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1. Part 1: Recommended Dose (RD) in patients with ISM (Time Frame - 3 months): Selection of the RD to be used in Part 2, Part 3 and Part M of the study
2. Part 2: Proportion of responders, defined as ≥30% reduction in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS) (Time Frame - 6 months): Response rate in patients with ISM
3. Part 3: Long-term safety and tolerability of BLU-263 as assessed by the number of adverse events and serious adverse events (Time Frame - up to 5 years)
4. Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) (Time Frame - up to 5 years): The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms
Secondary outcome:
1. Part 1: Mean change in measures of mast cell burden (Time Frame - 3 Months)
2. Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) (Time Frame - 3 Months): The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms
3. Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores (Time Frame - 3 months): Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms
4. Part 1: Time to achieve 30% reduction inIndolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores (Time Frame - 3 months): Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-110 and a lower score represents lower symptom burden
5. Part 2: Proportion of patients with a ≥50% reduction in serum tryptase (Time Frame - 6 months)
6. Part 2: The proportion of patients who achieve at least a 50% reduction in peripheral blood KIT D816V allele fraction, or a reduction to undetectable levels. (Time Frame - 6 months)
7. Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) (Time Frame - 6 months): The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms
8. Part 2: Proportion of patients with a ≥50% reduction in bone marrow mast cells or reduction to no aggregates for patients with aggregates at Baseline (Time Frame - 6 months)
9. Part 2: Mean change in measures of mast cell burden (Time Frame - 6 months)
10. Part 2: Change in number of best supportive care medications (Time Frame - 6 Months)
11. Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores (Time Frame - 6 months): Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms
12. Part 2: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score (Time Frame - 6 months): Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms
13. Part 2: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores (Time Frame - 6 months): Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-10 and a lower score represents lower symptom burden
14. Part 2: Mean change in the Mast Cell Quality of Life (MC-QoL) score (Time Frame - 6 months): The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life.
15. Part 2: Safety of BLU-263 as assessed by number of adverse events and serious adverse events (Time Frame - up to 5 years)
16. Part 3: Mean change in measures of mast cell burden (Time Frame - approximately 5 years)
17. Part 3: Change in number of best supportive care medications (Time Frame - approximately 5 years)
18. Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom score (Time Frame - approximately 5 years): Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms
19. Part 3: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score (Time Frame - approximately 5 years): Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms
20. Part 3: Mean change in the Mast Cell Quality of Life (MC-QoL) score (Time Frame - approximately 5 years): The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life.
21. Part 3: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Scores (Time Frame - 12 months): Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-110 and a lower score represents lower symptom burden
Experimental: (Part 1) BLU-263 Dose 1 + BSC Patients will receive best supportive care (BSC) and Dose 1 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.
Experimental: (Part 1) BLU-263 Dose 2 + BSC Patients will receive best supportive care (BSC) and Dose 2 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.
Experimental: (Part 1) BLU-263 Dose 3 + BSC Patients will receive best supportive care (BSC) and Dose 3 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.
Placebo Comparator: (Part 1) Placebo + BSC Patients will receive best supportive care (BSC) and matching placebo tablets. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily until completion of Part 1
Experimental: (Part 2) BLU-263 RD + BSC Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily for approximately 24 weeks
Placebo Comparator: (Part 2) Placebo + BSC Patients will receive best supportive care (BSC) and matching placebo tablets. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily once daily for approximately 24 weeks
Experimental: (Part 3) BLU-263 RD + BSC Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablet in an open-label fashion for up to 5 years.
Experimental: (Part M) BLU-263 RD + BSC Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily for the duration of participation in the study.
Experimental: PK Groups (Dose 2 or Dose 3) Patients will receive best supportive care (BSC) and Dose 2 or Dose 3 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally for the duration of participation in the study.