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

Sponsor
Blueprint Medicines Corporation (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04910685
Collaborator
(none)
443
Enrollment
36
Locations
9
Arms
79
Anticipated Duration (Months)
12.3
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Study Design

Study Type:
Interventional
Anticipated Enrollment :
443 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
In Part 1 of the study, patients with ISM will be randomly assigned to 1 of 3 doses of BLU-263 + BSC or to placebo + BSC. Once the recommended dose (RD) of BLU-263 is identified in Part 1, patients with ISM in Part 2 will be randomly assigned to receive BLU-263 at the RD + BSC or matching placebo + BSC. Patients will be randomized 2:1 to BLU-263:placebo. In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study (including those initially randomized to placebo) will participate in a long-term open-label extension, receiving BLU-263 at the RD + BSC. In Part M of the study patients with monoclonal mast cell activation syndrome will receive BLU-263 + BSC at the RD in an open-label fashion. The study also includes PK groups that will enroll patients with ISMIn Part 1 of the study, patients with ISM will be randomly assigned to 1 of 3 doses of BLU-263 + BSC or to placebo + BSC. Once the recommended dose (RD) of BLU-263 is identified in Part 1, patients with ISM in Part 2 will be randomly assigned to receive BLU-263 at the RD + BSC or matching placebo + BSC. Patients will be randomized 2:1 to BLU-263:placebo. In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study (including those initially randomized to placebo) will participate in a long-term open-label extension, receiving BLU-263 at the RD + BSC. In Part M of the study patients with monoclonal mast cell activation syndrome will receive BLU-263 + BSC at the RD in an open-label fashion. The study also includes PK groups that will enroll patients with ISM
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study of BLU-263 in Indolent Systemic Mastocytosis
Actual Study Start Date :
Nov 30, 2021
Anticipated Primary Completion Date :
Aug 31, 2023
Anticipated Study Completion Date :
Jun 30, 2028

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

  1. Part 1: Recommended Dose (RD) in patients with ISM [3 months]

    Selection of the RD to be used in Part 2, Part 3 and Part M of the study

  2. Part 2: Proportion of responders, defined as ≥30% reduction in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS) [6 months]

    Response rate in patients with ISM

  3. 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]

  4. Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) [up to 5 years]

    The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms

Secondary Outcome Measures

  1. Part 1: Mean change in measures of mast cell burden [3 Months]

  2. Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) [3 Months]

    The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms

  3. Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores [3 months]

    Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

  4. Part 1: Time to achieve 30% reduction inIndolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores [3 months]

    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

  5. Part 2: Proportion of patients with a ≥50% reduction in serum tryptase [6 months]

  6. 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]

  7. Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) [6 months]

    The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms

  8. 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]

  9. Part 2: Mean change in measures of mast cell burden [6 months]

  10. Part 2: Change in number of best supportive care medications [6 Months]

  11. Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores [6 months]

    Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

  12. Part 2: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score [6 months]

    Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

  13. Part 2: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores [6 months]

    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

  14. Part 2: Mean change in the Mast Cell Quality of Life (MC-QoL) score [6 months]

    The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life.

  15. Part 2: Safety of BLU-263 as assessed by number of adverse events and serious adverse events [up to 5 years]

  16. Part 3: Mean change in measures of mast cell burden [approximately 5 years]

  17. Part 3: Change in number of best supportive care medications [approximately 5 years]

  18. Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom score [approximately 5 years]

    Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

  19. Part 3: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score [approximately 5 years]

    Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

  20. Part 3: Mean change in the Mast Cell Quality of Life (MC-QoL) score [approximately 5 years]

    The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life.

  21. Part 3: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Scores [12 months]

    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

Other Outcome Measures

  1. Part M: the proportion of patient who achieve at least a 30% reduction in Mast Cell Quality of Life (MC-QoL) score [6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:
16 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

    1. 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.
    1. 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.
    1. 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.
    1. Patients must have BSC for ISM symptom management stabilized for at least 14 days prior to starting screening procedures.
    1. 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

    1. 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.
    1. Patients must have tryptase < 20 ng/mL.
    1. Patients must have KIT D816V in peripheral blood (PB) or BM and/or CD25+ Mast cells in BM.
    1. 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

    1. See inclusion criteria for All patients and Part 1/Part 2
    1. 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.
    1. Patient has been diagnosed with another myeloproliferative disorder.
    1. Patient has organ damage C-findings attributable to SM.
    1. Patient has clinically significant, uncontrolled, cardiovascular disease
    1. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.
    1. Patient has previously received treatment with any targeted KIT inhibitors.
    1. 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.
    1. 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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Stanford Cancer Institute Palo Alto California United States 94305
2 Brigham and Women's Hospital Boston Massachusetts United States 02115
3 Michigan Medicine University of Michigan Ann Arbor Michigan United States 48109
4 Roswell Park Cancer Institute Buffalo New York United States 14263
5 Columbia University Medical Center New York New York United States 10032
6 Huntsman Cancer Institute, University of Utah Salt Lake City Utah United States 84112
7 Princess Alexandra Hospital Woolloongabba Queensland Australia
8 The Alfred Hospital Melbourne Victoria Australia 3004
9 Kepler Universitatsklinikum, Med Campus III. Clinic of Internal Medicine 3 - Hematology and Oncology Linz Austria 4021
10 Unitversitair Ziekenhuis Antwerpen Edegem Antwerpen Belgium
11 CHU de Caen Caen France
12 CHU Grenoble Grenoble Cedex 9 France 38043
13 CHU de Limoges Limoges Cedex France 87042
14 CHU de Nantes Nantes France 44093
15 Hôpital de la Pitié Salpétrière Paris France 75013
16 Hôpital Necker - Départementd 'HématologieA dultes Paris France 75015
17 CHU Toulouse - Hopital Larrey Toulouse France
18 Universitätsklinikum RWTH Aachen Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation Aachen Germany
19 University Clinic Erlangen Erlangen Germany 91054
20 University Clinic Hamburg Eppendorf Hamburg Germany 20246
21 Universitätsmedizin Mannheim III. Medizinische Klinik Universität Heidelberg Medizinische Fakultät Mannheim Mannheim Germany 68167
22 Dipartimentod i Oncoematologia Istituto Scientifico Romagnolop er lo studio e la cura dei tumori (IRST)- IRCCS Meldola Forli-Cesena Italy 47014
23 SOD Ematologia (Ambulatori)- AOUC Azienda Ospedaliero Universitaria Careggi Firenze Toscana Italy 50134
24 Unita Operativa di Ematologia AOU Policlinico S. Orsola-Malpighi Bologna Italy 40138
25 S.C. Ematologia Fondazione I.R.C.C.S. Policlinico San Matteo Pavia Italy 27100
26 S.S.D. Immunologia Clinica e Allergologia Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona Salerno Italy 84131
27 Unità Operativa di Allergologia Azienda Ospedaliera Universitaria Integrata di Verona Verona Italy 37126
28 ErasmusMC Rotterdam Zuid-Holland Netherlands 3015 GD
29 University Medical Center Groningen Groningen Netherlands 9713 GZ
30 Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santo Antonio dos Capuchos Lisbon Portugal 1169-050
31 CHUPorto, EPE - Hospital de Santo António Porto Portugal 4099-001
32 Hospital Universitario Vall d'Hebron Barcelona Spain
33 Hospital Universitario Ramon y Cajal Madrid Spain 28034
34 Hospital Virgen del Valle - Instituto de Estudios de Mastocitosis de Castilla-La Mancha Toledo Spain 45071
35 University Hospital Basel Basel Switzerland C-4031
36 Luzerner Kantonsspital Luzern Switzerland 6000

Sponsors and Collaborators

  • Blueprint Medicines Corporation

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Blueprint Medicines Corporation
ClinicalTrials.gov Identifier:
NCT04910685
Other Study ID Numbers:
  • BLU-263-1201
First Posted:
Jun 2, 2021
Last Update Posted:
Aug 19, 2022
Last Verified:
Aug 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Mastocytosis
Mastocytosis, Systemic

Study Results

No Results Posted as of Aug 19, 2022