An Open-label, Phase 1 Dose Escalation Study of Oral ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 133
- 试验地点
- 12
- 主要终点
- Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The purpose of this study is to assess the safety and tolerability of ASP8273 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). This study will also determine the pharmacokinetics (PK) of ASP8273, evaluate the potential inhibition of CYP3A4 by ASP8273 and the antitumor activity of ASP8273 as well as determine the effect of food on the bioavailability of ASP8273.
详细描述
This study is composed of 2 parts: part 1 is the dose escalation phase and part 2 is the recommended Phase 2 dose (RP2D) phase, Food Effect (FE) cohort and Exon 20 cohort.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Non-child bearing potential or able to follow birth control requirements
- •Eastern Cooperative Oncology Group (ECOG) ≤ 1
- •Life expectancy ≥ 12 weeks
- •Laboratory criteria as:
- •Neutrophil count ≥ 1,500/mm3
- •Platelet count ≥ 7.5 x 104 /mm3
- •Hemoglobin ≥ 9.0 g/dL
- •Lymphocyte count ≥ 500/mm3
- •Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation
- •Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN
- •Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI)
- •Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Inclusion Criteria for Exon 20 cohort:
- •Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. Local testing may determine eligibility and a tumor sample should also be sent for central testing.
- •Subjects must have at least 1 measurable lesion based on RECIST version 1.1.
排除标准
- •Any ongoing toxicity ≥ Grade 2 attributable to prior Non-Small-Cell Lung Cancer (NSCLC) treatment
- •Prior EGFR inhibitor within 6 days; received prior treatment with any other agent with antitumor activity chemotherapy, radiotherapy, or immunotherapy within 14 days; any investigational therapy within 28 days or 5 half-lives, whichever is shorter; blood transfusion or hemopoietic factor within 14 days; major surgery within 14 days; any strong CYP3A4 inhibitors within 7 days
- •Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) or Human Immunodeficiency Virus (HIV)
- •Symptomatic Central Nervous System (CNS) metastasis
- •Active infection requiring systemic therapy within 14 days
- •Severe or uncontrolled systemic diseases including uncontrolled hypertension
- •History of or active interstitial lung disease
- •Screening QTcF >450 msec or current medication known to prolong QT
- •≥ Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months
- •History of gastrointestinal ulcer or bleeding within 3 months; any digestive tract dysfunction
- •Concurrent corneal disorder or ophthalmologic condition making subject unsuitable
- •RP2D cohort subjects: contraindications to midazolam, any other midazolam within 7 days, or any medications or supplements known to be strong CYP3A inhibitors within 7 days or inducers within 12 days
- •Any other malignancy requiring treatment
研究组 & 干预措施
ASP8273 Dose Escalation cohort (part 1)
oral
干预措施: naquotinib (Drug)
ASP8273 Response Expansion cohort (part 1)
oral
干预措施: naquotinib (Drug)
ASP8273 and Midazolam RP2D Expansion cohort (part 2)
oral
干预措施: naquotinib (Drug)
ASP8273 and Midazolam RP2D Expansion cohort (part 2)
oral
干预措施: midazolam (Drug)
Food Effect Fasted cohort (part 2)
oral
干预措施: naquotinib (Drug)
Food Effect Fed cohort (part 2)
oral
干预措施: naquotinib (Drug)
Exon 20 Cohort (part 2)
oral
干预措施: naquotinib (Drug)
结局指标
主要结局
Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)
时间窗: up to 18 months
A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using NCI CTCAE v4.03.
Safety and tolerability as assessed by adverse events (AEs)
时间窗: up to 18 months
An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Safety and tolerability as assessed by laboratory tests
时间窗: up to 18 months
Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.
Safety and tolerability as assessed by vital signs
时间窗: up to 18 months
Vital signs to be measured includes blood pressure, pulse rate and temperature.
Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)
时间窗: up to 18 months
次要结局
- Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F(Cycle 0: Dose Escalation Days 1-2, FE Days 1-6; Cycle 1: Dose Escalation/Response Expansion/RP2D/FE Days 1,8,15, RP2D Day 21, Exon 20 Days 8,15; Cycle 2 & 3: Dose Escalation/Response Expansion/RP2D Days 1,2, FE Day 1; Exon 20 days 1, 2 & Cycle 3)
- Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F(Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2)
- Best overall response rate(Up to 18 months)
- Disease control rate(Up to 18 months)
- Progression free survival(Up to 18 months)