Clinical trial NCT03731260: (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
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Indolent Systemic Mastocytosis
Lead sponsor: Blueprint Medicines Corporation
Sponsor class: INDUSTRY
First posted: 2018-11-06
Enrollment: 251
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Part 1: Recommended Phase 2 dose (RP2D) in patients with ISM
timeFrame: 9 months
measure: Part 2: Mean change in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) as compared to placebo
timeFrame: 6 months
measure: Part 3: Number of Participants with Adverse Events
timeFrame: Up to 5 years
Secondary outcomes:
measure: Part 2: Proportion of patients with a ≥50% reduction in serum tryptase
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: Part 2: Proportion of patients with ≥50% reduction in ISM-SAF TSS
timeFrame: 6 months
measure: Part 2: Proportion of patients with ≥30% reduction in ISM-SAF TSS
timeFrame: 6 months
measure: Part 2: Proportion of patients with a ≥50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline
timeFrame: 6 months
measure: Parts 1, 2, and 3: Change in serum tryptase
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change in KIT D816V allele burden in blood
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change in bone marrow mast cells
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change in best supportive care (BSC) concomitant medication usage
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change from Baseline in ISM-SAF Score
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change in Mastocytosis Quality of Life Questionnaire (MC-QoL)
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change in Patient's Global Impression of Symptom Severity (PGIS)
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change in 12-item Short Form Health Survey (SF-12)
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change in Patients' Global Impression of Change (PGIC)
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Change in EuroQuol 5 Dimensions 5 Levels (EQ 5D-5L)
timeFrame: Up to 5 years
measure: Parts 1, 2, and 3: Safety of avapritinib as assessed by number of adverse events
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute, Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Hospital
state: Kansas
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: Michigan Medicine, University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Health System (DUHS)
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center
state: Virginia
city: Edegem
country: Belgium
facility: University Hospital Antwerp
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Odense
country: Denmark
facility: Odense Universitetshospital, ORCA/Allergicentret, Hudafdeling I og Allergicenter
city: Marseille
country: France
facility: Hôpital de la Timone, Service de dermatologie
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière, Service de Dermatologie
city: Toulouse
country: France
facility: CHU Toulouse Larrey, CEREMAST, Service de Dermatologie et Allergologie cutanée
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Hamburg
country: Germany
facility: University Clinic Hamburg Eppendorf, University Cancer Center Hamburg (UCCH)
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Hämatologie/Onkologie
city: Mainz
country: Germany
facility: Universitätsklinik Mainz, Universitäts-Hautklinik, Clinical Research Center
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim, III. Medizinische Klinik
city: Munich
country: Germany
facility: Klinikum rechts der Isar, Technische Universität München
city: Bologna
country: Italy
facility: A.O.U di Bologna - IRCCS, Istituto di Ematologia Lorenzo e Ariosto Seragnoli, Ematologia
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Poloclinico, UOC Ematologia
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: Azienda Ospedaliera Universitaria Integrata di Verona
city: Groningen
country: Netherlands
facility: University Medical Center Groningen (UMCG)
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Oslo
country: Norway
facility: Oslo Universitetssykehus, Rikshospitalet, Department of Hematology
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Toledo
country: Spain
facility: lnstituto de Estudios de Mastocitosis de Castilla la Mancha, Hospital Virgen del Valle - Complejo Hospitalario de Toledo
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Hematologimottagningen R51
city: Uppsala
country: Sweden
facility: Akademiska sjukhuset, Hematologmottagningen/101A
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde, Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
city: Wirral
country: United Kingdom
facility: Clatterbridge Cancer Centre NHS Foundation Trust
Study officials:
References:
citation: 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.