Clinical Trials /

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

NCT02561988

Description:

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).

Related Conditions:
  • Aggressive Systemic Mastocytosis
  • Hematologic and Lymphocytic Disorder
  • Hematopoietic and Lymphoid System Neoplasm
  • Mast Cell Leukemia
  • Myelodysplastic Syndromes
  • Myeloid Neoplasm
  • Systemic Mastocytosis with an Associated Hematological Neoplasm (SM-AHN)
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
  • Official Title: A Phase 1 Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: BLU-285-2101
  • SECONDARY ID: 2015-001661-12
  • NCT ID: NCT02561988

Conditions

  • Aggressive Systemic Mastocytosis
  • Systemic Mastocytosis-associated Hematologic Non-mast Cell Disease
  • Mast Cell Leukemia
  • Relapsed or Refractory Myeloid Malignancies

Interventions

DrugSynonymsArms
AvapritinibAvapritinib (also known as BLU-285)

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Avapritinib (also known as BLU-285)ExperimentalAvapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.
  • Avapritinib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of avapritinib (also known as BLU-285)
Time Frame:During cycle 1 (28 days) of treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Maximum plasma concentration of avapritinib
Time Frame:Every cycle (28 days) up to cycle 4
Safety Issue:
Description: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
Measure:Time to maximum plasma concentration of avapritinib
Time Frame:Every cycle (28 days) up to cycle 4
Safety Issue:
Description: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
Measure:Overall Response Rate
Time Frame:8, 24, 40, 68 and every 24 weeks until patient terminates from the study (approximately 24 months)
Safety Issue:
Description: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)
Measure: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)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:Defined as change from Baseline
Measure: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
Safety Issue:
Description:Defined as change from Baseline
Measure: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
Safety Issue:
Description:Defined as change from Baseline
Measure:Change in liver volume by imaging
Time Frame:Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days)
Safety Issue:
Description:mL
Measure:Change in spleen volume by imaging
Time Frame:Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days)
Safety Issue:
Description:mL

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Blueprint Medicines Corporation

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