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

• Elenestinib (Drug), also known as BLU-263: Elenestinib oral tablet
• Placebo (Drug): Placebo oral tablet

Primary outcomes

• Part 1: Number of participants with Treatment-emergent Adverse Events (TEAEs) [Up to 12 weeks]
• Part 1: Mean change from baseline in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS) [Baseline, Week 13]
• Part 2: Mean change from baseline in ISM-SAF TSS [Baseline, Week 49]
• Part 3: Number of participants with Adverse Events (AEs) [Up to 5 years]
• Part 3: Change from baseline in ISM-SAF TSS [Baseline up to 5 years]

Secondary outcomes

• Part 1: Change from baseline in serum tryptase [Baseline, Week 13]
• Part 1: Change from baseline in KIT D816V allele fraction in blood [Baseline, Week 13]
• Part 1: Change from baseline in Bone Marrow (BM) mast cells [Baseline, Week 13]
• Part 1: Mean change from baseline in ISM-SAF individual symptom scores [Baseline, Week 13]
• Part 1: Time to achieve 30% reduction from baseline in ISM-SAF TSS [Baseline up to Week 13]
• Part 1: Time to achieve 30% reduction from baseline in ISM-SAF domain scores [Baseline up to Week 13]
• Part 2: Proportion of participants achieving normalized tryptase [Baseline up to Week 49]
• Part 2: Proportion of participants who achieve an undetectable level or at least a 50% reduction in KIT D816V Variant Allele Frequency (VAF) [Baseline up to Week 49]
• Part 2: Proportion of participants achieving symptom control as defined by achieving mild symptoms [Baseline up to Week 49]
• Part 2: Mean percent change from baseline in Bone Mineral Density (BMD) [Baseline, Week 49]
• Part 2: Mean change from baseline in the annualized rate of anaphylaxis events [Baseline, Weeks 25 to 48]
• Part 2: Mean change from baseline in Quality of Life (QoL) scores [Baseline, Week 49]
• Part 2: Mean change from baseline in ISM-SAF domain scores [Baseline, Week 49]
• Part 2: Number of participants with AEs [Up to Week 49]
• Part 2: Proportion of participants with a 50% reduction in ISM-SAF TSS [Baseline, Weeks 24 and 48]
• Part 2: Proportion of participants with a 50% reduction in ISM-SAF domain scores [Baseline, Weeks 24 and 48]
• Part 2: Proportion of participants with a 30% reduction in ISM-SAF TSS [Baseline, Weeks 24 and 48]
• Part 2: Proportion of participants with a 30% reduction in ISM-SAF domain scores [Baseline, Weeks 24 and 48]
• Part 3: Proportion of participants achieving symptom control as defined by achieving mild symptoms [Baseline up to 5 years]
• Part 3: Change from baseline in ISM-SAF domain scores [Baseline, up to 5 years]
• Part 3: Proportion of participants achieving a normalized tryptase [Baseline up to 5 years]
• Part 3: Change from baseline in BMD [Baseline up to 5 years]
• Part 3: Change from baseline in the annualized rate of anaphylaxis events [Baseline up to 5 years]
• Parts 2 and 3: Change from baseline in serum tryptase [Baseline up to 5 years]
• Parts 2 and 3: Change from baseline in KIT D816V allele fraction in blood [Baseline up to 5 years]
• Parts 2 and 3: Change from baseline in Bone Marrow (BM) mast cells [Baseline up to 5 years]
• Parts 2 and 3: Proportion of participants achieving controlled disease [Baseline up to 5 years]
• Parts 2 and 3: Change from baseline in skin lesions as assessed by the fractional body surface area of the most affected skin area [Baseline up to 5 years]
• Parts 2 and 3: Change from baseline in the number of concomitant medications identified as SDT [Baseline up to 5 years]
• Parts 2 and 3: Change from baseline in ISM-SAF Individual Symptom Scores [Baseline up to 5 years]
• Parts 2 and 3: Change from baseline in ISM-SAF Lead (most severe) Symptom Score [Baseline up to 5 years]
• Parts 2 and 3: Change from baseline in QoL scores [Baseline up to 5 years]
• Part S: Number of participants with AEs [Baseline up to 5 years]
• Part S: Proportion of participants who achieve a Pure Pathologic Response (PPR) [Baseline up to 5 years]
• Part S: Mean change from baseline in ISM-SAF [Baseline, Week 25]
• Part K: Number of participants with AEs [Baseline up to 5 years]
• Part K: Change from baseline in serum tryptase [Baseline up to 5 years]
• Part K: Change from baseline in KIT D816V allele fraction in blood [Baseline up to 5 years]
• Part K: Mean change from baseline in ISM-SAF TSS [Baseline up to 5 years]
• Part K: Change from baseline in QoL scores [Baseline up to 5 years]

Sex: All, ages: 18 Years to any

Key Inclusion Criteria:

All Participants:

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

Part 1 and PK groups:

* Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review
* Participant 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 symptom-directed therapies administered: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
* Participants must have SDT for ISM symptom management stabilized for at least 14 days prior to starting screening procedures.
* For participants receiving corticosteroids, the dose must be ≤ 20 mg/day prednisone or equivalent, and the dose must be stable for ≥ 14 days.

Part K:

-Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review

Part S:

-Participant has confirmed diagnosis of SSM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO diagnostic criteria.

Part 2:

-Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review

Key Exclusion Criteria:

* Participant has been diagnosed with any of the following WHO systemic mastocytosis (SM) sub-classifications: cutaneous mastocytosis only, SM with an associated hematologic neoplasm of non-MC lineage (SM-AHN), aggressive SM, mast cell leukemia, or mast cell sarcoma.
* Participant has been diagnosed with another myeloproliferative disorder.
* Participant has organ damage attributable to SM.
* Participant has clinically significant, uncontrolled, cardiovascular disease
* Participant has a QT interval corrected using Fridericia's formula (QTcF) > > 470 milliseconds (msec) (for females) or > 450 msec (for males).
* Participant 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.
* Time since any cytoreductive therapy including masitinib 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.
* Participant has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the screening period.

Other protocol-defined criteria apply.