(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

Phase 2

Completed

• Conditions: Systemic Mastocytosis With an Associated Hematologic Neoplasm; Mast Cell Leukemia; Aggressive Systemic Mastocytosis; Advanced Systemic Mastocytosis
• Interventions: Drug: Avapritinib

• Registration Number: NCT03580655
• Lead Sponsor: Blueprint Medicines Corporation

Brief 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)

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-05-03
• Study First Submitted QC: 2018-06-26
• Study First Posted: 2018-07-09
• Study Start: 2018-11-21
• Primary Completion: 2024-12-18
• Study Completion: 2024-12-18
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-29
• Last Update Posted: 2025-04-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 107

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) < 30 mL/min/1.73m2 or creatinine > 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Avapritinib	Avapritinib	Avapritinib will be administered as an immediate release tablet, orally, continuously, in 28-day cycles

Primary Outcome Measures

Name	Time	Method
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

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

Trial Locations

Locations (32)

Stanford Cancer Institute; 🇺🇸 Stanford, California, United States

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States

The University of Kansas Cancer Center; 🇺🇸 Westwood, Kansas, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Roswell Park Comprehensive Cancer Center; 🇺🇸 Buffalo, New York, United States

Herbert Irving Comprehensive Cancer Center; 🇺🇸 New York, New York, United States

University of Pennsylvania, Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Texas, MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

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