A Phase 1/2, open-label, 2-arm study evaluating BLU-263 as monotherapy and in combination with azacitidine, in patients with KIT altered hematologic malignancies

The goal of this clinical trial is to evaluate elenestinib (BLU-263) in participants with
Advanced Systemic Mastocytosis (AdvSM), SM with an associated hematologic neoplasm (SM-AHN),
and other hematologic malignancies. The main questions it aims to answer are:

- Determine Recommended Dose of elenestinib (BLU-263) monotherapy for participants with
AdvSM

- Safety and tolerability of elenestinib (BLU-263) monotherapy

- Efficacy of elenestinib (BLU-263) monotherapy in participants with AdvSM

- Determine Recommended Dose of elenestinib (BLU-263) in combination with azacitidine in
participants with AdvSM

- Safety and tolerability of elenestinib (BLU-263) in combination with azacitidine

- Efficacy of elenestinib (BLU-263) in combination with azacitidine in participants with
AdvSM

The estimated study duration for each participant will be approximately 4 years: 2 years of
treatment followed by 2 years of follow-up. Participants may be required to attend monthly
visits for the first six months, followed by quarterly visits for the remainder of the study.

Key Inclusion Criteria :

- Participant has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of
0-2

- Participant must have a new Bone Marrow (BM) biopsy or may use archival tissue if
taken within 56 days prior to C1D1 and participant must be willing to have follow-up
BM Biopsies.

- Participants receiving antineoplastic therapy within the preceding 12 weeks must have
discontinued therapy due to disease progression, refractory disease, lack of efficacy,
or intolerance.

- Participants treated with 1 prior selective KIT inhibitor (such as avapritinib or
CGT9486) will be permitted on study after confirmation of KIT D816V mutation and with
written approval of the study Sponsor. Participants who discontinued treatment with a
prior selective KIT inhibitor due to a severe AE that was thought to be related to
prior treatment will not be eligible to participate in the study.

Arm 1 (Monotherapy): Participants must have one of the following AdvSM diagnoses, based on
World Health Organization (WHO) diagnostic criteria.

Before enrollment, diagnosis of AdvSM must be confirmed based on Central Pathology
Laboratory assessment of BM:

1. Aggressive SM (ASM).

2. SM-AHN that in the opinion of the Investigator is not considered to be a candidate for
Hypomethylating agent (HMA) monotherapy. Incidental indolent, low-grade lymphoid AHNs
(eg, chronic lymphocytic leukemia) not requiring treatment are eligible.

3. Mast cell leukemia (MCL), including diagnoses with an AHN component, that does not
require a C-finding.

4. Upon discussion with the Sponsor, other relapsed or refractory hematologic neoplasms
with evidence of aberrant KIT or PDGFR may be considered for enrollment. (eg,
participants with chronic myeloid neoplasms, such as subvariants of MDS/MPN that
harbor activating KIT exon 17 mutations but do not fulfill the diagnostic criteria of
SM-AHN, and participants with myeloid/lymphoid neoplasms with PDGFRa/b fusion genes
and mutations conferring resistance to imatinib, such as T674I or D842V).

Key Exclusion Criteria:

- Diagnosis of a Philadelphia chromosome positive malignancy

- Acute myeloid leukemia.

- If the participant is receiving corticosteroids, and the dose has not been stable for
≥7 days.

- Within the 14 days prior to enrollment, participant has received any antineoplastic
therapy (including midostaurin, avapritinib and other tyrosine kinase inhibitors
[TKIs]) or an investigational agent.

- Participant has received hydroxyurea within 7 days prior to the first dose of
elenestinib (BLU-263).

- Participant received prior HMA therapy (e.g., azacitidine, decitabine) for the current
diagnosis.

- Participant must not be eligible for allogenic hematopoietic stem cell
transplantation.

- Participant received prior radiotherapy within 14 days of screening BM biopsy.

- Participant received any hematopoietic growth factor (except erythropoietin) within 14
days of screening BM biopsy, or requiring growth factors to maintain adequate
neutrophil or platelet levels.

Those participants maintained on a chronic dose of erythropoietin, whose hemoglobin is
stable, and dose of erythropoietin has not been changed in the prior 28 days are allowed on
study.

- Participant received >1 prior selective KIT inhibitor (eg: avapritinib or
bezuclastinib).

- Participant have any of the following laboratory abnormalities on last laboratory
assessment within 14 days prior to the first dose of initiation of study drug: a.
Alanine aminotransferase and aspartate aminotransferase > 3 × ULN; > 5 × ULN if
associated with clinically suspected liver infiltration by mastocytosis or another
disease for which the patient enrolled into the study b. Total bilirubin > 1.5 × ULN;
> 3 × ULN if associated with liver infiltration by the disease being treated or in the
presence of Gilbert's Disease. (In the case of Gilbert's disease, a direct bilirubin >
2.0 ULN would be an exclusion) c. Estimated (Cockcroft-Gault formula) or measured
creatinine clearance < 40 mL/min d. Absolute neutrophil count < 0.5 × 10^9/L

- Participant has had a major surgical procedure within 14 days of the first dose of
study drug.

- History of another primary malignancy that has been diagnosed or required therapy
within 1 year prior to the first dose of study drug. The following are exempt from the
1-year limit: completely resected basal cell and squamous cell skin cancer, curatively
treated localized prostate cancer, GI stromal tumor, and completely resected carcinoma
in situ of any site.

- Mean resting QTcF > 480 msec, a history of prolonged QT syndrome or Torsades de
pointes, or a familial history of prolonged QT syndrome.

- Clinically significant, uncontrolled, cardiovascular disease.

Arm 1 (Monotherapy):

- Myelodysplastic Syndrome (MDS) that is very high- or high-risk as defined by the
International Prognostic Scoring System for Myelodysplastic Syndromes-Revised
(IPSS-R).

- A myeloid AHN with ≥10% BM or peripheral blood blasts.

- Platelet count <50 x 10^9/L (within 4 weeks prior to the first dose of study drug) or
receiving platelet transfusions or thrombopoietin receptor agonists (TPO-RA) within
the prior 14 days.