(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis

Key Inclusion Criteria:

All Patients

-1. Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.

Part 1 and Part 2

• 2. Patient must have moderate-to-severe symptoms based on minimum mean total symptom score (TSS) of the ISM Symptom Assessment Form (ISM-SAF) over the 14-day eligibility screening period.
• 3. Patient has confirmed diagnosis of ISM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO diagnostic criteria. Archival biopsy may be used if completed within the past 12 months.
• 4. Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms, as determined by the Investigator, with at least 2 of the following symptomatic therapies administered: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
• 5. Patients must have BSC for ISM symptom management stabilized for at least 14 days prior to starting screening procedures.
• 6. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days.

Part M

• 7. Patients must have mMCAS, confirmed by Central Pathology Review of BM biopsy. An archival biopsy may be used if completed within the past 12 months.
• 8. Patients must have tryptase < 20 ng/mL.
• 9. Patients must have KIT D816V in peripheral blood (PB) or BM and/or CD25+ Mast cells in BM.
• 10. Patients must have symptoms consistent with mast cell activation (despite BSC) in at least two organ systems characterized by cutaneous flushing, tachycardia, syncope, hypotension, diarrhea, nausea, vomiting and gastro-intestinal cramping) and serum blood tryptase (sBT) levels above 8 ng/mL OR Severe (Ring and Messmer grading ≥ II, recurrent anaphylaxis, including but not limited to hymenoptera venom, drug or food, regardless of sBT levels.

PK Groups

• 11. See inclusion criteria for All patients and Part 1/Part 2
• 12. Accrual may be limited to patients who have specific disease manifestations (ie, GI involvement) or are taking acid-reducing agents to better explore the impact of these features on PK.

Key Exclusion Criteria:

• 1. Patient has been diagnosed with any of the following WHO systemic mastocytosis (SM) sub-classifications: cutaneous mastocytosis only, smoldering SM, SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia, or mast cell sarcoma.
• 2. Patient has been diagnosed with another myeloproliferative disorder.
• 3. Patient has organ damage C-findings attributable to SM.
• 4. Patient has clinically significant, uncontrolled, cardiovascular disease
• 5. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.
• 6. Patient has previously received treatment with any targeted KIT inhibitors.
• 7. Patient has a history of a primary malignancy that has been diagnosed or required therapy within 3 years. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
• 8. Time since any cytoreductive therapy including mastinib and midostaurin should be at least 5 half-lives or 14 days (whichever is longer), and for cladribine, interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5 half-lives of the drug (whichever is longer), before beginning the screening period.
• 9.Patient has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the screening period.