(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

Study Overview
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Brief Summary
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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)

Official Title
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An Open-label, Single Arm, Phase 2 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
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Advanced Systemic Mastocytosis, Aggressive Systemic Mastocytosis, Systemic Mastocytosis With an Associated Hematologic Neoplasm, Mast Cell Leukemia

Intervention / Treatment
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* Drug: Avapritinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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). Patient must have a serum tryptase ≥ 20 ng/mL. Patient must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 3. Key Exclusion Criteria: Patient has received prior treatment with avapritinib. 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. 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). 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. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec. 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). Platelet count < 50,000/μL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s). 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. 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.) Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 or creatinine > 1.5 × ULN. Patient has a primary brain malignancy or metastases to the brain. Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avapritinib<br>Avapritinib will be administered as an immediate release tablet, orally, continuously, in 28-day cycles | Drug: Avapritinib<br>* Avapritinib tablet<br>* Other names: BLU-285;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) based on modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria |  | 10 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change from Baseline in Advanced Systemic Mastocytosis-Symptom Assessment Form (AdvSM-SAF) Total Symptom Score | 0 - 80 points (higher value represents worse symptom outcomes) | 10 Months | 
| Objective response rate | Including morphologic complete remission (mCR), morphologic CR with partial recovery of peripheral blood (mCRh), and morphologic partial remission (mPR) based on Pure Pathologic Response | Approximately 4 years after the first subjected enrolled | 
| Time-to-response (TTR) | Months | 10 Months | 
| Duration of Response (DOR) | Months | 10 Months | 
| Progression-free Survival (PFS) | Months | 10 Months | 
| Overall Survival (OS) | Months | 10 Months | 
| Changes in bone marrow mast cells | percentage | 10 Months | 
| Change in serum tryptase | ng/mL | 10 Months | 
| Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden | percentage | 10 Months | 
| Change in liver volume by imaging | mL | 10 Months | 
| Change in spleen volume by imaging | mL | 10 Months | 
| Clinical benefit based on modified IWG-MRT-ECNM consensus criteria |  | 10 Months | 
| Change in PGIS | 0 - 10 points (higher value represents worse symptom outcomes) | 10 Months | 
| Change in EORTC QLQ-C30 | 0 - 100 points (lower value represents worse quality of life) | 10 Months | 
| Safety of Avapritinib as assessed by incidence of adverse events | CTCAE version 4.0 | 10 Months | 
| Area Under Curve (0 to Tau) for Avapritinib | h•ng/mL | 4 Months |