Aggressive Systemic Mastocytosis, Mast Cell Leukemia, Relapsed or Refractory Myeloid Malignancies, Systemic Mastocytosis-associated Hematologic Non-mast Cell Disease
Conditions
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:, dose-escalation (Part 1) and expansion (Part 2).
Interventions
DRUGAvapritinib
Sponsors
Blueprint Medicines Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum tolerated dose (MTD) of avapritinib (also known as BLU-285) | 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 | Approximately 24 months |
| Recommended Phase 2 dose (RP2D) of avapritinib | Approximately 24 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Morphologic response | ≥ 12 weeks | Including morphologic complete remission (mCR), morphologic CR with partial recovery of peripheral blood (mCRh), and morphologic partial remission (mPR) based on Pure Pathologic Response |
| 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 | 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 | Part 2 only - Day 1 of Cycles 1-12 | Defined as change from Baseline |
| Maximum plasma concentration of avapritinib | 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 |
| Changes in patient reported outcomes using the advanced SM symptom assessment form (AdvSM-SAF) | Part 2 only - daily from Day -7 through Cycle 12 | Defined as change from Baseline |
| Change in liver volume by imaging | Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days) | mL |
| Change in spleen volume by imaging | Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days) | mL |
| 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) | Part 2 only - Day 1 of Cycles 1-12 | Defined as change from Baseline |
| Time to maximum plasma concentration of avapritinib | 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 | 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) |
Countries
United Kingdom, United States
Outcome results
None listed