(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

Overview

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.

Interventions

• Drug Elenestinib
  Elenestinib oral tablet
• Drug Placebo
  Placebo oral tablet

Primary outcome measures

• Part 1: Number of participants with Treatment-emergent Adverse Events (TEAEs) [Time frame: Up to 12 weeks]
• Part 1: Mean change from baseline in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS) [Time frame: Baseline, Week 13]
• Part 2: Mean change from baseline in ISM-SAF TSS [Time frame: Baseline, Week 49]
• Part 3: Number of participants with Adverse Events (AEs) [Time frame: Up to 5 years]
• Part 3: Change from baseline in ISM-SAF TSS [Time frame: Baseline up to 5 years]

Secondary outcome measures (12)

• Part 1: Change from baseline in serum tryptase [Time frame: Baseline, Week 13]
• Part 1: Change from baseline in KIT D816V allele fraction in blood [Time frame: Baseline, Week 13]
• Part 1: Change from baseline in Bone Marrow (BM) mast cells [Time frame: Baseline, Week 13]
• Part 1: Mean change from baseline in ISM-SAF individual symptom scores [Time frame: Baseline, Week 13]
• Part 1: Time to achieve 30% reduction from baseline in ISM-SAF TSS [Time frame: Baseline up to Week 13]
• Part 1: Time to achieve 30% reduction from baseline in ISM-SAF domain scores [Time frame: Baseline up to Week 13]
• Part 2: Proportion of participants achieving normalized tryptase [Time frame: Baseline up to Week 49]
• Part 2: Proportion of participants who achieve an undetectable level or at least a 50% reduction in KIT D816V Variant Allele Frequency (VAF) [Time frame: Baseline up to Week 49]
• Part 2: Proportion of participants achieving symptom control as defined by achieving mild symptoms [Time frame: Baseline up to Week 49]
• Part 2: Mean percent change from baseline in Bone Mineral Density (BMD) [Time frame: Baseline, Week 49]
• Part 2: Mean change from baseline in the annualized rate of anaphylaxis events [Time frame: Baseline, Weeks 25 to 48]
• Part 2: Mean change from baseline in Quality of Life (QoL) scores [Time frame: Baseline, Week 49]

Eligibility criteria

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

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 14 centers

• University of Alabama at Birmingham — Birmingham
• David Geffen School of Medicine at UCLA — Los Angeles
• Stanford Cancer Institute — Palo Alto
• UCHealth Blood Disorders and Cell Therapies Center - Anschutz Medical Campus — Aurora
• Winship Cancer Institute, Emory University — Atlanta
• Brigham and Women's Hospital — Boston
• Michigan Medicine University of Michigan — Ann Arbor
• Mayo Clinic — Rochester
• … and 6 more centers

France · 9 centers

• CHU Amiens-Picardie — Amiens
• CHU de Caen — Caen
• CHU Grenoble — Grenoble
• CHU de Limoges — Limoges
• CHU de Nantes — Nantes
• Hôpital de la Pitié Salpétrière — Paris
• Hôpital Necker - Départementd 'HématologieA dultes — Paris
• CHU de Poitiers — Poitiers
• … and 1 more center

Italy · 7 centers

• UOC Ematologia — Milan
• SOD Ematologia (Ambulatori)- AOUC Azienda Ospedaliero Universitaria Careggi — Florence
• Unita Operativa di Ematologia AOU Policlinico S. Orsola-Malpighi — Bologna
• AOU Policlinico G.Rodolico - San Marco — Catania
• S.C. Ematologia Fondazione I.R.C.C.S. Policlinico San Matteo — Pavia
• S.S.D. Immunologia Clinica e Allergologia Azienda Ospedaliera Universitaria San Giovanni d — Salerno
• Unità Operativa di Allergologia Azienda Ospedaliera Universitaria Integrata di Verona — Verona

Germany · 6 centers

• Universitätsklinikum RWTH Aachen Klinik für Hämatologie, Onkologie, Hämostaseologie und St — Aachen
• Charité - Universitätsmedizin Berlin Institute of Allergology — Berlin
• University Clinic Erlangen — Erlangen
• University Clinic Hamburg Eppendorf — Hamburg
• Universitätsmedizin Mannheim III. Medizinische Klinik Universität Heidelberg Medizinische — Mannheim
• LMU Klinikum — Munich

United Kingdom · 6 centers

• University Hospital of Wales — Cardiff
• University Hospital of Wales — Cardiff
• University College London Hospitals (UCLH), Haematology Cancer Clinical Trials Unit — London
• Guy's and St Thomas's NHS Foundation Trust — London
• Cancer and Haematology Centre — Oxford
• University Hospital Plymouth NHS Trust — Plymouth

Belgium · 3 centers

• Unitversitair Ziekenhuis Antwerpen — Edegem
• Universitair Ziekenhuis Gent — Ghent
• CHU Tivoli — La Louvière

Netherlands · 3 centers

• ErasmusMC — Rotterdam
• University Medical Center Groningen — Groningen
• Maastricht UMC+ — Maastricht

Portugal · 3 centers

• Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santo Antonio dos Capuchos — Lisbon
• CHUPorto, EPE - Hospital de Santo António — Porto
• Centro Hospitalar Universitario Sao Joao, E.P.E. — Porto

Spain · 3 centers

• Hospital Universitario Vall d'Hebron — Barcelona
• Hospital Universitario Ramon y Cajal — Madrid
• Hospital Virgen del Valle - Instituto de Estudios de Mastocitosis de Castilla-La Mancha — Toledo

Turkey (Türkiye) · 3 centers

• Ankara Universitesi Tip Fakultesi Cebeci Hastanesi — Ankara
• lstanbul Universitesi lstanbul Tip Fakultesi Hastanesi — Istanbul
• Mersin VM Medikal Park Hastanesi — Mersin

Argentina · 2 centers

• CHP Centro Hematologico Pavlovsky — Buenos Aires
• Consultorios Medicos Dr. Doreski - Fundacion Respirar — Buenos Aires

Australia · 2 centers

• Princess Alexandra Hospital — Woolloongabba
• The Alfred Hospital — Melbourne

Czechia · 2 centers

• Fakultní nemocnice Brno, Interní hematologická a onkologická klinika — Brno
• Fakultní nemocnice Královské Vinohrady, Hematologická klinika 3. LF UK v Praze a FNKV — Prague

Greece · 2 centers

• University General Hospital - General Hospital of West Attica — Chaïdári
• General Hospital of Thessaloniki "G. Papanikolaou" — Thessaloniki

Poland · 2 centers

• Uniwersyteckie Centrum Kliniczne Klinika Alergologii — Gdansk
• Samodzielny Publiczny Za kład Opieki Zdrowotnej Szpital Uniwersytecki w Krakowie — Krakow

Switzerland · 2 centers

• University Hospital Basel — Basel
• Luzerner Kantonsspital — Lucerne

Austria · 1 center

• Kepler Universitatsklinikum, Med Campus III. Clinic of Internal Medicine 3 - Hematology an — Linz

Brazil · 1 center

• Hospital das Clínicas da Faculdade de Medicina da USP - HCFMUSP — São Paulo

Colombia · 1 center

• Fundación Valle del Lili — Cali

Ireland · 1 center

• Cork University Hospital — Cork

Norway · 1 center

• Oslo University Hospital — Oslo

Sweden · 1 center

• Uppsala University Hospital — Uppsala

Identifiers

NCT: NCT04910685 · BLU-263-1201

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗