Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies (AZURE)

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• 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. Arm 2 (Combination Therapy): A2_1. Intermediate, low, or very low risk MDS. A2_2. Known hypersensitivity to azacitidine or any of their ingredients. A2_3. Platelet count < 75 x 109/L (within 4 weeks of the first dose of study drug) or receiving platelet transfusions or TPO-RA within the prior 14 days.