NCT03580655已完成2 期
An Open-label, Single Arm, Phase 2 Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 107
- 试验地点
- 63
- 主要终点
- Objective response rate (ORR) based on modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria
研究概览
简要总结
This is an open-label, single arm, Phase 2 study evaluating the efficacy and safety of avapritinib (BLU-285) in patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL)
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
- •Patient must have a diagnosis of aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) or mast cell leukemia (MCL) based on World Health Organization diagnostic criteria. Before enrollment, the Study Steering Committee must confirm the diagnosis of AdvSM (based on Central Pathology Laboratory assessment of bone marrow).
- •Patient must have a serum tryptase ≥ 20 ng/mL.
- •Patient must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to
排除标准
- •Patient has received prior treatment with avapritinib.
- •Patient has received any cytoreductive therapy (including midostaurin and other TKIs, hydroxyurea, azacitidine) or an investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon and any antibody therapy (eg, brentuximab vedotin) less than 28 days before obtaining screening BM biopsy for this study.
- •Patient has eosinophilia and known positivity for the FIP1L1 PGDFRA fusion, unless the patient has demonstrated relapse or PD on prior imatinib therapy. Patients with eosinophilia (> 1.5 × 10^9/L), who do not have a detectable KIT D816 mutation, must be tested for a PDGFRA fusion mutation by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).
- •Patient has history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug. The following are exempt from the 3-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
- •Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.
- •Patient has a known risk or recent history (12 months before the first dose of study drug) of intracranial bleeding (eg, brain aneurysm, concomitant vitamin K antagonist use).
- •Platelet count < 50,000/μL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s).
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x the upper limit of normal (ULN); no restriction if due to suspected liver infiltration by mast cells.
- •Bilirubin >1.5 × ULN; no restriction if due to suspected liver infiltration by mast cells or Gilbert's disease. (In the case of Gilbert's disease, a direct bilirubin >2 × ULN would be an exclusion.)
- •Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 or creatinine > 1.5 × ULN.
- •Patient has a primary brain malignancy or metastases to the brain.
- •Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication.
研究组 & 干预措施
Avapritinib
Experimental
Avapritinib will be administered as an immediate release tablet, orally, continuously, in 28-day cycles
干预措施: Avapritinib (Drug)
结局指标
主要结局
Objective response rate (ORR) based on modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria
时间窗: 10 Months
Overall Response Rate (ORR) Based on Modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (mIWG-MRT-ECNM) Response Criteria
时间窗: Baseline through Month 65
ORR was defined as the percentage of participants with a confirmed best response of complete remission (CR), complete remission with partial recovery of peripheral blood counts (CRh), partial remission (PR), or clinical improvement (CI) by mIWG-MRT-ECNM criteria. The mIWG-MRT-ECNM criteria were based on findings from bone marrow biopsy and aspirate, and peripheral blood smear; bone marrow cytogenetics; other extracutaneous tissue biopsies (when available); liver and spleen imaging; and other clinical and laboratory parameters.
次要结局
- Mean Change from Baseline in Advanced Systemic Mastocytosis-Symptom Assessment Form (AdvSM-SAF) Total Symptom Score(10 Months)
- Time-to-response (TTR)(10 Months)
- Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden(10 Months)
- Change in spleen volume by imaging(10 Months)
- Duration of Response (DOR)(10 Months)
- Changes in bone marrow mast cells(10 Months)
- Change in serum tryptase(10 Months)
- Safety of Avapritinib as assessed by incidence of adverse events(10 Months)
- Clinical benefit based on modified IWG-MRT-ECNM consensus criteria(10 Months)
- Progression-free Survival (PFS)(10 Months)
- Change in EORTC QLQ-C30(10 Months)
- Objective response rate(Approximately 4 years after the first subjected enrolled)
- Overall Survival (OS)(10 Months)
- Change in liver volume by imaging(10 Months)
- Change in PGIS(10 Months)
- Area Under Curve (0 to Tau) for Avapritinib(4 Months)
- Mean Change From Baseline in Advanced Systemic Mastocytosis-Symptom Assessment Form (AdvSM-SAF) Total Symptom Score (TTS)(Baseline up to Month 6 (Cycle 6, Day 1))
- ORR Based on mIWG-MRT-ECNM Response Criteria as Assessed by Local Investigator(Baseline through Month 19)
- Time-to-Response (TTR)(Baseline through Month 65)
- Duration of Response (DOR)(Baseline through Month 65)
- Progression-free Survival (PFS)(Baseline through Month 65)
- Overall Survival (OS)(Baseline through Month 65)
- Objective Response Rate(Baseline through Month 65)
- Clinical Benefit Rate(Baseline through Month 65)
- Percent Change From Baseline in Bone Marrow Mast Cells(Baseline up to Month 65)
- Percent Change From Baseline in Serum Tryptase(Baseline up to Month 65)
- Percent Change From Baseline in V-kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog Aspartate 816 Valine (KIT D816V) Mutation Burden(Baseline up to Month 65)
- Percent Change From Baseline in Liver Volume by Imaging(Baseline up to Month 65)
- Percent Change From Baseline in Spleen Volume by Imaging(Baseline up to Month 65)
- Mean Change From Baseline in AdvSM-SAF Skin and Gastrointestinal Domain Scores at Month 10(Baseline, Month 10)
- Mean Change From Baseline in AdvSM-SAF Individual Symptom Scores (Severity) at Month 10(Baseline, Month 10)
- Mean Change From Baseline in AdvSM-SAF Individual Symptom Scores (Episodes) at Month 10(Baseline, Month 10)
- Change From Baseline in Patient's Global Impression of Symptom Severity (PGIS)(Baseline, Cycle 1, Day 15 and Day 1 of Cycle 2, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11, Cycle 14, and Cycle 17 (28 days/cycle))
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)(Baseline, Cycle 1, Day 15 and Day 1 of Cycle 2, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11, Cycle 14, and Cycle 17 (28 days/cycle))
- Number of Participants Experiencing Treatment-emergent Adverse Events (TEAE)(Baseline through Month 65)
- Maximum Plasma Concentration (Cmax) of a Single Dose of Avapritinib(Day 1 of Cycle 1 (1 hour postdose) (28 days/cycle))
- Correlation Between TSS and Serum Tryptase(Baseline, Month 10)
研究者
研究点 (63)
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