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

Phase 2

Recruiting

Conditions: mast cell disease
10018849

Registration Number: NL-OMON55851

Lead Sponsor: Blueprint Medicines Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 3

Inclusion Criteria

1. Patients who are >= 18 years of age.
2. Patients must have 1 of the following diagnoses as confirmed by World Health
Organization (WHO) diagnostic criteria. Before enrollment, the SSC must confirm
the diagnosis of AdvSM (based on Central Pathology Laboratory assessment of
BM): • ASM. • SM-AHN. The AHN must be myeloid, with additional criteria defined
in the protocol. • MCL, including diagnoses with an AHN component.
3. Patients with SM-AHN should have received prior treatment for the AHN
component of disease if, in the opinion of the Investigator, such therapy was
appropriate.
4. Patient must have a BM biopsy taken within 56 days of C1D1, assessed by the
Central Pathology Laboratory.
5. Cohort 1 only: Patient must have at least 1 measurable C-finding per
modified IWG-MRT-ECNM criteria, attributed to SM and evaluable for response
assessment unless diagnosis is MCL, which does not require a C-finding.
Laboratory abnormality C-findings should not be assessed until the required
washout period from last cytoreductive therapy has been met. If a C-finding
improves during the Screening period, prior to dosing, and no longer meets
criteria for evaluability, it can no longer be counted as a C-finding.In
addition,
• Patients must have documented evidence of mast cell aggregates in the bone
marrow or other extracutaneous organ based on central pathology.
• Patient must be willing to have follow up biopsies of affected organ(s) to
document response.
Measurable C-findings:

o Cytopenias: • ANC < 1.0 × 10^9/L or • Hemoglobin < 10 g/dL or • Platelet
count < 75 × 109/L.
NOTE: Cytopenias attributable to prior cytoreductive therapy or causes other
than SM may not be used as C-findings. o Symptomatic ascites or pleural
effusion requiring medical intervention such as:
• Use of diuretics (Grade 2) or
• >= 2 therapeutic paracenteses or thoracenteses (Grade 3) at least 28 days
apart over the 12 weeks before
C1D-8 and 1 of the procedures is performed during the 6 weeks before C1D-8.
o >= Grade 2 abnormalities in direct bilirubin (> 1.5 × upper limit of normal
[ULN]), aspartate aminotransferase (AST; > 3.0 × ULN), alanine aminotransferase
(ALT; > 3.0 × ULN), or alkaline phosphatase (> 2.5 × ULN) with 1 of the
following present:
• Ascites or
• Clinically relevant portal hypertension or
• Liver MC infiltration that is biopsy-proven or
• No other identified cause of abnormal liver function.
o >= Grade 2 hypoalbuminemia (< 3.0 g/dL).
o A spleen that is palpable >= 5 cm below the left costal margin.
o Transfusion-dependent anemia defined as:
• Transfusion of >= 6 units packed red blood cells (PRBCs) in the 12 weeks
before C1D-8 and
• Most recent transfusion occurring during the 4 weeks before C1D-8 and
• Transfusion administered for hemoglobin <= 8.5 g/dL and
• Reason for transfusion is not bleeding, hemolysis, or therapy-related.
6. Patient must have a serum tryptase >= 20 ng/mL.
7. Patients receiving cytoreductive therapy within the preceding 12 weeks must
have discontinued therapy due to disease progression, refractory disease, lack
of efficacy, or intolerance.
8. Patient's non-antineoplastic SM therapies (ie, BSC; eg, H1 and H2 blockers).
must be stable (same dose, no new medications for SM) for >= 14 days C1D-8. This
criterion is not applicab

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. If the patient has progressive disease and it is in the
patient's best 1 day before the screening BM biopsy with approval from the
Medical Monitor.Cytoreductive therapy may not be restarted during Screening or
while on study.3. Patient has received prior radiotherapy within 14 days before
the screening BM biopsy, unless given to palliate specific sites of disease
(eg, bone lesion). 4. Patient received any hematopoietic growth factor within
14 days of screening BM biopsy. 5. Patient requires therapy with a concomitant
medication that is a strong inhibitor, strong inducer, or moderate inducer of
CYP3A4. 6. Patient has had a major surgical procedure within 14 days of the
first dose of study drug. Surgical procedures such as central venous catheter
placement, BM biopsy, and feeding tube placement are considered minor surgical
procedures. 7. Patient is a candidate for allogeneic hematopoietic stem cell
transplantation for treatment of SM, in the opinion of the Investigator. 8.
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). 9. 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. 10. Patient meets any of the following
laboratory criteria: o AST or ALT > 3.0 × ULN; no restriction if due to
suspected liver infiltration by MCs. o Bilirubin > 1.5 × ULN; no restriction if
due to suspected liver infiltration by MCs or Gilbert*s disease. (In the case
of Gilbert's disease,
a direct bilirubin > 2.0 × ULN would be an exclusion.) o Estimated glomerular
filtration rate (eGFR) < 30 mL/min/1.73m^2 or creatinine> 1.5 × ULN.
oPlatelet count < 50,000/µL (within 4 weeks of the first dose of study
drug) or receiving platelet transfusion(s)
11. Patient has a QT interval corrected using Fridericia*s formula (QTcF) >
450 msec. 12. Patient has a history of a seizure disorder (eg, epilepsy) or
requirement for antiseizure medication. 13. Patient has a history of a
cerebrovascular accident or transient ischemic attacks within 1 year before the
first dose of study drug. 14. 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).).
15. Patient has a primary brain malignancy or metastases to the brain. 16.
Patient has clinically significant, uncontrolled cardiovascular dise

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary:<br /><br>• Adjudicated ORR (CR/CRh + PR + CI) based on modified IWG-MRT-ECNM criteria,<br /><br>confirmed 12 weeks after initial response in patients in Cohort 1 only. </p><br>

Secondary Outcome Measures