Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies

Inclusion Criteria:

For Part 1:Patients must have one of the following diagnoses based on World Heath
Organization (WHO) diagnostic criteria:

- Aggressive systemic mastocytosis (ASM).

- Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) and at least 1
C-finding attributable to systemic mastocytosis (SM). The AHN must be myeloid, with
the following exceptions that are excluded: Acute myeloid leukemia (AML),
Myelodysplastic syndrome (MDS) that is very high- or high-risk as defined by the
International prognostic scoring system for myelodysplastic syndromes (IPSS-R) and
Philadelphia chromosome positive malignancies.

- Mast cell leukemia (MCL).

- Histologically- or cytologically- confirmed myeloid malignancy that is relapsed or
refractory to standard treatments. AML, MDS that is very high- or high-risk as defined
by the IPSS-R, and Philadelphia chromosome positive malignancies are excluded.

- Upon discussion with the sponsor, other relapsed or refractory, potentially
avapritinib-responsive hematologic neoplasms (e.g., evidence of aberrant KIT or
platelet derived growth factor receptor (PDGFR) signaling) may be considered for
enrollment.

For Part 2, patients must have one of the following diagnoses, based on WHO diagnostic
criteria:

- ASM.

- SM-AHN that also has at least 1 C-finding attributable to SM. The AHN must be myeloid,
with the following exceptions that are excluded: AML, MDS that is very high- or
high-risk as defined by the IPSS-R, and Philadelphia chromosome positive malignancies.

- MCL.

For Part 2, Cohort 2, patients must have at least 1 measurable C-finding per modified
IWG-MRT-ECNM criteria at Baseline, attributed to SM unless diagnosis is MCL, which does not
require a C-finding.

- Cytopenias: ANC < 1.0 × 10⁹/L or hemoglobin < 10 g/dL or platelet count < 75 × 10⁹/L.

- Symptomatic ascites or pleural effusion requiring medical intervention such as: use of
diuretics (Grade 2) or ≥ 2 therapeutic paracenteses or thoracenteses (Grade 3) at
least 28 days apart over the 12 weeks before study entry and 1 of the procedures is
performed during the 6 weeks before study start (C1D1).

- ≥ Grade 2 abnormalities in direct bilirubin (> 1.5 × upper limit of normal [ULN]),
aspartate aminotransferase (AST; > 3.0 × ULN), alanine aminotransferase (ALT; > 3.0 ×
ULN), or alkaline phosphatase (> 2.5 × ULN) with 1 of the following present: ascites
or clinically relevant portal hypertension or liver mast cell infiltration that is
biopsy-proven or no other identified cause of abnormal liver function.

- ≥ Grade 2 hypoalbuminemia (< 3.0 g/dL).

- A spleen that is palpable ≥ 5 cm below the left costal margin.

- Transfusion-dependent anemia defined as: transfusion of ≥ 6 units packed red blood
cells (PRBCs) in the 12 weeks before start of treatment (C1D1) and most recent
transfusion occurring during the preceding 4 weeks and transfusion administered for
hemoglobin ≤ 8.5 g/dL and reason for transfusion is not bleeding, hemolysis, or
therapy-related.

- Transfusion-dependent thrombocytopenia, defined as: transfusion of ≥ 6 units of
apheresed platelets (or ≥ 6 pools of random donor or buffy coat platelets) during the
12 weeks preceding treatment (C1D1) and ≥ 2 units transfused during the preceding 4
weeks and transfusions administered for platelet count < 20 × 10⁹/L.

- > 10% weight loss that is medically documented over the preceding 24 weeks (± 12
weeks).

Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

Exclusion Criteria:

- QT interval corrected using Fridericia's formula (QTcF) >470 milliseconds

- Platelet count <25,000/mL

- Absolute neutrophil count <500/mL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >3 x the upper
limit of normal (ULN); >5 × ULN if associated with clinically suspected liver
infiltration by mastocytosis or another disease for which the patient enrolled into
the study

- 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

- Estimated (Cockroft-Gault formula) or measured creatinine clearance <40 mL/min

- Brain malignancy or metastases to the brain

- History of a seizure disorder or requirement for anti-seizure medication

- Known risk of intracranial bleeding, such as a brain aneurysm or history of subdural
or subarachnoid bleeding

- Eosinophilia and known positivity for the FIP1L1-PGDFRA fusion, unless the patient has
demonstrated relapse or progressive disease on prior imatinib therapy