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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 : Active, not recruiting
First Posted : July 9, 2018
Last Update Posted : December 21, 2020
Sponsor:
Information provided by (Responsible Party):
Blueprint Medicines Corporation

Tracking Information
First Submitted Date  ICMJE May 3, 2018
First Posted Date  ICMJE July 9, 2018
Last Update Posted Date December 21, 2020
Actual Study Start Date  ICMJE November 21, 2018
Estimated Primary Completion Date May 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 26, 2018)
Objective response rate (ORR) based on modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis consensus response criteria in patients with AdvSM treated with avapritinib. [ Time Frame: 10 Months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 3, 2020)
  • 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)
  • Objective response rate [ Time Frame: Approximately 4 years after the first subjected enrolled ]
    Including morphologic complete remission (mCR), morphologic CR with partial recovery of peripheral blood (mCRh), and morphologic partial remission (mPR) based on Pure Pathologic Response
  • Time-to-response (TTR) [ Time Frame: 10 Months ]
    Months
  • Duration of Response (DOR) [ Time Frame: 10 Months ]
    Months
  • Progression-free Survival (PFS) [ Time Frame: 10 Months ]
    Months
  • Overall Survival (OS) [ Time Frame: 10 Months ]
    Months
  • Changes in bone marrow mast cells [ Time Frame: 10 Months ]
    percentage
  • Change in serum tryptase [ Time Frame: 10 Months ]
    ng/mL
  • Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden [ Time Frame: 10 Months ]
    percentage
  • Change in liver volume by imaging [ Time Frame: 10 Months ]
    mL
  • Change in spleen volume by imaging [ Time Frame: 10 Months ]
    mL
  • Clinical benefit based on modified IWG-MRT-ECNM consensus criteria [ Time Frame: 10 Months ]
  • Change in PGIS [ Time Frame: 10 Months ]
    0 - 10 points (higher value represents worse symptom outcomes)
  • Change in EORTC QLQ-C30 [ Time Frame: 10 Months ]
    0 - 100 points (lower value represents worse quality of life)
  • Safety of Avapritinib as assessed by incidence of adverse events [ Time Frame: 10 Months ]
    CTCAE version 4.0
  • Area Under Curve (0 to Tau) for Avapritinib [ Time Frame: 4 Months ]
    h•ng/mL
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2018)
  • 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)
  • Time-to-response (TTR) [ Time Frame: 10 Months ]
    Months
  • Duration of Response (DOR) [ Time Frame: 10 Months ]
    Months
  • Progression-free Survival (PFS) [ Time Frame: 10 Months ]
    Months
  • Overall Survival (OS) [ Time Frame: 10 Months ]
    Months
  • Changes in bone marrow mast cells [ Time Frame: 10 Months ]
    percentage
  • Change in serum tryptase [ Time Frame: 10 Months ]
    ng/mL
  • Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden [ Time Frame: 10 Months ]
    percentage
  • Change in liver volume by imaging [ Time Frame: 10 Months ]
    mL
  • Change in spleen volume by imaging [ Time Frame: 10 Months ]
    mL
  • Clinical benefit based on modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria [ Time Frame: 10 Months ]
  • Change in PGIS [ Time Frame: 10 Months ]
    0 - 10 points (higher value represents worse symptom outcomes)
  • Change in EORTC QLQ-C30 [ Time Frame: 10 Months ]
    0 - 100 points (lower value represents worse quality of life)
  • Safety of Avapritinib as assessed by incidence of adverse events [ Time Frame: 10 Months ]
    CTCAE version 4.0
  • Area Under Curve (0 to Tau) for Avapritinib [ Time Frame: 4 Months ]
    h•ng/mL
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE (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
Official Title  ICMJE 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
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)
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Systemic Mastocytosis
  • Aggressive Systemic Mastocytosis
  • Systemic Mastocytosis With an Associated Hematologic Neoplasm
  • Mast Cell Leukemia
Intervention  ICMJE Drug: Avapritinib
Avapritinib tablet
Other Name: BLU-285
Study Arms  ICMJE Experimental: Avapritinib
Avapritinib will be administered as an immediate release tablet, orally, continuously, in 28-day cycles
Intervention: Drug: Avapritinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: July 10, 2019)
103
Original Estimated Enrollment  ICMJE
 (submitted: June 26, 2018)
60
Estimated Study Completion Date  ICMJE May 2022
Estimated Primary Completion Date May 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 (12 months before the first dose of study drug) of intracranial bleeding (eg, brain aneurysm, concomitant vitamin K antagonist use).
  7. Platelet count < 50,000/μL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s).
  8. 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.
  9. 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.)
  10. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 or creatinine > 1.5 × ULN.
  11. Patient has a primary brain malignancy or metastases to the brain.
  12. Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Canada,   Denmark,   France,   Germany,   Italy,   Netherlands,   Norway,   Poland,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03580655
Other Study ID Numbers  ICMJE BLU-285-2202
2017-004836-13 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Blueprint Medicines Corporation
Study Sponsor  ICMJE Blueprint Medicines Corporation
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Blueprint Medicines Corporation
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP