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(EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies

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ClinicalTrials.gov Identifier: NCT02561988
Recruitment Status : Recruiting
First Posted : September 29, 2015
Last Update Posted : November 11, 2019
Sponsor:
Information provided by (Responsible Party):
Blueprint Medicines Corporation

Tracking Information
First Submitted Date  ICMJE September 15, 2015
First Posted Date  ICMJE September 29, 2015
Last Update Posted Date November 11, 2019
Actual Study Start Date  ICMJE March 10, 2016
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 22, 2018)
  • Maximum tolerated dose (MTD) of avapritinib (also known as BLU-285) [ Time Frame: During cycle 1 (28 days) of treatment ]
  • Number of patients with adverse and serious adverse events and changes in physical findings, vital signs, clinical laboratory results and ECG findings [ Time Frame: Approximately 24 months ]
  • Recommended Phase 2 dose (RP2D) of avapritinib [ Time Frame: Approximately 24 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 25, 2015)
  • Maximum tolerated dose (MTD) of BLU-285 [ Time Frame: During cycle 1 (28 days) of treatment ]
  • Number of patients with adverse and serious adverse events and changes in physical findings, vital signs, clinical laboratory results and ECG findings [ Time Frame: Approximately 24 months ]
  • Recommended Phase 2 dose (RP2D) of BLU-285 [ Time Frame: Approximately 24 months ]
Change History Complete list of historical versions of study NCT02561988 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2019)
  • Maximum plasma concentration of avapritinib [ Time Frame: Every cycle (28 days) up to cycle 4 ]
    Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 8 and 24 hrs post dose (plus 10 and 48 hrs post dose in Part 2) on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1
  • Time to maximum plasma concentration of avapritinib [ Time Frame: Every cycle (28 days) up to cycle 4 ]
    Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 8 and 24 hrs post dose (plus 10 and 48 hrs post dose in Part 2) on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1
  • Overall Response Rate [ Time Frame: 8, 24, 40, 68 and every 24 weeks until patient terminates from the study (approximately 24 months) ]
    Including complete remission (CR), CR with partial recovery of peripheral blood (CRh), partial remission (PR) and clinical improvement (CI) using modified International Working Group Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European competence network on mastocytosis (ECNM) criteria; and duration of response (DOR)
  • Changes in levels of serum tryptase and levels of V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) D816V allele burden in blood [ Time Frame: Cycle (C)1Day (D)1, C1D15, C2D1, C3D1, C5D1, C7D1, C11D1, C18D1 every 6 cycles thereafter and at disease progression. (approximately 24 months) ]
  • Changes in patient reported symptoms and quality of life using the Patient Global Impression of Symptom Severity (PGIS) scale [ Time Frame: Part 2 only - Day 1 of Cycles 1-12 ]
    Defined as change from Baseline
  • Changes in patient reported quality of life using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C-30) [ Time Frame: Part 2 only - Day 1 of Cycles 1-12 ]
    Defined as change from Baseline
  • Changes in patient reported outcomes using the advanced SM symptom assessment form (AdvSM-SAF) [ Time Frame: Part 2 only - daily from Day -7 through Cycle 12 ]
    Defined as change from Baseline
  • Change in liver volume by imaging [ Time Frame: Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days) ]
    mL
  • Change in spleen volume by imaging [ Time Frame: Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days) ]
    mL
Original Secondary Outcome Measures  ICMJE
 (submitted: September 25, 2015)
  • Maximum plasma concentration of BLU-285 [ Time Frame: Every cycle (28 days) up to cycle 4 ]
    Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 8 and 24 hrs post dose on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1
  • Time to maximum plasma concentration of BLU-285 [ Time Frame: Every cycle (28 days) up to cycle 4 ]
    Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 8 and 24 hrs post dose on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1
  • Overall Response Rate [ Time Frame: 8, 24, 40, 68 and every 24 weeks until patient terminates from the study (approximately 24 months) ]
    Defined as either complete remission (CR) or partial remission (PR); Clinical improvement rate, Duration of response; and Progression Free Survival will be measured as per International Working Group Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European competence network on mastocytosis (ECNM) consensus response criteria
  • Changes in levels of serum tryptase and levels of V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) D816V allele burden in blood [ Time Frame: Cycle (C)1Day (D)1, C1D15, C2D1, C3D1, C5D1, C7D1, C11D1, C18D1 every 6 cycles thereafter and at disease progression. (approximately 24 months) ]
  • Changes in patient reported symptoms and quality of life using the Patient Global Impression of Change (PGIC) scale [ Time Frame: Part 2 only - Day 1 of Cycles 2-12 ]
    Defined as change from Day 1 of Cycle 2 on a 7 point scale
  • Changes in patient reported quality of life using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C-30) [ Time Frame: Part 2 only - Day 1 of Cycles 1-12 ]
    Defined as change from baseline on a scale of 0-100
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE (EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
Official Title  ICMJE A Phase 1 Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
Brief Summary This is a Phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antineoplastic activity of avapritinib (also known as BLU-285), administered orally (PO), in adult patients with advanced systemic mastocytosis and other relapsed or refractory myeloid malignancies. The study consists of 2 parts, a dose-escalation part (Part 1) and an expansion part (Part 2).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Aggressive Systemic Mastocytosis
  • Systemic Mastocytosis-associated Hematologic Non-mast Cell Disease
  • Mast Cell Leukemia
  • Relapsed or Refractory Myeloid Malignancies
Intervention  ICMJE Drug: Avapritinib
Study Arms  ICMJE Experimental: Avapritinib (also known as BLU-285)
Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 10, 2019)
80
Original Estimated Enrollment  ICMJE
 (submitted: September 25, 2015)
60
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

For Part 1:Patients must have one of the following diagnoses based on World Heath Organization (WHO) diagnostic criteria:

  • Aggressive systemic mastocytosis (ASM).
  • Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) and at least 1 C-finding attributable to systemic mastocytosis (SM). The AHN must be myeloid, with the following exceptions that are excluded: Acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS) that is very high- or high-risk as defined by the International prognostic scoring system for myelodysplastic syndromes (IPSS-R) and Philadelphia chromosome positive malignancies.
  • Mast cell leukemia (MCL).
  • Histologically- or cytologically- confirmed myeloid malignancy that is relapsed or refractory to standard treatments. AML, MDS that is very high- or high-risk as defined by the IPSS-R, and Philadelphia chromosome positive malignancies are excluded.
  • Upon discussion with the sponsor, other relapsed or refractory, potentially avapritinib-responsive hematologic neoplasms (e.g., evidence of aberrant KIT or platelet derived growth factor receptor (PDGFR) signaling) may be considered for enrollment.

For Part 2, patients must have one of the following diagnoses, based on WHO diagnostic criteria:

  • ASM.
  • SM-AHN. The AHN must be myeloid, with the following exceptions that are excluded: AML, MDS that is very high- or high-risk as defined by the IPSS-R, and Philadelphia chromosome positive malignancies.
  • MCL.

For Part 2, Cohort 2, patients must have at least 1 measurable C-finding per modified IWG-MRT-ECNM criteria at Baseline, attributed to SM unless diagnosis is MCL, which does not require a C-finding.

  • Cytopenias: ANC < 1.0 × 10⁹/L or hemoglobin < 10 g/dL or platelet count < 75 × 10⁹/L.
  • Symptomatic ascites or pleural effusion requiring medical intervention such as: use of diuretics (Grade 2) or ≥ 2 therapeutic paracenteses or thoracenteses (Grade 3) at least 28 days apart over the 12 weeks before study entry and 1 of the procedures is performed during the 6 weeks before study start (C1D1).
  • ≥ Grade 2 abnormalities in direct bilirubin (> 1.5 × upper limit of normal [ULN]), aspartate aminotransferase (AST; > 3.0 × ULN), alanine aminotransferase (ALT; > 3.0 × ULN), or alkaline phosphatase (> 2.5 × ULN) with 1 of the following present: ascites or clinically relevant portal hypertension or liver mast cell infiltration that is biopsy-proven or no other identified cause of abnormal liver function.
  • ≥ Grade 2 hypoalbuminemia (< 3.0 g/dL).
  • A spleen that is palpable ≥ 5 cm below the left costal margin.
  • Transfusion-dependent anemia defined as: transfusion of ≥ 6 units packed red blood cells (PRBCs) in the 12 weeks before start of treatment (C1D1) and most recent transfusion occurring during the preceding 4 weeks and transfusion administered for hemoglobin ≤ 8.5 g/dL and reason for transfusion is not bleeding, hemolysis, or therapy-related.

Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

Exclusion Criteria:

  • QT interval corrected using Fridericia's formula (QTcF) >480 milliseconds
  • Platelet count <50,000/μL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s)
  • Absolute neutrophil count <500/μL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >3 x the upper limit of normal (ULN); >5 × ULN if associated with clinically suspected liver infiltration by mastocytosis or another disease for which the patient enrolled into the study
  • Total bilirubin >1.5 × ULN; >3 × ULN if associated with liver infiltration by the disease being treated or in the presence of Gilbert's Disease (In the case of Gilbert's disease, a direct bilirubin > 2.0 ULN would be an exclusion.)
  • Estimated (Cockroft-Gault formula) or measured creatinine clearance <40 mL/min
  • Brain malignancy or metastases to the brain
  • History of a seizure disorder or requirement for anti-seizure medication
  • Known risk of intracranial bleeding, such as a brain aneurysm or history of subdural or subarachnoid bleeding
  • Eosinophilia and known positivity for the FIP1L1-PGDFRA fusion, unless the patient has demonstrated relapse or progressive disease on prior imatinib therapy
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: Blueprint Medicines 617-714-6707 medinfo@blueprintmedicines.com
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02561988
Other Study ID Numbers  ICMJE BLU-285-2101
2015-001661-12 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
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 November 2019

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