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(PATHFINDER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis

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ClinicalTrials.gov Identifier: NCT03580655
Recruitment Status : Recruiting
First Posted : July 9, 2018
Last Update Posted : September 18, 2019
Sponsor:
Information provided by (Responsible Party):
Blueprint Medicines Corporation

Brief Summary:
This is an open-label, single arm, Phase 2 study evaluating the efficacy and safety of avapritinib (BLU-285) in patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL)

Condition or disease Intervention/treatment Phase
Advanced Systemic Mastocytosis Aggressive Systemic Mastocytosis Systemic Mastocytosis With an Associated Hematologic Neoplasm Mast Cell Leukemia Drug: Avapritinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 103 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Single Arm, Phase 2 Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis
Actual Study Start Date : November 21, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : November 2023


Arm Intervention/treatment
Experimental: Avapritinib
Avapritinib will be administered as an immediate release tablet, orally, continuously, in 28-day cycles
Drug: Avapritinib
Avapritinib tablet
Other Name: BLU-285




Primary Outcome Measures :
  1. Objective response rate (ORR) based on modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria [ Time Frame: 10 Months ]

Secondary Outcome Measures :
  1. Mean Change from Baseline in Advanced Systemic Mastocytosis-Symptom Assessment Form (AdvSM-SAF) Total Symptom Score [ Time Frame: 10 Months ]
    0 - 80 points (higher value represents worse symptom outcomes)

  2. Time-to-response (TTR) [ Time Frame: 10 Months ]
    Months

  3. Duration of Response (DOR) [ Time Frame: 10 Months ]
    Months

  4. Progression-free Survival (PFS) [ Time Frame: 10 Months ]
    Months

  5. Overall Survival (OS) [ Time Frame: 10 Months ]
    Months

  6. Changes in bone marrow mast cells [ Time Frame: 10 Months ]
    percentage

  7. Change in serum tryptase [ Time Frame: 10 Months ]
    ng/mL

  8. Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden [ Time Frame: 10 Months ]
    percentage

  9. Change in liver volume by imaging [ Time Frame: 10 Months ]
    mL

  10. Change in spleen volume by imaging [ Time Frame: 10 Months ]
    mL

  11. Clinical benefit based on modified IWG-MRT-ECNM consensus criteria [ Time Frame: 10 Months ]
  12. Change in PGIS [ Time Frame: 10 Months ]
    0 - 10 points (higher value represents worse symptom outcomes)

  13. Change in EORTC QLQ-C30 [ Time Frame: 10 Months ]
    0 - 100 points (lower value represents worse quality of life)

  14. Safety of Avapritinib as assessed by incidence of adverse events [ Time Frame: 10 Months ]
    CTCAE version 4.0

  15. Area Under Curve (0 to Tau) for Avapritinib [ Time Frame: 4 Months ]
    h•ng/mL



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Patient must have a diagnosis of aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) or mast cell leukemia (MCL) based on World Health Organization diagnostic criteria. Before enrollment, the Study Steering Committee must confirm the diagnosis of AdvSM (based on Central Pathology Laboratory assessment of bone marrow).
  2. Patient must have a serum tryptase ≥ 20 ng/mL.
  3. Patient must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 3.

Key Exclusion Criteria:

  1. Patient has received prior treatment with avapritinib.
  2. Patient has received any cytoreductive therapy (including midostaurin and other TKIs, hydroxyurea, azacitidine) or an investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon and any antibody therapy (eg, brentuximab vedotin) less than 28 days before obtaining screening BM biopsy for this study.
  3. Patient has eosinophilia and known positivity for the FIP1L1 PGDFRA fusion, unless the patient has demonstrated relapse or PD on prior imatinib therapy. Patients with eosinophilia (> 1.5 × 10^9/L), who do not have a detectable KIT D816 mutation, must be tested for a PDGFRA fusion mutation by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).
  4. Patient has history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug. The following are exempt from the 3-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
  5. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.
  6. Patient has a known risk or recent history (within the preceding 1 year) of intracranial bleeding (eg, brain aneurysm). Platelet count < 25,000/μL at baseline; platelet transfusions may be given to maintain platelet count over 25,000/μL.
  7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x the upper limit of normal (ULN); no restriction if due to suspected liver infiltration by mast cells.
  8. Bilirubin >1.5 × ULN; no restriction if due to suspected liver infiltration by mast cells or Gilbert's disease. (In the case of Gilbert's disease, a direct bilirubin >2 × ULN would be an exclusion.)
  9. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 or creatinine > 1.5 × ULN.
  10. Patient has a primary brain malignancy or metastases to the brain.
  11. Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication.

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): NCT03580655


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

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Sponsors and Collaborators
Blueprint Medicines Corporation

Additional Information:
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Responsible Party: Blueprint Medicines Corporation
ClinicalTrials.gov Identifier: NCT03580655     History of Changes
Other Study ID Numbers: BLU-285-2202
2017-004836-13 ( EudraCT Number )
First Posted: July 9, 2018    Key Record Dates
Last Update Posted: September 18, 2019
Last Verified: September 2019

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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
Hematologic Neoplasms
Leukemia, Mast-Cell
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Skin Diseases
Immune Complex Diseases
Hypersensitivity
Immune System Diseases
Neoplasms by Site
Hematologic Diseases
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid