Clinical trial NCT04910685: (HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis
Official title: A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study of BLU-263 in Indolent Systemic Mastocytosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Indolent Systemic Mastocytosis
Smoldering Systemic Mastocytosis
Keywords: ISM
SSM
Lead sponsor: Blueprint Medicines Corporation
Sponsor class: INDUSTRY
First posted: 2021-06-02
Enrollment: 534
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Part 1 and Part 2: Randomized, Blinded Part 3, Part K, Part S and PK groups: Non-randomized, Open-label
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blind, placebo-controlled, Phase 2/3 study comparing the efficacy and safety of elenestinib (BLU-263) + symptom directed therapy (SDT) with placebo + SDT in participants with indolent systemic mastocytosis (ISM) whose symptoms are not adequately controlled by SDT. Parts 1 and 2 will enroll participants with ISM. Participants enrolled in Part 2 will roll over onto Part 3 to receive treatment with elenestinib in an open-label fashion following completion of the earlier Part. Part K will enroll participants with ISM who have previously received an approved selective KIT inhibitor. The study also includes pharmacokinetic (PK) groups that will enroll participants with ISM.


Eligibility criteria: Key Inclusion Criteria:

All Participants:

-Participant must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.

Part 1 and PK groups:

* Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review
* Participant must have failed to achieve adequate symptom control for 1 or more Baseline symptoms, as determined by the Investigator, with at least 2 of the following symptom-directed therapies administered: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
* Participants must have SDT for ISM symptom management stabilized for at least 14 days prior to starting screening procedures.
* For participants receiving corticosteroids, the dose must be ≤ 20 mg/day prednisone or equivalent, and the dose must be stable for ≥ 14 days.

Part K:

-Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review

Part S:

-Participant has confirmed diagnosis of SSM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO diagnostic criteria.

Part 2:

-Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review

Key Exclusion Criteria:

* Participant has been diagnosed with any of the following WHO systemic mastocytosis (SM) sub-classifications: cutaneous mastocytosis only, SM with an associated hematologic neoplasm of non-MC lineage (SM-AHN), aggressive SM, mast cell leukemia, or mast cell sarcoma.
* Participant has been diagnosed with another myeloproliferative disorder.
* Participant has organ damage attributable to SM.
* Participant has clinically significant, uncontrolled, cardiovascular disease
* Participant has a QT interval corrected using Fridericia's formula (QTcF) \> \> 470 milliseconds (msec) (for females) or \> 450 msec (for males).
* Participant has a history of a primary malignancy that has been diagnosed or required therapy within 3 years. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
* Time since any cytoreductive therapy including masitinib and midostaurin should be at least 5 half-lives or 14 days (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 screening period.
* Participant has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy \< 14 days before beginning the screening period.

Other protocol-defined criteria apply.

Primary outcomes:
measure: Part 1: Number of participants with Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to 12 weeks
measure: Part 1: Mean change from baseline in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS)
timeFrame: Baseline, Week 13
measure: Part 2: Mean change from baseline in ISM-SAF TSS
timeFrame: Baseline, Week 49
measure: Part 3: Number of participants with Adverse Events (AEs)
timeFrame: Up to 5 years
measure: Part 3: Change from baseline in ISM-SAF TSS
timeFrame: Baseline up to 5 years
Secondary outcomes:
measure: Part 1: Change from baseline in serum tryptase
timeFrame: Baseline, Week 13
measure: Part 1: Change from baseline in KIT D816V allele fraction in blood
timeFrame: Baseline, Week 13
measure: Part 1: Change from baseline in Bone Marrow (BM) mast cells
timeFrame: Baseline, Week 13
measure: Part 1: Mean change from baseline in ISM-SAF individual symptom scores
timeFrame: Baseline, Week 13
measure: Part 1: Time to achieve 30% reduction from baseline in ISM-SAF TSS
timeFrame: Baseline up to Week 13
measure: Part 1: Time to achieve 30% reduction from baseline in ISM-SAF domain scores
timeFrame: Baseline up to Week 13
measure: Part 2: Proportion of participants achieving normalized tryptase
timeFrame: Baseline up to Week 49
measure: Part 2: Proportion of participants who achieve an undetectable level or at least a 50% reduction in KIT D816V Variant Allele Frequency (VAF)
timeFrame: Baseline up to Week 49
measure: Part 2: Proportion of participants achieving symptom control as defined by achieving mild symptoms
timeFrame: Baseline up to Week 49
measure: Part 2: Mean percent change from baseline in Bone Mineral Density (BMD)
timeFrame: Baseline, Week 49
measure: Part 2: Mean change from baseline in the annualized rate of anaphylaxis events
timeFrame: Baseline, Weeks 25 to 48
measure: Part 2: Mean change from baseline in Quality of Life (QoL) scores
timeFrame: Baseline, Week 49
measure: Part 2: Mean change from baseline in ISM-SAF domain scores
timeFrame: Baseline, Week 49
measure: Part 2: Number of participants with AEs
timeFrame: Up to Week 49
measure: Part 2: Proportion of participants with a 50% reduction in ISM-SAF TSS
timeFrame: Baseline, Weeks 24 and 48
measure: Part 2: Proportion of participants with a 50% reduction in ISM-SAF domain scores
timeFrame: Baseline, Weeks 24 and 48
measure: Part 2: Proportion of participants with a 30% reduction in ISM-SAF TSS
timeFrame: Baseline, Weeks 24 and 48
measure: Part 2: Proportion of participants with a 30% reduction in ISM-SAF domain scores
timeFrame: Baseline, Weeks 24 and 48
measure: Part 3: Proportion of participants achieving symptom control as defined by achieving mild symptoms
timeFrame: Baseline up to 5 years
measure: Part 3: Change from baseline in ISM-SAF domain scores
timeFrame: Baseline, up to 5 years
measure: Part 3: Proportion of participants achieving a normalized tryptase
timeFrame: Baseline up to 5 years
measure: Part 3: Change from baseline in BMD
timeFrame: Baseline up to 5 years
measure: Part 3: Change from baseline in the annualized rate of anaphylaxis events
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Change from baseline in serum tryptase
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Change from baseline in KIT D816V allele fraction in blood
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Change from baseline in Bone Marrow (BM) mast cells
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Proportion of participants achieving controlled disease
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Change from baseline in skin lesions as assessed by the fractional body surface area of the most affected skin area
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Change from baseline in the number of concomitant medications identified as SDT
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Change from baseline in ISM-SAF Individual Symptom Scores
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Change from baseline in ISM-SAF Lead (most severe) Symptom Score
timeFrame: Baseline up to 5 years
measure: Parts 2 and 3: Change from baseline in QoL scores
timeFrame: Baseline up to 5 years
measure: Part S: Number of participants with AEs
timeFrame: Baseline up to 5 years
measure: Part S: Proportion of participants who achieve a Pure Pathologic Response (PPR)
timeFrame: Baseline up to 5 years
measure: Part S: Mean change from baseline in ISM-SAF
timeFrame: Baseline, Week 25
measure: Part K: Number of participants with AEs
timeFrame: Baseline up to 5 years
measure: Part K: Change from baseline in serum tryptase
timeFrame: Baseline up to 5 years
measure: Part K: Change from baseline in KIT D816V allele fraction in blood
timeFrame: Baseline up to 5 years
measure: Part K: Mean change from baseline in ISM-SAF TSS
timeFrame: Baseline up to 5 years
measure: Part K: Change from baseline in QoL scores
timeFrame: Baseline up to 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Stanford Cancer Institute
state: California
city: Boston
country: United States
facility: Brigham and Women's Hospital
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: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Houston
country: United States
facility: The University of Texas, MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, University of Utah
state: Utah
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Linz
country: Austria
facility: Kepler Universitatsklinikum, Med Campus III. Clinic of Internal Medicine 3 - Hematology and Oncology
city: Edegem
country: Belgium
facility: Unitversitair Ziekenhuis Antwerpen
state: Antwerpen
city: Amiens
country: France
facility: CHU Amiens-Picardie
city: Caen
country: France
facility: CHU de Caen
city: Grenoble Cedex 9
country: France
facility: CHU Grenoble
city: Limoges Cedex
country: France
facility: CHU de Limoges
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hôpital de la Pitié Salpétrière
city: Paris
country: France
facility: Hôpital Necker - Départementd 'HématologieA dultes
city: Poitiers
country: France
facility: CHU de Poitiers
city: Toulouse
country: France
facility: CHU Toulouse - Hopital Larrey
city: Aachen
country: Germany
facility: Universitätsklinikum RWTH Aachen Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin Institute of Allergology
city: Erlangen
country: Germany
facility: University Clinic Erlangen
city: Hamburg
country: Germany
facility: University Clinic Hamburg Eppendorf
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim III. Medizinische Klinik Universität Heidelberg Medizinische Fakultät Mannheim
city: Munich
country: Germany
facility: LMU Klinikum
city: Meldola
country: Italy
facility: Dipartimentod i Oncoematologia Istituto Scientifico Romagnolop er lo studio e la cura dei tumori (IRST)- IRCCS
state: Forli-Cesena
city: Milano
country: Italy
facility: UOC Ematologia
state: Lombardia
city: Firenze
country: Italy
facility: SOD Ematologia (Ambulatori)- AOUC Azienda Ospedaliero Universitaria Careggi
state: Toscana
city: Bologna
country: Italy
facility: Unita Operativa di Ematologia AOU Policlinico S. Orsola-Malpighi
city: Pavia
country: Italy
facility: S.C. Ematologia Fondazione I.R.C.C.S. Policlinico San Matteo
city: Salerno
country: Italy
facility: S.S.D. Immunologia Clinica e Allergologia Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona
city: Verona
country: Italy
facility: Unità Operativa di Allergologia Azienda Ospedaliera Universitaria Integrata di Verona
city: Rotterdam
country: Netherlands
facility: ErasmusMC
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Lisbon
country: Portugal
facility: Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santo Antonio dos Capuchos
city: Porto
country: Portugal
facility: CHUPorto, EPE - Hospital de Santo António
city: Porto
country: Portugal
facility: Centro Hospitalar Universitario Sao Joao, E.P.E.
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Toledo
country: Spain
facility: Hospital Virgen del Valle - Instituto de Estudios de Mastocitosis de Castilla-La Mancha
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: Wales
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: London
country: United Kingdom
facility: Guy's and St Thomas's NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Cancer and Haematology Centre
city: Plymouth
country: United Kingdom
facility: University Hospital Plymouth NHS Trust
Study officials:
References: