(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

Indolent Systemic Mastocytosis Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03731260
• Other study ID #: BLU-285-2203
• Secondary ID: 2018-000588-99
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 16, 2019
• Est. completion date: January 31, 2028

Study information

• Verified date: June 2023
• Source: Blueprint Medicines Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 251
• Est. completion date: January 31, 2028
• Est. primary completion date: June 23, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Indolent Systemic Mastocytosis
• Mastocytosis

Intervention

Drug:
• Avapritinib
Avapritinib tablet
• Placebo
Placebo tablet

Locations

Country	Name	City	State
Belgium	University Hospital Antwerp	Edegem
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	St. Michael's Hospital	Toronto	Ontario
Denmark	Odense Universitetshospital, ORCA/Allergicentret, Hudafdeling I og Allergicenter	Odense
France	Hôpital de la Timone, Service de dermatologie	Marseille
France	Hôpital Pitié-Salpêtrière, Service de Dermatologie	Paris
France	CHU Toulouse Larrey, CEREMAST, Service de Dermatologie et Allergologie cutanée	Toulouse
Germany	Uniklinik RWTH Aachen	Aachen
Germany	Charité Universitätsmedizin Berlin	Berlin
Germany	University Clinic Hamburg Eppendorf, University Cancer Center Hamburg (UCCH)	Hamburg
Germany	Universitätsklinikum Schleswig-Holstein, Hämatologie/Onkologie	Lübeck
Germany	Universitätsklinik Mainz, Universitäts-Hautklinik, Clinical Research Center	Mainz
Germany	Universitätsmedizin Mannheim, III. Medizinische Klinik	Mannheim
Germany	Klinikum rechts der Isar, Technische Universität München	Munich
Italy	A.O.U di Bologna - IRCCS, Istituto di Ematologia Lorenzo e Ariosto Seragnoli, Ematologia	Bologna
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Poloclinico, UOC Ematologia	Milan
Italy	A.O. OO.RR. S.Giovanni di Dio e Ruggi d'Aragona, University of Salerno	Salerno
Italy	Azienda Ospedaliera Universitaria Integrata di Verona	Verona
Netherlands	University Medical Center Groningen (UMCG)	Groningen
Netherlands	Erasmus Medical Center	Rotterdam
Norway	Oslo Universitetssykehus, Rikshospitalet, Department of Hematology	Oslo
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	lnstituto de Estudios de Mastocitosis de Castilla la Mancha, Hospital Virgen del Valle - Complejo Hospitalario de Toledo	Toledo
Sweden	Karolinska University Hospital, Hematologimottagningen R51	Stockholm
Sweden	Akademiska sjukhuset, Hematologmottagningen/101A	Uppsala
Switzerland	University Hospital Basel	Basel
United Kingdom	NHS Greater Glasgow and Clyde, Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital	London
United Kingdom	Clatterbridge Cancer Centre NHS Foundation Trust	Wirral
United States	Michigan Medicine, University of Michigan	Ann Arbor	Michigan
United States	Winship Cancer Institute, Emory University	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Rush University Medical Center	Chicago	Illinois
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Duke University Health System (DUHS)	Durham	North Carolina
United States	University of Texas, MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	University of Kansas Hospital	Kansas City	Kansas
United States	Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Stanford Cancer Institute	Stanford	California
United States	H. Lee Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Blueprint Medicines Corporation

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  France,  Germany,  Italy,  Netherlands,  Norway,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Recommended Phase 2 dose (RP2D) in patients with ISM		9 months
Primary	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
Primary	Part 3: Number of Participants with Adverse Events		Up to 5 years
Secondary	Part 2: Proportion of patients with a =50% reduction in serum tryptase		6 months
Secondary	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
Secondary	Part 2: Proportion of patients with =50% reduction in ISM-SAF TSS		6 months
Secondary	Part 2: Proportion of patients with =30% reduction in ISM-SAF TSS		6 months
Secondary	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
Secondary	Parts 1, 2, and 3: Change in serum tryptase		Up to 5 years
Secondary	Parts 1, 2, and 3: Change in KIT D816V allele burden in blood		Up to 5 years
Secondary	Parts 1, 2, and 3: Change in bone marrow mast cells		Up to 5 years
Secondary	Parts 1, 2, and 3: Change in best supportive care (BSC) concomitant medication usage		Up to 5 years
Secondary	Parts 1, 2, and 3: Change from Baseline in ISM-SAF Score		Up to 5 years
Secondary	Parts 1, 2, and 3: Change in Mastocytosis Quality of Life Questionnaire (MC-QoL)		Up to 5 years
Secondary	Parts 1, 2, and 3: Change in Patient's Global Impression of Symptom Severity (PGIS)		Up to 5 years
Secondary	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
Secondary	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
Secondary	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
Secondary	Parts 1, 2, and 3: Safety of avapritinib as assessed by number of adverse events	CTCAE version 5.0	Up to 5 years

External Links

•   More information about the study