(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

NCT03731260 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: BLU-285-22032018-000588-99
• Study Type: interventional
• Target: 251
• Locations: 13 countries
• Sites: 49

Brief Summary

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.

Conditions

Indolent Systemic Mastocytosis

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (16)

• 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

Study Arms (7)

(Part 1) Avapritinib Dose 1 + BSC

EXPERIMENTAL

Avapritinib will be administered orally in continuous 28-day cycles

Drug: Avapritinib

(Part 1) Avapritinib Dose 2 + BSC

EXPERIMENTAL

Avapritinib will be administered orally in continuous 28-day cycles

Drug: Avapritinib

(Part 1) Avapritinib Dose 3 + BSC

EXPERIMENTAL

Avapritinib will be administered orally in continuous 28-day cycles

Drug: Avapritinib

(Part 1) Placebo + BSC

PLACEBO COMPARATOR

Placebo will be administered orally in continuous 28-day cycles

Drug: Placebo

(Part 2) Avapritinib RP2D + BSC

EXPERIMENTAL

Avapritinib will be administered orally in continuous 28-day cycles

Drug: Avapritinib

(Part 2) Placebo + BSC

PLACEBO COMPARATOR

Placebo will be administered orally in continuous 28-day cycles

Drug: Placebo

(Part 3) Avapritinib RP2D + BSC

EXPERIMENTAL

Avapritinib will be administered orally in continuous 28-day cycles

Drug: Avapritinib

Interventions

Avapritinib DRUG

Avapritinib tablet

Also known as: BLU-285

(Part 1) Avapritinib Dose 1 + BSC; (Part 1) Avapritinib Dose 2 + BSC; (Part 1) Avapritinib Dose 3 + BSC; (Part 2) Avapritinib RP2D + BSC; (Part 3) Avapritinib RP2D + BSC

Placebo DRUG

Placebo tablet

(Part 1) Placebo + BSC; (Part 2) Placebo + BSC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and central review of B- and C-findings by WHO diagnostic criteria.
• \. 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.
• \. Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms.
• \. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days.
• \. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2.

You may not qualify if:

• \. 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.
• \. Patient must not have received prior treatment with avapritinib.
• \. 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.
• \. 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.
• \. Patient must not have received any hematopoietic growth factor the preceding 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment.
• \. Patient must not have a QT interval corrected using Fridericia's formula (QTcF) of \> 480 msec.

Sponsors & Collaborators

• Blueprint Medicines Corporation: lead

Study Sites (49)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

Stanford Cancer Institute

Stanford, California, 94305, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

H. Lee Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Winship Cancer Institute, Emory University

Atlanta, Georgia, 30322, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

University of Kansas Hospital

Kansas City, Kansas, 66160, United States

Location

Brigham & Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Michigan Medicine, University of Michigan

Ann Arbor, Michigan, 48106, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Herbert Irving Comprehensive Cancer Center

New York, New York, 10032, United States

Location

Duke University Health System (DUHS)

Durham, North Carolina, 27710, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

University of Texas, MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Virginia Commonwealth University Medical Center

Richmond, Virginia, 23298, United States

Location

University Hospital Antwerp

Edegem, 2650, Belgium

Location

Tom Baker Cancer Centre

Calgary, Alberta, T2N 4N2, Canada

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7, Canada

Location

St. Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Odense Universitetshospital, ORCA/Allergicentret, Hudafdeling I og Allergicenter

Odense, DK-5000, Denmark

Location

Hôpital de la Timone, Service de dermatologie

Marseille, 13385, France

Location

Hôpital Pitié-Salpêtrière, Service de Dermatologie

Paris, 75013, France

Location

CHU Toulouse Larrey, CEREMAST, Service de Dermatologie et Allergologie cutanée

Toulouse, 31059, France

Location

Uniklinik RWTH Aachen

Aachen, 52074, Germany

Location

Charité Universitätsmedizin Berlin

Berlin, 10117, Germany

Location

University Clinic Hamburg Eppendorf, University Cancer Center Hamburg (UCCH)

Hamburg, 20246, Germany

Location

Universitätsklinikum Schleswig-Holstein, Hämatologie/Onkologie

Lübeck, 23538, Germany

Location

Universitätsklinik Mainz, Universitäts-Hautklinik, Clinical Research Center

Mainz, 55131, Germany

Location

Universitätsmedizin Mannheim, III. Medizinische Klinik

Mannheim, 68167, Germany

Location

Klinikum rechts der Isar, Technische Universität München

Munich, 80802, Germany

Location

A.O.U di Bologna - IRCCS, Istituto di Ematologia Lorenzo e Ariosto Seragnoli, Ematologia

Bologna, 40138, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Poloclinico, UOC Ematologia

Milan, 20122, Italy

Location

A.O. OO.RR. S.Giovanni di Dio e Ruggi d'Aragona, University of Salerno

Salerno, 84131, Italy

Location

Azienda Ospedaliera Universitaria Integrata di Verona

Verona, 37126, Italy

Location

University Medical Center Groningen (UMCG)

Groningen, 9713 GZ, Netherlands

Location

Erasmus Medical Center

Rotterdam, 3015 GD, Netherlands

Location

Oslo Universitetssykehus, Rikshospitalet, Department of Hematology

Oslo, 0372, Norway

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

lnstituto de Estudios de Mastocitosis de Castilla la Mancha, Hospital Virgen del Valle - Complejo Hospitalario de Toledo

Toledo, 45071, Spain

Location

Karolinska University Hospital, Hematologimottagningen R51

Stockholm, 141 86, Sweden

Location

Akademiska sjukhuset, Hematologmottagningen/101A

Uppsala, 751 85, Sweden

Location

University Hospital Basel

Basel, 4031, Switzerland

Location

NHS Greater Glasgow and Clyde, Beatson West of Scotland Cancer Centre

Glasgow, G12 OXL, United Kingdom

Location

Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital

London, SE1 9RT, United Kingdom

Location

Clatterbridge Cancer Centre NHS Foundation Trust

Metropolitan Borough of Wirral, CH63 4JY, United Kingdom

Location

Related Publications (3)

• Worth S, George TI, Shaheen DJ, Roche M, Vachhani P. Chronic Anaphylaxis With Indolent Systemic Mastocytosis: A Case Report. Case Rep Hematol. 2025 Nov 6;2025:9562195. doi: 10.1155/crh/9562195. eCollection 2025.

  PMID: 41244098 DERIVED

• 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.

  PMID: 38320129 DERIVED

• 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.

  PMID: 34663404 DERIVED

MeSH Terms

Conditions

Mastocytosis, Systemic

Interventions

avapritinib

Condition Hierarchy (Ancestors)

Mastocytosis; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Mast Cell Activation Disorders; Immune System Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: In Part 1 of the study, patients will be randomly assigned to 1 of 3 doses of avapritinib or to placebo + BSC. Once the recommended phase 2 dose (RP2D) of avapritinib is identified in Part 1, patients in Part 2 will be randomly assigned to receive avapritinib at the RP2D + BSC or matching placebo + BSC. In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study (including those initially randomized to placebo) may participate in a long-term open-label extension, receiving avapritinib at the RP2D + BSC.

Study Record Dates

• First Submitted: October 30, 2018
• First Posted: November 6, 2018
• Study Start: April 16, 2019
• Primary Completion (Estimated): June 23, 2027
• Study Completion (Estimated): June 23, 2027
• Last Updated: September 23, 2025

Record last verified: 2025-09

Locations

DE (7); SE (2); FR (3); NO (1); DK (1); GB (3); IT (4); CA (3); CH (1); US (19); NL (2); ES (2); BE (1)