A Phase I, Open-label Trial to Investigate the Safety, Tolerability, and Pharmacokinetics of EMD525797 After Single Dose and Repeated Dosing at Different Dose Levels in Japanese Patients With Advanced or Metastatic Solid Tumors and Progressive Diseases Following Prior Chemotherapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Number of Subjects With Dose-limiting Toxicities (DLTs)
研究概览
简要总结
The primary objectives are to assess the safety and tolerability of single and repeated doses of EMD525797, and characterize Pharmacokinetics (PK). The secondary objectives are to investigate the immunogenicity and Progressive disease (PD), and to assess the anti-tumor activity of EMD525797.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Age greater than or equal to (>=) 20 years
- •Histologically or cytologically proven advanced or metastatic solid tumor
- •Evidence of progressive disease after standard chemotherapy or no standard chemotherapy
- •Confirmation of availability of formalin-fixed paraffin-embedded (FFPE) tumor block(s) or tissue sections
- •Presence of at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 complete tumor assessment to be performed within the 30 days prior to the first EMD525797 administration
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- •Estimated life expectancy of at least 3 months
- •Absolute Neutrophil Count (ANC) >= 1.5 x 10^9 per liter (/Liter)
- •Platelets >= 100 x 10^9/Liter
- •Haemoglobin >= 9.0 gram per deciliter (g/dL) (without transfusions)
- •Total bilirubin less than or equal to (<=) 1.5 x upper limit of normal (ULN)
- •Aspartate transaminase (AST), alanine transaminase (ALT) less than or equal to (<=) 3 x ULN
- •In subjects with hepatic metastasis, total bilirubin <= 3 x ULN, AST and ALT <= 5 x ULN
- •Prothrombin time (PT), prothrombin time/international normalized ratio (PT/INR), and activated partial thromboplastin time (APTT) within normal limits
- •Creatinine clearance >= 50 milliliter per minute (mL/min)
- •Other protocol defined inclusion criteria could also apply
排除标准
- •Previous treatment with anti-integrin therapy
- •Radiotherapy to bone lesions, systemic surgery, orthopedic surgery (all within the 4 week prior to treatment with EMD525797), clinically significant unhealed wound, or unrecovered bone fracture
- •Chronic doses of oral steroids, defined as >= 10 milligram of prednisone equivalents per day
- •Confirmed or clinically suspected brain or leptomeningeal metastases
- •Known hypersensitivity to EMD525797 or its excipients
- •History of allergic reactions to other monoclonal antibody therapy
- •Antibody treatment within the past 8 weeks or chemotherapy within the 4 weeks prior to treatment with EMD525797
- •Uncontrolled diabetes
- •Uncontrolled hypertension defined as systolic blood pressure >= 160 millimeter of mercury (mmHg) and/or diastolic blood pressure >= 100 millimeter of mercury (mmHg) under resting conditions
- •Autoimmune diseases
- •Current history of chronic daily acetylsalicylic acid (ASS) therapy (ASS at doses <=100 mg is permitted)
- •Bleeding disorders;
- •History of thromboembolic events (history of superficial thrombophlebitis is not an exclusion
- •Anticoagulants within the past 10 days prior to the first treatment and during treatment period
- •Severe peripheral vascular disease or ulceration
- •Unstable angina pectoris, or myocardial infarction or other severe heart diseases within the past 6 months before treatment with EMD 525797
- •Clinical significant abnormal ECG at screening
- •Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent
- •Known HIV infection, active or chronic carrier of hepatitis B virus (HBV antigen positive or HBV DNA positive) or hepatitis C virus (HCV antibody positive)
- •Other protocol defined exclusion criteria could also apply
结局指标
主要结局
Number of Subjects With Dose-limiting Toxicities (DLTs)
时间窗: Baseline up to Week 4
DLT was defined as any Grade 3 or 4 haematological or non-haematological toxicity occurring at any dose level until the end of Week 4, and suspected to be reasonably related to the investigational medicinal product by the Investigator and/or Sponsor. Toxicities not considered to be DLTs are as follows- Allergic reactions or anaphylaxis; any Grade 3 or 4 out-of-range laboratory values without any clinical correlate, which were reversible within 7 days, unless the Investigator decided this event is clinically significant. For this reason Grade 3 or 4 out-of-range laboratory values must be re-assessed within 7 days. In case the Investigator provides the subject any treatment(s) due to the out-of-range laboratory values, the event was regarded as a DLT.
Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Multiple Dose
时间窗: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above LLQ.
Total Body Clearance at Steady State (CLss) of EMD 525797
时间窗: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL of drug in serum was calculated as : CL= Dose/ AUC0-inf. Area under the serum concentration-time curve from time zero to infinity (AUC0-inf), calculated as AUC0-t + AUCextra. AUCextra represents an extrapolated value obtained by Clast / λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above LLQ and λz is the elimination rate constant.
Pharmacokinetics of EMD 525797 - Trough Values
时间窗: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
The observed serum concentration immediately before next dosing determined directly from the serum concentration-time profile of each subject (= trough concentration).
Maximum Observed Serum Concentration (Cmax) of EMD 525797:After Multiple Dose
时间窗: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Maximum Observed Serum Concentration (Cmax): After Single Dose
时间窗: Pre-dose, hour 1(end of infusion [EOI]), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Single Dose
时间窗: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above Lower limit of quantification (LLQ).
Total Body Clearance (CL) of EMD 525797: After Single Dose
时间窗: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Total body clearance of drug in serum was calculated: as CL= Dose divided by Area under the serum concentration-time curve from time zero to infinity (AUC0-inf).
Apparent Volume of Distribution (Vz): After Single Dose
时间窗: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by elimination rate constant \[λz\]) following single dose. Area under the serum concentration-time curve from time zero to infinity, calculated (AUC0-inf) as AUC0-t + AUCextra. AUCextra represents an extrapolated value obtained by Clast / λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above LLQ and λz is the elimination rate constant. And the elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data. A minimum of three points is required to calculate λz.
Apparent Volume of Distribution: After Multiple Dose
时间窗: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/(Area under the serum concentration-time curve within one complete dosing interval \[AUCtau\]\* λz) following multiple dose.
次要结局
- Number of Subjects With Overall Tumor Response(Baseline up to Week 36)
- Elimination Rate Constant ( λ z): After Multiple Dose(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Minimum Observed Serum Concentration (Cmin) After Multiple Doses(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Multiple Dose(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Volume of Distribution at Steady State (Vss)(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Number of Subjects With Clinical Benefit(Baseline up to Week 36)
- Progression-free Survival (PFS)(From first dosing date until disease progression or death, maximum up to Week 36)
- Apparent Terminal Half Life (t1/2): After Multiple Dose(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Time to Maximum Observed Serum Concentration (Tmax): After Single Dose(Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1)
- Time to Maximum Observed Serum Concentration (Tmax): After Multiple Dose(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Elimination Rate Constant (λz): After Single Dose(Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1)
- Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Single Dose(Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1)
- Percentage Peak-Trough Fluctuation (PTF)(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Apparent Terminal Half Life (t1/2): After Single Dose(Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1)
- Observed Serum Concentration Immediately Before Next Dosing (Cpre)(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Average Serum Concentration at Steady State (Cav)(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Mean Residency Time (MRT0-inf)(Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1)
- Mean Residence Time at Steady State (MRTss)(Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5)
- Accumulation Ratio (Rac)(Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 and Week 5)