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(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

Sponsor
Blueprint Medicines Corporation (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03731260
Collaborator
(none)
251
Enrollment
49
Locations
7
Arms
92.6
Anticipated Duration (Months)
5.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
251 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
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.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.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Apr 16, 2019
Anticipated Primary Completion Date :
Jun 1, 2022
Anticipated Study Completion Date :
Jan 1, 2027

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Part 1: Recommended Phase 2 dose (RP2D) in patients with ISM [9 months]

    2. Part 2: Proportion of responders, defined as ≥30% reduction in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) [6 months]

      0 - 110 points (higher value represents worse symptom outcomes)

    Secondary Outcome Measures

    1. Part 2: Proportion of patients with a ≥50% reduction in serum tryptase [6 months]

    2. 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]

    3. Part 2: Mean change in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) [6 months]

    4. 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]

    5. Change in serum tryptase [Up to 5 years]

    6. Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) allele burden in blood [Up to 5 years]

    7. Change in bone marrow mast cells [Up to 1 year after the end of Part 1 and Part 2]

    8. Change in best supportive care (BSC) concomitant medication usage [Up to 5 years]

    9. Change in Mastocytosis Quality of Life Questionnaire (MC-QoL) [Each study visit through Part 3 Cycle 12 (28-day cycles)]

      0 - 100 points (higher value represents worse symptom outcomes)

    10. Change in Patient's Global Impression of Symptom Severity (PGIS) [Each study visit through Part 3 Cycle 12 (28-day cycles)]

      0 - 10 points (higher value represents worse symptom outcomes)

    11. Change in 12-item Short Form Health Survey (SF-12) [Each study visit through Part 3 Cycle 12 (28-day cycles)]

      0 - 100 points (higher value represents better symptom outcomes)

    12. Change in Patients' Global Impression of Change (PGIC) [Each study visit through Part 3 Cycle 12 (28-day cycles)]

      1 - 7 (higher value represents worse symptom outcomes)

    13. Change in EuroQuol 5 Dimensions 5 Levels (EQ 5D-5L) [Each study visit through Part 3 Cycle 12 (28-day cycles)]

      0 - 100 (higher value represents better symptom outcomes)

    14. Safety of avapritinib as assessed by number of adverse events [Up to 5 years]

      CTCAE version 5.0

    15. Part 1 and Part 2 only: Area Under Curve (0 to Tau) for avapritinib [Every cycle (28 days) up to Cycle 4 (Part 1) and Cycle 7 (Part 2)]

      h•ng/mL

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.
      1. 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.
      1. Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms.
      1. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days.
      1. 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.
      1. Patient must not have received prior treatment with avapritinib.
      1. 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.
      1. 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.
      1. Patient must not have received any hematopoietic growth factor the preceding 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment.
      1. Patient must not have a QT interval corrected using Fridericia's formula (QTcF) of

    480 msec.

    Contacts and Locations

    Locations

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

    Sponsors and Collaborators

    • Blueprint Medicines Corporation

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Blueprint Medicines Corporation
    ClinicalTrials.gov Identifier:
    NCT03731260
    Other Study ID Numbers:
    • BLU-285-2203
    • 2018-000588-99
    First Posted:
    Nov 6, 2018
    Last Update Posted:
    Feb 2, 2022
    Last Verified:
    Jan 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Mastocytosis
    Mastocytosis, Systemic

    Study Results

    No Results Posted as of Feb 2, 2022