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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 : August 1, 2018
Sponsor:
Information provided by (Responsible Party):
Blueprint Medicines Corporation

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).

Condition or disease Intervention/treatment Phase
Aggressive Systemic Mastocytosis Systemic Mastocytosis-associated Hematologic Non-mast Cell Disease Mast Cell Leukemia Relapsed or Refractory Myeloid Malignancies Drug: Avapritinib Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 85 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
Study Start Date : December 2015
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: Avapritinib (also known as BLU-285)
Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.
Drug: Avapritinib



Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of avapritinib (also known as BLU-285) [ Time Frame: During cycle 1 (28 days) of treatment ]
  2. 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 ]
  3. Recommended Phase 2 dose (RP2D) of avapritinib [ Time Frame: Approximately 24 months ]

Secondary Outcome Measures :
  1. 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 Cohort 2 of Part 2) on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1

  2. 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 Cohort 2 of Part 2) on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1

  3. 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)

  4. 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) ]
  5. 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

  6. 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

  7. 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

  8. 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

  9. 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



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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

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 that also has at least 1 C-finding attributable to SM. 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.
  • Transfusion-dependent thrombocytopenia, defined as: transfusion of ≥ 6 units of apheresed platelets (or ≥ 6 pools of random donor or buffy coat platelets) during the 12 weeks preceding treatment (C1D1) and ≥ 2 units transfused during the preceding 4 weeks and transfusions administered for platelet count < 20 × 10⁹/L.
  • > 10% weight loss that is medically documented over the preceding 24 weeks (± 12 weeks).

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

Exclusion Criteria:

  • QT interval corrected using Fridericia's formula (QTcF) >470 milliseconds
  • Platelet count <25,000/mL
  • Absolute neutrophil count <500/mL
  • 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
  • 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

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): NCT02561988


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

Locations
United States, California
Stanford Cancer Institute Recruiting
Stanford, California, United States, 94305
United States, Colorado
University of Colorado Cancer Center Recruiting
Denver, Colorado, United States, 80045
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan Health System Recruiting
Ann Arbor, Michigan, United States, 48109
United States, New York
Mount Sinai Hospital Recruiting
New York, New York, United States, 10029
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
United States, Utah
Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
United Kingdom
Beatson West of Scotland Cancer Centre Recruiting
Glasgow, United Kingdom, G12 0XL
Guy's Hospital Recruiting
London, United Kingdom, SE1 9RT
Sponsors and Collaborators
Blueprint Medicines Corporation

Responsible Party: Blueprint Medicines Corporation
ClinicalTrials.gov Identifier: NCT02561988     History of Changes
Other Study ID Numbers: BLU-285-2101
2015-001661-12 ( EudraCT Number )
First Posted: September 29, 2015    Key Record Dates
Last Update Posted: August 1, 2018
Last Verified: July 2018

Additional relevant MeSH terms:
Neoplasms
Mastocytosis
Mastocytosis, Systemic
Leukemia, Mast-Cell
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Skin Diseases
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid