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

Indolent Systemic Mastocytosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04910685
• Other study ID #: BLU-263-1201
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: November 30, 2021
• Est. completion date: June 30, 2028

Study information

• Verified date: October 2023
• Source: Blueprint Medicines Corporation
• Contact: Blueprint Medicines
• Phone: 617-714-6707
• Email: medinfo[@]blueprintmedicines.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 443
• Est. completion date: June 30, 2028
• Est. primary completion date: June 30, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Indolent Systemic Mastocytosis
• Mast Cell Activation Syndrome
• Mastocytosis

Intervention

Drug:
• BLU-263
BLU-263 tablet
• Placebo
Placebo Tablet

Locations

Country	Name	City	State
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	Kepler Universitatsklinikum, Med Campus III. Clinic of Internal Medicine 3 - Hematology and Oncology	Linz
Belgium	Unitversitair Ziekenhuis Antwerpen	Edegem	Antwerpen
France	CHU Amiens-Picardie	Amiens
France	CHU de Caen	Caen
France	CHU Grenoble	Grenoble Cedex 9
France	CHU de Limoges	Limoges Cedex
France	CHU de Nantes	Nantes
France	Hôpital de la Pitié Salpétrière	Paris
France	Hôpital Necker - Départementd 'HématologieA dultes	Paris
France	CHU de Poitiers	Poitiers
France	CHU Toulouse - Hopital Larrey	Toulouse
Germany	Universitätsklinikum RWTH Aachen Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation	Aachen
Germany	Charité - Universitätsmedizin Berlin Institute of Allergology	Berlin
Germany	University Clinic Erlangen	Erlangen
Germany	University Clinic Hamburg Eppendorf	Hamburg
Germany	Universitätsmedizin Mannheim III. Medizinische Klinik Universität Heidelberg Medizinische Fakultät Mannheim	Mannheim
Germany	LMU Klinikum	Munich
Italy	Unita Operativa di Ematologia AOU Policlinico S. Orsola-Malpighi	Bologna
Italy	SOD Ematologia (Ambulatori)- AOUC Azienda Ospedaliero Universitaria Careggi	Firenze	Toscana
Italy	Dipartimentod i Oncoematologia Istituto Scientifico Romagnolop er lo studio e la cura dei tumori (IRST)- IRCCS	Meldola	Forli-Cesena
Italy	UOC Ematologia	Milano	Lombardia
Italy	S.C. Ematologia Fondazione I.R.C.C.S. Policlinico San Matteo	Pavia
Italy	S.S.D. Immunologia Clinica e Allergologia Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona	Salerno
Italy	Unità Operativa di Allergologia Azienda Ospedaliera Universitaria Integrata di Verona	Verona
Netherlands	University Medical Center Groningen	Groningen
Netherlands	ErasmusMC	Rotterdam	Zuid-Holland
Norway	Oslo University Hospital	Oslo
Portugal	Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santo Antonio dos Capuchos	Lisbon
Portugal	Centro Hospitalar Universitario Sao Joao, E.P.E.	Porto
Portugal	CHUPorto, EPE - Hospital de Santo António	Porto
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Virgen del Valle - Instituto de Estudios de Mastocitosis de Castilla-La Mancha	Toledo
Switzerland	University Hospital Basel	Basel
Switzerland	Luzerner Kantonsspital	Luzern
United Kingdom	University Hospital of Wales	Cardiff	Wales
United Kingdom	Cancer and Haematology Centre	Oxford
United States	Michigan Medicine University of Michigan	Ann Arbor	Michigan
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	The University of Texas, MD Anderson Cancer Center	Houston	Texas
United States	Columbia University Medical Center	New York	New York
United States	Stanford Cancer Institute	Palo Alto	California
United States	Mayo Clinic	Rochester	Minnesota
United States	Huntsman Cancer Institute, University of Utah	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Blueprint Medicines Corporation

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  France,  Germany,  Italy,  Netherlands,  Norway,  Portugal,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Part M: the proportion of patient who achieve at least a 30% reduction in Mast Cell Quality of Life (MC-QoL) score		6 months
Primary	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
Primary	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
Primary	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
Primary	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	Part 1: Mean change in measures of mast cell burden		3 Months
Secondary	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
Secondary	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
Secondary	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
Secondary	Part 2: Proportion of patients with a =50% reduction in serum tryptase		6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	Part 2: Mean change in measures of mast cell burden		6 months
Secondary	Part 2: Change in number of best supportive care medications		6 Months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part 2: Safety of BLU-263 as assessed by number of adverse events and serious adverse events		up to 5 years
Secondary	Part 3: Mean change in measures of mast cell burden		approximately 5 years
Secondary	Part 3: Change in number of best supportive care medications		approximately 5 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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