NCT02561988已完成1 期
A Phase 1 Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 86
- 试验地点
- 11
- 主要终点
- Number of patients with adverse and serious adverse events and changes in physical findings, vital signs, clinical laboratory results and ECG findings
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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.
- •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.
排除标准
- •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
研究组 & 干预措施
Avapritinib (also known as BLU-285)
Experimental
Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.
干预措施: Avapritinib (Drug)
结局指标
主要结局
Number of patients with adverse and serious adverse events and changes in physical findings, vital signs, clinical laboratory results and ECG findings
时间窗: Approximately 24 months
Recommended Phase 2 dose (RP2D) of avapritinib
时间窗: Approximately 24 months
Maximum tolerated dose (MTD) of avapritinib (also known as BLU-285)
时间窗: During cycle 1 (28 days) of treatment
次要结局
- Time to maximum plasma concentration of avapritinib(Every cycle (28 days) up to cycle 4)
- Morphologic response(≥ 12 weeks)
- 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)
- 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)
- Maximum plasma concentration of avapritinib(Every cycle (28 days) up to cycle 4)
- Change in liver volume by imaging(Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days))
- Overall Response Rate(8, 24, 40, 68 and every 24 weeks until patient terminates from the study (approximately 24 months))
- 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 outcomes using the advanced SM symptom assessment form (AdvSM-SAF)(Part 2 only - daily from Day -7 through Cycle 12)
- Change in spleen volume by imaging(Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days))
研究者
研究点 (11)
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