A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients with EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 224
- 试验地点
- 16
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. YH25448 is expected to beneficial for the NSCLC patients with brain metastasis due to good blood brain barrier (BBB) penetration property as well as for the treatment of primary lung lesion and extracranial lesions. This study will be conducted to evaluate the safety, tolerability and efficacy of YH25448 in locally advanced or metastatic NSCLC patients with EGFR mutations.
详细描述
This is a first time in patient study primarily designed to evaluate the safety, tolerability, and efficacy of YH25448 in in patients with EGFR mutation positive (EGFRm+) advanced NSCLC with or without asymptomatic brain metastasis who progressed following prior therapy with an EGFR TKIs agent. This study is composed of 3 parts; part A is a dose escalation phase, part B is a dose expansion phase and part C is a dose extension phase.
In dose escalation phase, YH25448 will be escalated to reach either a maximum tolerated or absorbable dose in patients as defined by dose-limiting toxicity in NSCLC patients who progressed following prior EGFR TKIs treatment to evaluate the safety and tolerability. In dose expansion phase, further safety, tolerability, pharmacokinetic(PK) and efficacy will be evaluated at each dose level(s) of dose escalation phase in NSCLC patients who progressed following prior EGFR TKIs treatment and harbouring confirmed T790M mutation. In dose extension phase, additional 2 cohorts (2nd line therapy cohort, 1st line therapy cohort) will be enrolled to further assess the efficacy, safety, tolerability, and PK of YH25448 at the maximum tolerated dose (MTD) or recommended dose (RD) defined through dose escalation phase and dose expansion phase. Results of these studies will serve as the evidence for further clinical development.
This study will also characterize the metabolite(s) profile of YH25448 and determine PK of its metabolite(s) in biological samples if necessary. Also, exploratory correlation between biomarker profiles and pharmacokinetics/pharmacodynamics will be analyzed.
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
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 3 months.
- •At least one measurable extracranial lesion, not previously irradiated and not chosen biopsy during the study screening period.
- •Prior to enrolling in the study, patients must have central confirmation of T790M+ mutation status from a sample taken after documented progression on the EGFR-TKIs therapy according to cohort.
排除标准
- •Spinal cord compression.
- •Brain metastases with symptomatic and/or requiring steroid for at least 2 weeks prior to start of study treatment.
- •Known intracranial hemorrhage which is unrelated to tumor.
- •Central Nervous System (CNS) complications that require urgent neurosurgical intervention (e.g. resection or shunt placement).
- •Leptomeningeal metastasis prior to study treatment.
- •Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
- •Any cardiovascular disease as followed.
- •History of symptomatic congestive heart failure (CHF) or serious cardiac arrhythmia requiring treatment
- •History of myocardial infarction or unstable angina within 6 months of the first dose of study treatment
- •Left ventricular ejection fraction (LVEF) < 50%
研究组 & 干预措施
YH25448
- Dose Escalation Phase: Consists of 7 Cohorts
- Dose Expansion Phase: Consists of 5 Cohorts
- Dose Extension Phase: Consists of 2 Cohorts
干预措施: YH25448 (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
Per Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of Complete Response (CR) or Partial Response (PR) (according to independent review), prior to progression or further anti-cancer therapy.
Safety and tolerability by Common Terminology Criteria for Adverse Events (CTCAE) v4.03
时间窗: Safety and tolerability profile will be collected from baseline until 28 days after the last dose, expected average 1 year.
To assess the safety and tolerability profile of YH25448 by Common Terminology Criteria for Adverse Events (CTCAE) v4.03; vital signs (blood pressure, pulse, weight); laboratory parameters (clinical chemistry, hematology, urinalysis); physical examination; centrally reviewed electrocardiograms (ECGs), echocardiogram or multiple gated acquisition scan and performance status.
次要结局
- Overall Survival (OS)(At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.)
- Progression-Free Survival (PFS)(At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.)
- Tumor shrinkage(At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.)
- Objective Intracranial Response Rate (OIRR)(At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.)
- Disease Control Rate (DCR)(At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.)
- Intracranial Progression Free Survival (IPFS).(At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.)
- Duration of Response (DoR)(At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.)
- Duration of Intracranial Response (DoIR)(At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.)