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

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ClinicalTrials.gov Identifier: NCT04910685
Recruitment Status : Recruiting
First Posted : June 2, 2021
Last Update Posted : July 28, 2022
Sponsor:
Information provided by (Responsible Party):
Blueprint Medicines Corporation

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
Indolent Systemic Mastocytosis Monoclonal Mast Cell Activation Syndrome Drug: BLU-263 Drug: Placebo Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated 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 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 : November 30, 2021
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : June 2028


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




Primary Outcome Measures :
  1. Part 1: Recommended Dose (RD) in patients with ISM [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: up to 5 years ]
  4. Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) [ Time Frame: 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 [ Time Frame: 3 Months ]
  2. Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 6 months ]
  7. Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) [ Time Frame: 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 [ Time Frame: 6 months ]
  9. Part 2: Mean change in measures of mast cell burden [ Time Frame: 6 months ]
  10. Part 2: Change in number of best supportive care medications [ Time Frame: 6 Months ]
  11. Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: up to 5 years ]
  16. Part 3: Mean change in measures of mast cell burden [ Time Frame: approximately 5 years ]
  17. Part 3: Change in number of best supportive care medications [ Time Frame: approximately 5 years ]
  18. Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom score [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 6 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04910685


Contacts
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Contact: Blueprint Medicines 617-714-6707 medinfo@blueprintmedicines.com

Locations
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Sponsors and Collaborators
Blueprint Medicines Corporation
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Responsible Party: Blueprint Medicines Corporation
ClinicalTrials.gov Identifier: NCT04910685    
Other Study ID Numbers: BLU-263-1201
First Posted: June 2, 2021    Key Record Dates
Last Update Posted: July 28, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Mastocytosis
Mastocytosis, Systemic
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Skin Diseases
Immune Complex Diseases
Hypersensitivity
Immune System Diseases