Clinical trial NCT03580655: (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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced Systemic Mastocytosis
Aggressive Systemic Mastocytosis
Systemic Mastocytosis With an Associated Hematologic Neoplasm
Mast Cell Leukemia
Lead sponsor: Blueprint Medicines Corporation
Sponsor class: INDUSTRY
First posted: 2018-07-09
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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)


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) \< 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.

Primary outcomes:
measure: 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
timeFrame: 10 Months
Secondary outcomes:
measure: Mean Change from Baseline in Advanced Systemic Mastocytosis-Symptom Assessment Form (AdvSM-SAF) Total Symptom Score
timeFrame: 10 Months
measure: Objective response rate
timeFrame: Approximately 4 years after the first subjected enrolled
measure: Time-to-response (TTR)
timeFrame: 10 Months
measure: Duration of Response (DOR)
timeFrame: 10 Months
measure: Progression-free Survival (PFS)
timeFrame: 10 Months
measure: Overall Survival (OS)
timeFrame: 10 Months
measure: Changes in bone marrow mast cells
timeFrame: 10 Months
measure: Change in serum tryptase
timeFrame: 10 Months
measure: Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden
timeFrame: 10 Months
measure: Change in liver volume by imaging
timeFrame: 10 Months
measure: Change in spleen volume by imaging
timeFrame: 10 Months
measure: Clinical benefit based on modified IWG-MRT-ECNM consensus criteria
timeFrame: 10 Months
measure: Change in PGIS
timeFrame: 10 Months
measure: Change in EORTC QLQ-C30
timeFrame: 10 Months
measure: Safety of Avapritinib as assessed by incidence of adverse events
timeFrame: 10 Months
measure: Area Under Curve (0 to Tau) for Avapritinib
timeFrame: 4 Months
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Westwood
country: United States
facility: The University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Mays Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Vienna
country: Austria
facility: Medizinische Universität Wien, Universitätsklinik für Innere Medizin I, Klinische Abteilung für Hämatologie und Hämostaseologie
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Odense
country: Denmark
facility: Odense University Hospital, Department of Haematology
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
city: Toulouse
country: France
facility: CHU Toulouse - Hôpital Larrey
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltranslplantation
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Zentrum für Onkologie
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Medizinische Klinik und Poliklinik I - Hämatologie und Zelltherapie, lnternistische Onkologie, Hämostaseologie
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim III. Medizinische Klinik
city: Munich
country: Germany
facility: Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München
city: Florence
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi, CRIMM - Centro di Ricerca ed Innovazione per le Malattie Mieloproliferative
city: Salerno
country: Italy
facility: A.O. OO.RR. S.Giovanni di Dio e Ruggi d'Aragona, University of Salerno
city: Verona
country: Italy
facility: Centro Ricerche Cliniche di Verona - Azienda Ospedaliera Universitaria Integrata di Verona
city: Groningen
country: Netherlands
facility: University Medical Center Groningen (UMCG)
city: Oslo
country: Norway
facility: Oslo University Hospital-Rikshospitalet, Hematology
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne, Klinika Hematologii i Transplantologii
city: Wrocław
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu, Klinice Hematologii, Nowotworów Krwi i Transplantacji Szpiku
city: Toledo
country: Spain
facility: lnstituto de Estudios de Mastocitosis de Castilla la Mancha, Hospital Virgen del Valle - Complejo Hospitalario de Toledo
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre - NHS Greater Glasgow and Clyde
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
Study officials:
References:
citation: Reiter A, Gotlib J, Alvarez-Twose I, Radia DH, Lubke J, Bobbili PJ, Wang A, Norregaard C, Dimitrijevic S, Sullivan E, Louie-Gao M, Schwaab J, Galinsky IA, Perkins C, Sperr WR, Sriskandarajah P, Chin A, Sendhil SR, Duh MS, Valent P, DeAngelo DJ. Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis. Leukemia. 2022 Aug;36(8):2108-2120. doi: 10.1038/s41375-022-01615-z. Epub 2022 Jul 5.
citation: Reiter A, Schwaab J, DeAngelo DJ, Gotlib J, Deininger MW, Pettit KM, Alvarez-Twose I, Vannucchi AM, Panse J, Platzbecker U, Hermine O, Dybedal I, Lin HM, Rylova SN, Ehlert K, Dimitrijevic S, Radia DH. Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. Blood Adv. 2022 Nov 8;6(21):5750-5762. doi: 10.1182/bloodadvances.2022007539.
citation: Gotlib J, Reiter A, Radia DH, Deininger MW, George TI, Panse J, Vannucchi AM, Platzbecker U, Alvarez-Twose I, Mital A, Hermine O, Dybedal I, Hexner EO, Hicks LK, Span L, Mesa R, Bose P, Pettit KM, Heaney ML, Oh ST, Sen J, Lin HM, Mar BG, DeAngelo DJ. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021 Dec;27(12):2192-2199. doi: 10.1038/s41591-021-01539-8. Epub 2021 Dec 6.