(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis

A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study of BLU-263 in Indolent Systemic Mastocytosis

This is a randomized, double-blind, placebo-controlled, Phase 2/3 study comparing the efficacy and safety of BLU-263 + best supportive care (BSC) with placebo + BSC in patients with indolent systemic mastocytosis (ISM) whose symptoms are not adequately controlled by BSC. Parts 1 and 2 will enroll patients with ISM. Patients enrolled in Part 1 or Part 2 will roll over onto Part 3 to receive treatment with BLU-263 in an open-label fashion following completion of the earlier Part. Part M will enroll patients with monoclonal mast cell activation syndrome (mMCAS). The study also includes PK groups that will enroll patients with ISM.

Study Overview

• Status: Recruiting
• Conditions: Indolent Systemic Mastocytosis; Monoclonal Mast Cell Activation Syndrome
• Intervention / Treatment: Drug: BLU-263; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 443
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Blueprint Medicines; Phone Number: 617-714-6707; Email: medinfo@blueprintmedicines.com

Study Locations

• Australia
  • Queensland
    • Woolloongabba, Queensland, Australia
      • Recruiting
      • Princess Alexandra Hospital
      • Principal Investigator: Robert Bird, MD
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • The Alfred Hospital
      • Principal Investigator: Tse-Chieh Teh, MD
• Austria
  • Linz, Austria, 4021
    • Recruiting
    • Kepler Universitatsklinikum, Med Campus III. Clinic of Internal Medicine 3 - Hematology and Oncology
    • Principal Investigator: Clemens Schmitt, MD
• Belgium
  • Antwerpen
    • Edegem, Antwerpen, Belgium
      • Recruiting
      • Unitversitair Ziekenhuis Antwerpen
      • Principal Investigator: Vito Sabato, MD
• France
  • Amiens, France, 80000
    • Recruiting
    • CHU Amiens-Picardie
    • Principal Investigator: Clement Gourguechon, MD
  • Caen, France
    • Recruiting
    • CHU de Caen
  • Grenoble Cedex 9, France, 38043
    • Recruiting
    • CHU Grenoble
  • Limoges Cedex, France, 87042
    • Recruiting
    • CHU de Limoges
  • Nantes, France, 44093
    • Recruiting
    • CHU de Nantes
    • Principal Investigator: Antoine Neel, MD
  • Paris, France, 75013
    • Recruiting
    • Hopital de la Pitie Salpetriere
    • Principal Investigator: Stephanie Barate, MD
  • Paris, France, 75015
    • Recruiting
    • Hôpital Necker - Départementd 'HématologieA dultes
    • Principal Investigator: Olivier Hermine, MD
  • Poitiers, France, 86000
    • Recruiting
    • CHU de Poitiers
    • Principal Investigator: Ewa Wierzbicka - Hainaut, MD
  • Toulouse, France
    • Recruiting
    • CHU Toulouse - Hôpital Larrey
    • Principal Investigator: Cristina Bulai-Livideanu, MD
• Germany
  • Aachen, Germany
    • Recruiting
    • Universitätsklinikum RWTH Aachen Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation
    • Principal Investigator: Jens Panse, MD
  • Berlin, Germany, 12203
    • Recruiting
    • Charité - Universitätsmedizin Berlin Institute of Allergology
    • Principal Investigator: Marcus Maurer, MD
  • Erlangen, Germany, 91054
    • Recruiting
    • University Clinic Erlangen
    • Principal Investigator: Nicola Wagner, MD
  • Hamburg, Germany, 20246
    • Recruiting
    • University Clinic Hamburg Eppendorf
    • Principal Investigator: Philippe Schafhausen, MD
  • Mannheim, Germany, 68167
    • Recruiting
    • Universitätsmedizin Mannheim III. Medizinische Klinik Universität Heidelberg Medizinische Fakultät Mannheim
    • Principal Investigator: Juliana Schwaab, MD
  • Munich, Germany, 80377
    • Recruiting
    • LMU Klinikum
    • Principal Investigator: Franziska Rueff, MD
• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • Unita Operativa di Ematologia AOU Policlinico S. Orsola-Malpighi
    • Principal Investigator: Cristina Papayannidis, MD, PhD
  • Pavia, Italy, 27100
    • Recruiting
    • S.C. Ematologia Fondazione I.R.C.C.S. Policlinico San Matteo
    • Principal Investigator: Chiara Elena, MD
  • Salerno, Italy, 84131
    • Recruiting
    • S.S.D. Immunologia Clinica e Allergologia Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona
    • Principal Investigator: Massimo Triggiani, MD
  • Verona, Italy, 37126
    • Recruiting
    • Unità Operativa di Allergologia Azienda Ospedaliera Universitaria Integrata di Verona
    • Principal Investigator: Patrizia Bonadonna, MD
  • Forli-Cesena
    • Meldola, Forli-Cesena, Italy, 47014
      • Recruiting
      • Dipartimentod i Oncoematologia Istituto Scientifico Romagnolop er lo studio e la cura dei tumori (IRST)- IRCCS
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Recruiting
      • UOC Ematologia
      • Principal Investigator: Frederica Irene Grifoni, MD
  • Toscana
    • Firenze, Toscana, Italy, 50134
      • Recruiting
      • SOD Ematologia (Ambulatori)- AOUC Azienda Ospedaliero Universitaria Careggi
      • Principal Investigator: Francesco Mannelli, MD
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Recruiting
    • University Medical Center Groningen
    • Principal Investigator: Hanneke Oude Elberink, MD
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
      • Recruiting
      • ErasmusMC
      • Principal Investigator: M.A.W. Hermans, MD, PhD
• Norway
  • Oslo, Norway, N-0424
    • Recruiting
    • Oslo University Hospital
    • Principal Investigator: Ingunn Dybedal, MD, PhD
• Portugal
  • Lisbon, Portugal, 1169-050
    • Recruiting
    • Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santo António dos Capuchos
    • Principal Investigator: Patrícia Ribeiro, MD
  • Porto, Portugal, 4099-001
    • Recruiting
    • CHUPorto, EPE - Hospital de Santo António
    • Principal Investigator: Renata Cabral, MD
  • Porto, Portugal, 4200-139
    • Recruiting
    • Centro Hospitalar Universitário São João, E.P.E.
    • Principal Investigator: Tiago Azenha Rama, MIM
• Spain
  • Barcelona, Spain
    • Recruiting
    • Hospital Universitario Vall d'Hebron
    • Principal Investigator: Mar Guilarte Clavero, MD
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramón y Cajal
    • Principal Investigator: David Gonzalez de Olano, MD
  • Toledo, Spain, 45071
    • Recruiting
    • Hospital Virgen del Valle - Instituto de Estudios de Mastocitosis de Castilla-La Mancha
    • Principal Investigator: Ivan Alvarz-Twose, MD, PhD
• Switzerland
  • Basel, Switzerland, C-4031
    • Recruiting
    • University Hospital Basel
    • Principal Investigator: Karin Hartmann, MD
  • Luzern, Switzerland, 6000
    • Recruiting
    • Luzerner Kantonsspital
    • Principal Investigator: Axel Rufer, MD
• United Kingdom
  • Oxford, United Kingdom, OX3 7LE
    • Recruiting
    • Cancer and Haematology Centre
    • Principal Investigator: Bethan Psaila, MD, PhD
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • Recruiting
      • University Hospital of Wales
      • Principal Investigator: Steven Knapper, MD
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • University of Alabama at Birmingham
      • Principal Investigator: Pankit Vachhani, MD
  • California
    • Palo Alto, California, United States, 94305
      • Recruiting
      • Stanford Cancer Institute
      • Principal Investigator: William Shomali, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Principal Investigator: Mariana Castells, MD
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • Michigan Medicine University of Michigan
      • Principal Investigator: Cem Akin, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Recruiting
      • Mayo Clinic
      • Principal Investigator: Thanai Pongdee, MD
  • New York
    • Buffalo, New York, United States, 14263
      • Recruiting
      • Roswell Park Cancer Institute
      • Principal Investigator: Elizabeth Griffiths, MD
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center
      • Principal Investigator: Joseph Jurcic, MD
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Recruiting
      • University of Cincinnati Medical Center
      • Principal Investigator: Johnathan Bernstein, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas, MD Anderson Cancer Center
      • Principal Investigator: Prithviraj Bose, MD
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Huntsman Cancer Institute, University of Utah
      • Principal Investigator: Tsewang Tashi, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

All Patients

-1. Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.

Part 1 and Part 2

• 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 has confirmed diagnosis of ISM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO diagnostic criteria. Archival biopsy may be used if completed within the past 12 months.
• 4. Patient 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 symptomatic therapies administered: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
• 5. Patients must have BSC for ISM symptom management stabilized for at least 14 days prior to starting screening procedures.
• 6. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days.

Part M

• 7. Patients must have mMCAS, confirmed by Central Pathology Review of BM biopsy. An archival biopsy may be used if completed within the past 12 months.
• 8. Patients must have tryptase < 20 ng/mL.
• 9. Patients must have KIT D816V in peripheral blood (PB) or BM and/or CD25+ Mast cells in BM.
• 10. Patients must have symptoms consistent with mast cell activation (despite BSC) in at least two organ systems characterized by cutaneous flushing, tachycardia, syncope, hypotension, diarrhea, nausea, vomiting and gastro-intestinal cramping) and serum blood tryptase (sBT) levels above 8 ng/mL OR Severe (Ring and Messmer grading ≥ II, recurrent anaphylaxis, including but not limited to hymenoptera venom, drug or food, regardless of sBT levels.

PK Groups

• 11. See inclusion criteria for All patients and Part 1/Part 2
• 12. Accrual may be limited to patients who have specific disease manifestations (ie, GI involvement) or are taking acid-reducing agents to better explore the impact of these features on PK.

Key Exclusion Criteria:

• 1. Patient has been diagnosed with any of the following WHO systemic mastocytosis (SM) sub-classifications: cutaneous mastocytosis only, smoldering SM, SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia, or mast cell sarcoma.
• 2. Patient has been diagnosed with another myeloproliferative disorder.
• 3. Patient has organ damage C-findings attributable to SM.
• 4. Patient has clinically significant, uncontrolled, cardiovascular disease
• 5. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.
• 6. Patient has previously received treatment with any targeted KIT inhibitors.
• 7. Patient 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.
• 8. Time since any cytoreductive therapy including mastinib 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.
• 9.Patient has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the screening period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: (Part 1) BLU-263 Dose 1 + BSC; Patients will receive best supportive care (BSC) and Dose 1 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.	Drug: BLU-263; BLU-263 tablet
Experimental: (Part 1) BLU-263 Dose 2 + BSC; Patients will receive best supportive care (BSC) and Dose 2 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.	Drug: BLU-263; BLU-263 tablet
Experimental: (Part 1) BLU-263 Dose 3 + BSC; Patients will receive best supportive care (BSC) and Dose 3 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.	Drug: BLU-263; BLU-263 tablet
Placebo Comparator: (Part 1) Placebo + BSC; Patients will receive best supportive care (BSC) and matching placebo tablets. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily until completion of Part 1	Drug: Placebo; Placebo Tablet
Experimental: (Part 2) BLU-263 RD + BSC; Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily for approximately 24 weeks	Drug: BLU-263; BLU-263 tablet
Placebo Comparator: (Part 2) Placebo + BSC; Patients will receive best supportive care (BSC) and matching placebo tablets. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily once daily for approximately 24 weeks	Drug: Placebo; Placebo Tablet
Experimental: (Part 3) BLU-263 RD + BSC; Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablet in an open-label fashion for up to 5 years.	Drug: BLU-263; BLU-263 tablet
Experimental: (Part M) BLU-263 RD + BSC; Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily for the duration of participation in the study.	Drug: BLU-263; BLU-263 tablet
Experimental: PK Groups (Dose 2 or Dose 3); Patients will receive best supportive care (BSC) and Dose 2 or Dose 3 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally for the duration of participation in the study.	Drug: BLU-263; BLU-263 tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Recommended Dose (RD) in patients with ISM	Selection of the RD to be used in Part 2, Part 3 and Part M of the study	3 months
Part 2: Proportion of responders, defined as ≥30% reduction in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS)	Response rate in patients with ISM	6 months
Part 3: Long-term safety and tolerability of BLU-263 as assessed by the number of adverse events and serious adverse events		up to 5 years
Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS)	The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms	up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2: Proportion of patients with a ≥50% reduction in serum tryptase		6 months
Part 1: Mean change in measures of mast cell burden		3 Months
Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS)	The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms	3 Months
Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores	Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms	3 months
Part 1: Time to achieve 30% reduction inIndolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores	Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-110 and a lower score represents lower symptom burden	3 months
Part 2: The proportion of patients who achieve at least a 50% reduction in peripheral blood KIT D816V allele fraction, or a reduction to undetectable levels.		6 months
Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS)	The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms	6 months
Part 2: Proportion of patients with a ≥50% reduction in bone marrow mast cells or reduction to no aggregates for patients with aggregates at Baseline		6 months
Part 2: Mean change in measures of mast cell burden		6 months
Part 2: Change in number of best supportive care medications		6 Months
Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores	Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms	6 months
Part 2: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score	Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms	6 months
Part 2: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores	Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-10 and a lower score represents lower symptom burden	6 months
Part 2: Mean change in the Mast Cell Quality of Life (MC-QoL) score	The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life.	6 months
Part 2: Safety of BLU-263 as assessed by number of adverse events and serious adverse events		up to 5 years
Part 3: Mean change in measures of mast cell burden		approximately 5 years
Part 3: Change in number of best supportive care medications		approximately 5 years
Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom score	Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms	approximately 5 years
Part 3: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score	Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms	approximately 5 years
Part 3: Mean change in the Mast Cell Quality of Life (MC-QoL) score	The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life.	approximately 5 years
Part 3: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Scores	Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-110 and a lower score represents lower symptom burden	12 months

Other Outcome Measures

Outcome Measure	Time Frame
Part M: the proportion of patient who achieve at least a 30% reduction in Mast Cell Quality of Life (MC-QoL) score	6 months

Collaborators and Investigators

• Sponsor: Blueprint Medicines Corporation

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: May 17, 2021
• First Submitted That Met QC Criteria: May 27, 2021
• First Posted (Actual): June 2, 2021

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 20, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Mastocytosis; Mastocytosis, Systemic; Mast Cell Activation Syndrome; Mast Cell Activation Disorders
• Other Study ID Numbers: BLU-263-1201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No