(PIONEER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, Versus Placebo in Patients With Indolent Systemic Mastocytosis

A 3-Part, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate Safety and Efficacy of Avapritinib (BLU-285), a Selective KIT Mutation-Targeted Tyrosine Kinase Inhibitor, in Indolent and Smoldering Systemic Mastocytosis With Symptoms Inadequately Controlled With Standard Therapy

This is a Phase 2, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of avapritinib + best supportive care (BSC) with placebo + BSC in patients with indolent systemic mastocytosis (ISM) whose symptoms are not adequately controlled by BSC. The study will be conducted in 3 parts. All patients will receive treatment with avapritinib during Part 3 including those rolling over from the placebo group.

Study Overview

• Status: Active, not recruiting
• Conditions: Indolent Systemic Mastocytosis
• Intervention / Treatment: Drug: Placebo; Drug: Avapritinib

• Study Type: Interventional
• Enrollment (Actual): 251
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Edegem, Belgium, 2650
    • University Hospital Antwerp
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
• Denmark
  • Odense, Denmark, DK-5000
    • Odense Universitetshospital, ORCA/Allergicentret, Hudafdeling I og Allergicenter
• France
  • Marseille, France, 13385
    • Hôpital de la Timone, Service de dermatologie
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière, Service de Dermatologie
  • Toulouse, France, 31059
    • CHU Toulouse Larrey, CEREMAST, Service de Dermatologie et Allergologie cutanée
• Germany
  • Aachen, Germany, 52074
    • Uniklinik RWTH Aachen
  • Berlin, Germany, 10117
    • Charité Universitätsmedizin Berlin
  • Hamburg, Germany, 20246
    • University Clinic Hamburg Eppendorf, University Cancer Center Hamburg (UCCH)
  • Lübeck, Germany, 23538
    • Universitätsklinikum Schleswig-Holstein, Hämatologie/Onkologie
  • Mainz, Germany, 55131
    • Universitätsklinik Mainz, Universitäts-Hautklinik, Clinical Research Center
  • Mannheim, Germany, 68167
    • Universitätsmedizin Mannheim, III. Medizinische Klinik
  • Munich, Germany, 80802
    • Klinikum rechts der Isar, Technische Universität München
• Italy
  • Bologna, Italy, 40138
    • A.O.U di Bologna - IRCCS, Istituto di Ematologia Lorenzo e Ariosto Seragnoli, Ematologia
  • Milan, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Poloclinico, UOC Ematologia
  • Salerno, Italy, 84131
    • A.O. OO.RR. S.Giovanni di Dio e Ruggi d'Aragona, University of Salerno
  • Verona, Italy, 37126
    • Azienda Ospedaliera Universitaria Integrata di Verona
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen (UMCG)
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus Medical Center
• Norway
  • Oslo, Norway, 0372
    • Oslo Universitetssykehus, Rikshospitalet, Department of Hematology
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Toledo, Spain, 45071
    • lnstituto de Estudios de Mastocitosis de Castilla la Mancha, Hospital Virgen del Valle - Complejo Hospitalario de Toledo
• Sweden
  • Stockholm, Sweden, 141 86
    • Karolinska University Hospital, Hematologimottagningen R51
  • Uppsala, Sweden, 751 85
    • Akademiska sjukhuset, Hematologmottagningen/101A
• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel
• United Kingdom
  • Glasgow, United Kingdom, G12 OXL
    • NHS Greater Glasgow and Clyde, Beatson West of Scotland Cancer Centre
  • London, United Kingdom, SE1 9RT
    • Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
  • Metropolitan Borough of Wirral, United Kingdom, CH63 4JY
    • Clatterbridge Cancer Centre NHS Foundation Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • California
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute, Emory University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Michigan Medicine, University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System (DUHS)
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas, MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• 1. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and central review of B- and C-findings by WHO diagnostic criteria.
• 2. Patient must have moderate-to-severe symptoms based on minimum mean total symptom score (TSS) of the ISM Symptom Assessment Form (ISM-SAF) over the 14-day eligibility screening period.
• 3. Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms.
• 4. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days.
• 5. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2.

Key Exclusion Criteria:

• 1. Patient has been diagnosed with any of the following WHO SM subclassifications: cutaneous mastocytosis only, smoldering SM, SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia, or mast cell sarcoma.
• 2. Patient must not have received prior treatment with avapritinib.
• 3. Patient must not have had any cytoreductive therapy including but not limited to masitinib and midostaurin, or investigational agent for < 14 days or 5 half-lives of the drug (whichever is longer), and for cladribine, interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5 half-lives of the drug (whichever is longer), before beginning the 14-day ISM-SAF eligibility TSS assessment.
• 4. Patient must not have received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment.
• 5. Patient must not have received any hematopoietic growth factor the preceding 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment.
• 6. Patient must not have a QT interval corrected using Fridericia's formula (QTcF) of > 480 msec.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: (Part 1) Avapritinib Dose 1 + BSC; Avapritinib will be administered orally in continuous 28-day cycles	Drug: Avapritinib; Avapritinib tablet; Other Names: BLU-285
Experimental: (Part 1) Avapritinib Dose 2 + BSC; Avapritinib will be administered orally in continuous 28-day cycles	Drug: Avapritinib; Avapritinib tablet; Other Names: BLU-285
Experimental: (Part 1) Avapritinib Dose 3 + BSC; Avapritinib will be administered orally in continuous 28-day cycles	Drug: Avapritinib; Avapritinib tablet; Other Names: BLU-285
Placebo Comparator: (Part 1) Placebo + BSC; Placebo will be administered orally in continuous 28-day cycles	Drug: Placebo; Placebo tablet
Experimental: (Part 2) Avapritinib RP2D + BSC; Avapritinib will be administered orally in continuous 28-day cycles	Drug: Avapritinib; Avapritinib tablet; Other Names: BLU-285
Placebo Comparator: (Part 2) Placebo + BSC; Placebo will be administered orally in continuous 28-day cycles	Drug: Placebo; Placebo tablet
Experimental: (Part 3) Avapritinib RP2D + BSC; Avapritinib will be administered orally in continuous 28-day cycles	Drug: Avapritinib; Avapritinib tablet; Other Names: BLU-285

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Recommended Phase 2 dose (RP2D) in patients with ISM		9 months
Part 2: Mean change in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) as compared to placebo	0 - 110 points (higher value represents worse symptom outcomes)	6 months
Part 3: Number of Participants with Adverse Events		Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2: Proportion of patients with a ≥50% reduction in serum tryptase		6 months
Part 2: Proportion of patients with a ≥50% reduction in peripheral blood V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) allele fraction or undetectable for patients with detectable mutation at Baseline		6 months
Part 2: Proportion of patients with ≥50% reduction in ISM-SAF TSS		6 months
Part 2: Proportion of patients with ≥30% reduction in ISM-SAF TSS		6 months
Part 2: Proportion of patients with a ≥50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline		6 months
Parts 1, 2, and 3: Change in serum tryptase		Up to 5 years
Parts 1, 2, and 3: Change in KIT D816V allele burden in blood		Up to 5 years
Parts 1, 2, and 3: Change in bone marrow mast cells		Up to 5 years
Parts 1, 2, and 3: Change in best supportive care (BSC) concomitant medication usage		Up to 5 years
Parts 1, 2, and 3: Change from Baseline in ISM-SAF Score		Up to 5 years
Parts 1, 2, and 3: Change in Mastocytosis Quality of Life Questionnaire (MC-QoL)		Up to 5 years
Parts 1, 2, and 3: Change in Patient's Global Impression of Symptom Severity (PGIS)		Up to 5 years
Parts 1, 2, and 3: Change in 12-item Short Form Health Survey (SF-12)	0 - 100 points (higher value represents better symptom outcomes)	Up to 5 years
Parts 1, 2, and 3: Change in Patients' Global Impression of Change (PGIC)	1 - 7 (higher value represents worse symptom outcomes)	Up to 5 years
Parts 1, 2, and 3: Change in EuroQuol 5 Dimensions 5 Levels (EQ 5D-5L)	0 - 100 (higher value represents better symptom outcomes)	Up to 5 years
Parts 1, 2, and 3: Safety of avapritinib as assessed by number of adverse events	CTCAE version 5.0	Up to 5 years

Collaborators and Investigators

• Sponsor: Blueprint Medicines Corporation

Publications and helpful links

General Publications

• Padilla B, Shields AL, Taylor F, Li X, Mcdonald J, Green T, Boral AL, Lin HM, Akin C, Siebenhaar F, Mar B. Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) in a phase 2 clinical study. Orphanet J Rare Dis. 2021 Oct 18;16(1):434. doi: 10.1186/s13023-021-02037-3.
• Gotlib J, Castells M, Elberink HO, Siebenhaar F, Hartmann K, Broesby-Olsen S, George TI, Panse J, Alvarez-Twose I, Radia DH, Tashi T, Bulai Livideanu C, Sabato V, Heaney M, Van Daele P, Cerquozzi S, Dybedal I, Reiter A, Pongdee T, Barete S, Ustun C, Schwartz L, Ward BR, Schafhausen P, Vadas P, Bose P, DeAngelo DJ, Rein L, Vachhani P, Triggiani M, Bonadonna P, Rafferty M, Butt NM, Oh ST, Wortmann F, Ungerstedt J, Guilarte M, Taparia M, Kuykendall AT, Arana Yi C, Ogbogu P, Gaudy-Marqueste C, Mattsson M, Shomali W, Giannetti MP, Bidollari I, Lin HM, Sulllivan E, Mar B, Scherber R, Roche M, Akin C, Maurer M. Avapritinib versus Placebo in Indolent Systemic Mastocytosis. NEJM Evid. 2023 Jun;2(6):EVIDoa2200339. doi: 10.1056/EVIDoa2200339. Epub 2023 May 23.

Helpful Links

• More information about the study

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2019
• Primary Completion (Estimated): June 23, 2027
• Study Completion (Estimated): June 23, 2027

Study Registration Dates

• First Submitted: October 30, 2018
• First Submitted That Met QC Criteria: November 2, 2018
• First Posted (Actual): November 6, 2018

Study Record Updates

• Last Update Posted (Estimated): September 23, 2025
• Last Update Submitted That Met QC Criteria: September 22, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mast Cell Activation Disorders; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Mastocytosis; Mastocytosis, Systemic; avapritinib
• Other Study ID Numbers: BLU-285-2203; 2018-000588-99 (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