mastcell disease
Conditions
Interventions
In Part 1, patients will receive treatment for 12 weeks, then continue on
assigned therapy and dose until the RP2D is determined, then roll over into
Part 3. In Part 2, patients will receive treatme
Sponsors
Blueprint Medicines Corporation
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Patient must be >= 18 years of age. 2. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and central review of B- and C-findings by WHO diagnostic criteria. 3. Patient must have moderate-to-severe symptoms based on minimum mean TSS over the 14-day eligibility screening period for assessment of TSS and. Minimum TSS for eligibility is >= 28. 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: H1 blockers, H2 blockers, Proton-pump inhibitors, Leukotriene inhibitors, Cromolyn sodium, Corticosteroids, Omalizumab. 5. The patient*s symptomatic SM therapies (eg, H1 and H2 blockers) must be stable (same dose, no new medications >= 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment). 6. For patients receiving corticosteroids, the dose must be = 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment. 7. Patient must have an ECOG-PS of 0 to 2. 8. Patient must be able to give written informed consent.
Exclusion criteria
Exclusion criteria: 1. Patient has been diagnosed with any of the following WHO SM subclassifications: o Cutaneous mastocytosis only (ie, without documentation of systemic involvement). o SM-AHN. o SSM o ASM. o MCL. o MC sarcoma. 2. Patient has been diagnosed with another myeloproliferative disorder (eg, myelodysplastic syndrome, myeloproliferative neoplasm). 3. Patient has any of the following organ damage C-findings attributable to SM: o Cytopenia. o Hepatomegaly with ascites and impaired liver function. o Palpable splenomegaly with hypersplenism. o Malabsorption with hypoalbuminemia and significant weight loss. o Skeletal lesions: large osteolytic lesions with pathologic fractures. o Life-threatening organ damage in other organ systems that is caused by MC infiltration in tissues. 4. Patient meets any of the following laboratory criteria: o Aspartate aminotransferase or alanine aminotransferase > 3.0 × upper limit of normal (ULN). o Total bilirubin > 1.5 × ULN; > 3.0 × ULN if due to Gilbert's disease. (In the case of Gilbert*s disease, a direct bilirubin > 2.0 × ULN is an exclusion.) o Albumin 1.5 × ULN o Absolute neutrophil count 480 msec. 9. Patient has a history of a seizure disorder (eg, epilepsy) or requires antiseizure medication. 10. Patient has a history of a cerebrovascular accident or transient ische
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1 • The RP2D in patients with ISM. Part 2 • Mean change in ISM-SAF TSS, from baseline to C7D1. Part 3 • The long-term safety and efficacy of avapritinib. | — |
Secondary
| Measure | Time frame |
|---|---|
| Key Secondary Endpoints (Part 2 Only): • Proportion of patients with a >=50% reduction in serum tryptase from baseline to C7D1. • Proportion of patients with a >=50% reduction in peripheral blood KIT D816V allele fraction from baseline to C7D1 or undetectable (=50% reduction in ISM-SAF TSS from baseline to C7D1. •Proportion of patients with >=30% reduction in ISM-SAF TSS from baseline to C7D1. • Proportion of patients with a >=50% reduction in bone marrow MCs from baseline to C7D1 or no aggregates for patients with aggregates at baseline. Additional Secondary Endpoints: Part 1 and Part 2 • Change in measures of MC burden from baseline to C4D1 (in Part 1) and to C7D1 (in Part 2): o Serum tryptase. o KIT D816V allele burden in blood. o Bone marrow MCs. • Change in BSC usage. • Change in GI and Skin domains, Neurocognitive symptom cluster (brain fog, headache and dizziness), and individual symptom scores of ISM-SAF. • Change in "lead (most severe) symptom" and *lead (most severe) domain/symptom cluster* score of ISM-SAF. • Change in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L. • Safety and tolerability of avapritinib, as assessed by AEs, vital signs, ECGs, and laboratory tests. • Pharmacokinetics of avapritinib. • Correlations between avapritinib exposure and safety and efficacy endpoints. Part 3 • Change in the following measures of MC burden: o Serum tryptase. o KIT D816V allele burden in blood. o Bone marrow MCs (optional at approximately 1 year after the end of Part 1 and Part 2 biopsy). • Change in BSC concomitant medication usage. • Change in "lead (most severe) symptom" and *lead (most severe) domain/symptom cluster* score of ISM-SAF. • Proportion of avapritinib treated patients with ISM achieving >=50% reduction in TSS at 1 year from Part 3 Baseline (and Part 1 or Part 2 Baseline for patients on same dose of avapritinib in both parts of the study). • Proportion of avapritinib treated patients with ISM achieving >=30% reduction | — |
Countries
Netherlands
Outcome results
None listed