(PIONEER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, Versus Placebo in Patients With Indolent Systemic Mastocytosis

• Avapritinib (Drug), also known as BLU-285: Avapritinib tablet
• Placebo (Drug): Placebo tablet

Primary outcomes

• Part 1: Recommended Phase 2 dose (RP2D) in patients with ISM [9 months]
• Part 2: Mean change in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) as compared to placebo [6 months]: 0 - 110 points (higher value represents worse symptom outcomes)
• Part 3: Number of Participants with Adverse Events [Up to 5 years]

Secondary outcomes

• Part 2: Proportion of patients with a ≥50% reduction in serum tryptase [6 months]
• Part 2: Proportion of patients with a ≥50% reduction in peripheral blood V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) allele fraction or undetectable for patients with detectable mutation at Baseline [6 months]
• Part 2: Proportion of patients with ≥50% reduction in ISM-SAF TSS [6 months]
• Part 2: Proportion of patients with ≥30% reduction in ISM-SAF TSS [6 months]
• Part 2: Proportion of patients with a ≥50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline [6 months]
• Parts 1, 2, and 3: Change in serum tryptase [Up to 5 years]
• Parts 1, 2, and 3: Change in KIT D816V allele burden in blood [Up to 5 years]
• Parts 1, 2, and 3: Change in bone marrow mast cells [Up to 5 years]
• Parts 1, 2, and 3: Change in best supportive care (BSC) concomitant medication usage [Up to 5 years]
• Parts 1, 2, and 3: Change from Baseline in ISM-SAF Score [Up to 5 years]
• Parts 1, 2, and 3: Change in Mastocytosis Quality of Life Questionnaire (MC-QoL) [Up to 5 years]
• Parts 1, 2, and 3: Change in Patient's Global Impression of Symptom Severity (PGIS) [Up to 5 years]
• Parts 1, 2, and 3: Change in 12-item Short Form Health Survey (SF-12) [Up to 5 years]: 0 - 100 points (higher value represents better symptom outcomes)
• Parts 1, 2, and 3: Change in Patients' Global Impression of Change (PGIC) [Up to 5 years]: 1 - 7 (higher value represents worse symptom outcomes)
• Parts 1, 2, and 3: Change in EuroQuol 5 Dimensions 5 Levels (EQ 5D-5L) [Up to 5 years]: 0 - 100 (higher value represents better symptom outcomes)
• Parts 1, 2, and 3: Safety of avapritinib as assessed by number of adverse events [Up to 5 years]: CTCAE version 5.0

Sex: All, ages: 18 Years to any

Key Inclusion Criteria:

* 1\. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and central review of B- and C-findings by WHO diagnostic criteria.
* 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 must have failed to achieve adequate symptom control for 1 or more Baseline symptoms.
* 4\. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days.
* 5\. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2.

Key Exclusion Criteria:

* 1\. Patient has been diagnosed with any of the following WHO SM subclassifications: cutaneous mastocytosis only, smoldering SM, SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia, or mast cell sarcoma.
* 2\. Patient must not have received prior treatment with avapritinib.
* 3\. Patient must not have had any cytoreductive therapy including but not limited to masitinib and midostaurin, or investigational agent for < 14 days or 5 half-lives of the drug (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 14-day ISM-SAF eligibility TSS assessment.
* 4\. Patient must not have received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment.
* 5\. Patient must not have received any hematopoietic growth factor the preceding 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment.
* 6\. Patient must not have a QT interval corrected using Fridericia's formula (QTcF) of > 480 msec.

• Results publication: Siebenhaar F, Broesby-Olsen S, Castells M, George TI, Livideanu CB, Alvarez-Twose I, Panse J, Barete S, Reiter A, Dybedal I, Akin C, Van Daele P, Radia DH, Cerquozzi S, Ustun C, Sabato V, Gotlib J, Rafferty M, DeAngelo DJ, Schafhausen P, Ungerstedt J, Ogbogu PU, Florell S, Wada DA, Rets A, Lin HM, Bidollari I, Hong J, Shaheen D, Lampson B, Hartmann K. Avapritinib improves cutaneous involvement in patients with indolent systemic mastocytosis: Results from the randomized, phase 2, interventional PIONEER study. J Am Acad Dermatol. 2026 Jun;94(6):1705-1713. doi: 10.1016/j.jaad.2026.02.025. Epub 2026 Feb 12. PMID 41690487
• Results publication: Worth S, George TI, Shaheen DJ, Roche M, Vachhani P. Chronic Anaphylaxis With Indolent Systemic Mastocytosis: A Case Report. Case Rep Hematol. 2025 Nov 6;2025:9562195. doi: 10.1155/crh/9562195. eCollection 2025. PMID 41244098
• Results publication: Gotlib J, Castells M, Elberink HO, Siebenhaar F, Hartmann K, Broesby-Olsen S, George TI, Panse J, Alvarez-Twose I, Radia DH, Tashi T, Bulai Livideanu C, Sabato V, Heaney M, Van Daele P, Cerquozzi S, Dybedal I, Reiter A, Pongdee T, Barete S, Ustun C, Schwartz L, Ward BR, Schafhausen P, Vadas P, Bose P, DeAngelo DJ, Rein L, Vachhani P, Triggiani M, Bonadonna P, Rafferty M, Butt NM, Oh ST, Wortmann F, Ungerstedt J, Guilarte M, Taparia M, Kuykendall AT, Arana Yi C, Ogbogu P, Gaudy-Marqueste C, Mattsson M, Shomali W, Giannetti MP, Bidollari I, Lin HM, Sulllivan E, Mar B, Scherber R, Roche M, Akin C, Maurer M. Avapritinib versus Placebo in Indolent Systemic Mastocytosis. NEJM Evid. 2023 Jun;2(6):EVIDoa2200339. doi: 10.1056/EVIDoa2200339. Epub 2023 May 23. PMID 38320129
• Results publication: Padilla B, Shields AL, Taylor F, Li X, Mcdonald J, Green T, Boral AL, Lin HM, Akin C, Siebenhaar F, Mar B. Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) in a phase 2 clinical study. Orphanet J Rare Dis. 2021 Oct 18;16(1):434. doi: 10.1186/s13023-021-02037-3. PMID 34663404

NIH grants: 2018