(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

Mast Cell Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03580655
• Other study ID #: BLU-285-2202
• Secondary ID: 2017-004836-13
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 21, 2018
• Est. completion date: January 31, 2026

Study information

• Verified date: August 2023
• Source: Blueprint Medicines Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 103
• Est. completion date: January 31, 2026
• Est. primary completion date: January 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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) < 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.

Related Conditions & MeSH terms

• Advanced Systemic Mastocytosis
• Aggressive Systemic Mastocytosis
• Hematologic Neoplasms
• Leukemia, Mast-Cell
• Mast Cell Leukemia
• Mastocytosis
• Systemic Mastocytosis With an Associated Hematologic Neoplasm

Intervention

Drug:
• Avapritinib
Avapritinib tablet

Locations

Country	Name	City	State
Austria	Medizinische Universität Wien, Universitätsklinik für Innere Medizin I, Klinische Abteilung für Hämatologie und Hämostaseologie	Vienna
Canada	St. Michael's Hospital	Toronto	Ontario
Denmark	Odense University Hospital, Department of Haematology	Odense
France	Hôpital Necker-Enfants Malades	Paris
France	CHU Toulouse - Hôpital Larrey	Toulouse
Germany	Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltranslplantation	Aachen
Germany	Universitätsklinikum Hamburg-Eppendorf, Zentrum für Onkologie	Hamburg
Germany	Universitätsklinikum Leipzig, Medizinische Klinik und Poliklinik I - Hämatologie und Zelltherapie, lnternistische Onkologie, Hämostaseologie	Leipzig
Germany	Universitätsmedizin Mannheim III. Medizinische Klinik	Mannheim
Germany	Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München	Munich
Italy	Azienda Ospedaliero-Universitaria Careggi, CRIMM - Centro di Ricerca ed Innovazione per le Malattie Mieloproliferative	Florence
Italy	A.O. OO.RR. S.Giovanni di Dio e Ruggi d'Aragona, University of Salerno	Salerno
Italy	Centro Ricerche Cliniche di Verona - Azienda Ospedaliera Universitaria Integrata di Verona	Verona
Netherlands	University Medical Center Groningen (UMCG)	Groningen
Norway	Oslo University Hospital-Rikshospitalet, Hematology	Oslo
Poland	Uniwersyteckie Centrum Kliniczne, Klinika Hematologii i Transplantologii	Gdansk
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu, Klinice Hematologii, Nowotworów Krwi i Transplantacji Szpiku	Wroclaw
Spain	lnstituto de Estudios de Mastocitosis de Castilla la Mancha, Hospital Virgen del Valle - Complejo Hospitalario de Toledo	Toledo
United Kingdom	Beatson West of Scotland Cancer Centre - NHS Greater Glasgow and Clyde	Glasgow
United Kingdom	Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital	London
United States	University of Michigan	Ann Arbor	Michigan
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Texas, MD Anderson Cancer Center	Houston	Texas
United States	Herbert Irving Comprehensive Cancer Center	New York	New York
United States	University of Pennsylvania, Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Mays Cancer Center	San Antonio	Texas
United States	Stanford Cancer Institute	Stanford	California
United States	The University of Kansas Cancer Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Blueprint Medicines Corporation

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Denmark,  France,  Germany,  Italy,  Netherlands,  Norway,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Time-to-response (TTR)	Months	10 Months
Secondary	Duration of Response (DOR)	Months	10 Months
Secondary	Progression-free Survival (PFS)	Months	10 Months
Secondary	Overall Survival (OS)	Months	10 Months
Secondary	Changes in bone marrow mast cells	percentage	10 Months
Secondary	Change in serum tryptase	ng/mL	10 Months
Secondary	Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden	percentage	10 Months
Secondary	Change in liver volume by imaging	mL	10 Months
Secondary	Change in spleen volume by imaging	mL	10 Months
Secondary	Clinical benefit based on modified IWG-MRT-ECNM consensus criteria		10 Months
Secondary	Change in PGIS	0 - 10 points (higher value represents worse symptom outcomes)	10 Months
Secondary	Change in EORTC QLQ-C30	0 - 100 points (lower value represents worse quality of life)	10 Months
Secondary	Safety of Avapritinib as assessed by incidence of adverse events	CTCAE version 4.0	10 Months
Secondary	Area Under Curve (0 to Tau) for Avapritinib	h•ng/mL	4 Months

External Links

•   More information about the study