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).
Title
- Brief Title: (EXPLORER) 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
Drug | Synonyms | Arms |
---|
Avapritinib | | Avapritinib (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
Name | Type | Description | Interventions |
---|
Avapritinib (also known as BLU-285) | Experimental | Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles. | |
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. 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
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 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 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: | Morphologic response |
Time Frame: | ≥ 12 weeks |
Safety Issue: | |
Description: | Including morphologic complete remission (mCR), morphologic CR with partial recovery of peripheral blood (mCRh), and morphologic partial remission (mPR) based on Pure Pathologic Response |
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: | Active, not recruiting |
Lead Sponsor: | Blueprint Medicines Corporation |
Last Updated
August 2, 2021