(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

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

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)

Study Overview

• Status: Active, not recruiting
• Conditions: Mast Cell Leukemia; Aggressive Systemic Mastocytosis; Advanced Systemic Mastocytosis; Systemic Mastocytosis With an Associated Hematologic Neoplasm
• Intervention / Treatment: Drug: Avapritinib

• Study Type: Interventional
• Enrollment (Estimated): 103
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medizinische Universität Wien, Universitätsklinik für Innere Medizin I, Klinische Abteilung für Hämatologie und Hämostaseologie
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
• Denmark
  • Odense, Denmark, DK-5000
    • Odense University Hospital, Department of Haematology
• France
  • Paris, France, 75015
    • Hopital Necker-Enfants Malades
  • Toulouse, France, 31059
    • CHU Toulouse - Hopital Larrey
• Germany
  • Aachen, Germany, 52074
    • Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltranslplantation
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf, Zentrum für Onkologie
  • Leipzig, Germany, 04103
    • Universitätsklinikum Leipzig, Medizinische Klinik und Poliklinik I - Hämatologie und Zelltherapie, lnternistische Onkologie, Hämostaseologie
  • Mannheim, Germany, 68167
    • Universitätsmedizin Mannheim III. Medizinische Klinik
  • Munich, Germany, 81675
    • Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München
• Italy
  • Florence, Italy, 50134
    • Azienda Ospedaliero-Universitaria Careggi, CRIMM - Centro di Ricerca ed Innovazione per le Malattie Mieloproliferative
  • Salerno, Italy, 84131
    • A.O. OO.RR. S.Giovanni di Dio e Ruggi d'Aragona, University of Salerno
  • Verona, Italy, 37134
    • Centro Ricerche Cliniche di Verona - Azienda Ospedaliera Universitaria Integrata di Verona
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen (UMCG)
• Norway
  • Oslo, Norway, 0372
    • Oslo University Hospital-Rikshospitalet, Hematology
• Poland
  • Gdańsk, Poland, 80-214
    • Uniwersyteckie Centrum Kliniczne, Klinika Hematologii i Transplantologii
  • Wrocław, Poland, 50-367
    • Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu, Klinice Hematologii, Nowotworów Krwi i Transplantacji Szpiku
• Spain
  • Toledo, Spain, 45071
    • lnstituto de Estudios de Mastocitosis de Castilla la Mancha, Hospital Virgen del Valle - Complejo Hospitalario de Toledo
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Centre - NHS Greater Glasgow and Clyde
  • London, United Kingdom, SE1 9RT
    • Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kansas
    • Westwood, Kansas, United States, 66205
      • The University of Kansas Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Comprehensive Cancer Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Abramson Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas, MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Mays Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Blueprint Medicines Corporation

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• More information about the study

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2018
• Primary Completion (Estimated): January 31, 2026
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: May 3, 2018
• First Submitted That Met QC Criteria: June 26, 2018
• First Posted (Actual): July 9, 2018

Study Record Updates

• Last Update Posted (Actual): August 2, 2023
• Last Update Submitted That Met QC Criteria: August 1, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Hematologic Diseases; Leukemia; Neoplasms, Connective Tissue; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mast Cell Activation Disorders; Hematologic Neoplasms; Mastocytosis; Mastocytosis, Systemic; Leukemia, Mast-Cell
• Other Study ID Numbers: BLU-285-2202; 2017-004836-13 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No