(pathfinder) study to evaluate efficacy and safety of avapritinib (blu-285), a selective kit mutation-targeted tyrosine kinase inhibitor, in patients with advanced systemic mastocytosis

Conditions: Advanced Systemic Mastocytosis; Aggressive Systemic Mastocytosis; Systemic Mastocytosis With an Associated Hematologic Neoplasm; Mast Cell Leukemia

Summary: this is an open-label, single arm, phase 2 study evaluating the efficacy and safety of avapritinib (blu-285) in patients with advanced systemic mastocytosis (advsm), including patients with aggressive sm (asm), sm with associated hematologic neoplasm (sm-ahn), and mast cell leukemia (mcl)


Eligibility criteria:
key inclusion criteria: 1. patient must have a diagnosis of aggressive systemic mastocytosis (asm), systemic mastocytosis with an associated hematologic neoplasm (sm-ahn) or mast cell leukemia (mcl) based on world health organization diagnostic criteria. before enrollment, the study steering committee must confirm the diagnosis of advsm (based on central pathology laboratory assessment of bone marrow). 2. patient must have a serum tryptase ≥ 20 ng/ml. 3. patient must have eastern cooperative oncology group (ecog) performance status (ps) of 0 to 3. key exclusion criteria: 1. patient has received prior treatment with avapritinib. 2. patient has received any cytoreductive therapy (including midostaurin and other tkis, hydroxyurea, azacitidine) or an investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon and any antibody therapy (eg, brentuximab vedotin) less than 28 days before obtaining screening bm biopsy for this study. 3. patient has eosinophilia and known positivity for the fip1l1 pgdfra fusion, unless the patient has demonstrated relapse or pd on prior imatinib therapy. patients with eosinophilia (\> 1.5 × 10\^9/l), who do not have a detectable kit d816 mutation, must be tested for a pdgfra fusion mutation by fluorescence in situ hybridization (fish) or polymerase chain reaction (pcr). 4. patient has history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug. the following are exempt from the 3-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site. 5. patient has a qt interval corrected using fridericia's formula (qtcf) \> 480 msec. 6. patient has a known risk or recent history (12 months before the first dose of study drug) of intracranial bleeding (eg, brain aneurysm, concomitant vitamin k antagonist use). 7. platelet count \< 50,000/μl (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s). 8. aspartate aminotransferase (ast) or alanine aminotransferase (alt) \>3 x the upper limit of normal (uln); no restriction if due to suspected liver infiltration by mast cells. 9. bilirubin \>1.5 × uln; no restriction if due to suspected liver infiltration by mast cells or gilbert's disease. (in the case of gilbert's disease, a direct bilirubin \>2 × uln would be an exclusion.) 10. estimated glomerular filtration rate (egfr) \ 1.5 × uln. 11. patient has a primary brain malignancy or metastases to the brain. 12. patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication.