daily. After completion of 12 weeks of treatment (C4D1), BM and skin
biopsy will be repeated for MC quantification by the Central Pathology
Laboratory and skin photographs (optional) may be taken in patients with
baseline mastocytosis in skin.
The RP2D will be determined based on the efficacy, safety, and PK at each dose
level. The major efficacy criterion for selection of the RP2D will be the dose
of avapritinib that produces the maximum reduction in TSS, as assessed using
the ISM-SAF at C4D1 compared with baseline (Day -14 to Day -1), but other
measures of efficacy (eg, change in serum tryptase) and other timepoints will
also be taken into consideration. Once C4D1 assessments are completed, patients
will continue on assigned therapy and dose until the RP2D is determined, at
which time all Part 1 patients will roll over to Part 3 where they will receive
avapritinib in an open-label fashion at the RP2D.
Part 2
In Part 2 of the study, approximately 204 ISM patients will be enrolled.
Patients will be randomly assigned to treatment based on a 2:1 ratio to receive
avapritinib 25 mg QD + BSC (approximately 136 patients) or matching placebo +
BSC (approximately 68 patients), respectively. Randomization will be stratified
based on serum tryptase levels at Screening (<20 ng/mL vs >= 20 ng/mL). In
addition, enrollment of patients with <20 ng/mL serum tryptase will be capped
at approximately 20% (ie, approximately 40 patients) of Part 2 enrollment.
Patients, study staff, and the Sponsor will be blinded to an individual
patient*s treatment assignment until Part 2 is complete and all patients roll
over into Part 3. Select personnel, primarily functioning in safety reporting
and conduct of the IDMC will be unblinded throughout the study.
Avapritinib and placebo dosing will be administered orally, QD, in continuous
28-day cycles. Patients will be assessed every 4 weeks through C7D1 for safety,
laboratory monitoring, and QoL assessments. Sparse PK sampling will be
performed in all patients and a subset will receive intensive PK. For patients
that opt to do so, skin photographs will be taken every 12 weeks in patients
with mastocytosis in skin. The ISM-SAF will be completed daily. After
completion of 6 cycles of treatment and the ISM-SAF through C7D1, BM and skin
biopsy will be repeated for MC quantification by the Central Pathology
Laboratory and skin photographs (optional) may be taken in patients with
baseline mastocytosis in skin. Each patient completing the C7D1 assessments
will roll over into the Part 3 long-term extension to receive avapritinib 25 mg
QD in an open-label fashion. After all patients roll over into Part 3, all Part
2 treatment assignments will be unblinded. At this point the primary endpoint
of mean change in ISM-SAF TSS from baseline to C7D1 and other efficacy
endpoints will be analyzed.
Because prolonged high-dose steroids may reduce symptom scores and some
objective measures of MC burden, patients who received prednisone greater than
20 mg daily or equivalent within 7 days before C7D1, or for greater than 14
consecutive days at any point from C1D1 to C7D1, will be excluded from the
primary efficacy analysis.
Part 3
After all patients complete Part 1 and t

In Part 1, patients will receive treatment for 12 weeks, then continue on
assigned therapy and dose until the RP2D is determined, then roll over into
Part 3. In Part 2, patients will receive treatment for at least 24 weeks, then
roll over to Part 3. Patients will continue to receive treatment in Part 3 for
up to 5 years, inclusive of Part 1 and Part 2.

For full details see appendix 1 in the protocol ( schedule of assessments)

- participation in this study is anticipated to be maximum 5 years but the
duration may be shorter or longer for any individual subject depending on
individual circumstances and choices and when a subject will start with the
study. This study includes a screening period of maximum 14 weeks, a treatment
period part 1 (12 weeks to 12 months) OR part 2 (approx 12 weeks) and a part 3
( minimum 8 weeks).

The subjects will visit the hospital approximately 20 times during part 1 (or
part 2) and part 3. A visit will take between 2 and 8 hours.
- physical examinations will be done and questions will be asked about medical
history.
- ECGs will be done
- weight, height, blood pressure, temperature, heartbeat will be measured
- blood and urine sampling will be done including PK sampling.
- The investigator will also test female participants of childbearing potential
for pregnancy.
• Bone marrow biopsy and aspirate will be done to confirm the SM diagnosis and
document the extent of the SM
• Brain MRI or CT will be done at screening to confirm that no brain related
issues are found
• Bone Densitometry Scan (DXA scan) will be done to evaluate if the bones are
less dense than normal due to SM
• Skin photographs will be performed in subjects who have skin
mastocytosis.After the photographs, 5-mm punch biopsies of both a skin lesion
and normal skin will be performed.
• Subjects need to complete electronic questionnaires that evaluates symptoms
related to SM and will complete Quality of Life questionnaires.

Possible side effects that are already known are described in the IB and
patient information and in section E9