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临床试验/NCT01014936
NCT01014936已完成1 期

A Phase I Open-label, Non-randomized, Dose-escalation First-in-man Trial to Investigate the c-Met Kinase Inhibitor MSC2156119J Under Three Different Regimens in Subjects With Advanced Solid Tumors

EMD Serono1 个研究点 分布在 1 个国家目标入组 149 人开始时间: 2009年11月30日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
1 期
状态
已完成
发起方
EMD Serono
入组人数
149
试验地点
1
主要终点
Recommended Phase 2 Dose (RP2D)
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is a an open-label, dose-escalation, first-in-man (FIM) study designed to explore MSC2156119J, in subjects with advanced solid tumors who have not responded to previous therapies or for whom no other therapies are available.

Subjects will be assigned one of the dosing regimens:

  • Regimen 1: MSC2156119J once daily for 14 days, followed by 7 days with no treatment (21-day cycle)
  • Regimen 2: MSC2156119J three times per week (e.g., Days 1, 3, and 5) for three weeks (21-day cycle)
  • Regimen 3: MSC2156119J every day for three weeks (21-day cycle)

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
18 Years 至 —（Adult, Older Adult）
性别
All
接受健康志愿者
否

入选标准

  • •Subject should read and fully understand the requirements of the trial, be willing to comply with all trial visits and assessments, and be willing and able to give informed consent
  • •Histologically or cytologically confirmed solid tumor, either refractory to standard therapy or for which no effective standard therapy is available
  • •Measurable or evaluable disease, as defined by RECIST 1.0
  • •Estimated life expectancy greater than (>) three months
  • •Men or women aged greater than or equal to (>=) 18 years
  • •Women of childbearing potential must have a negative blood pregnancy test at the Screening Visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are post-menopausal for at least 12 months, are surgically sterile, or are sexually inactive.
  • •Subjects and their partners must be willing to avoid pregnancy during the trial and until three months after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator, such as a two-barrier method or one-barrier method with spermicide or intrauterine device. This requirement begins two weeks before receiving the first trial treatment and ends one month after receiving the last treatment.
  • •ECOG performance status of 0 to 2
  • •Adequate hematological function:
  • •Hemoglobin >= 9.0 g/dL
  • •Neutrophils > 1.5 x 109/L
  • •Platelets >= 75 x 109/L
  • •Adequate liver function:
  • •Total bilirubin less than or equal to (<=) 1.5 x ULN (upper limit to normal)
  • •AST/ ALT ≤ 2.5 x ULN
  • •For subjects with liver metastases:
  • •Total bilirubin ≤ 1.5 x ULN
  • •AST/ ALT ≤ 5 x ULN
  • •Adequate renal function:
  • •Serum creatinine < 1.5 x ULN, and/or
  • •Calculated creatinine clearance > 60 mL/min
  • •Resolution of all acute chemotherapy, radiotherapy or surgery-related AEs to Grade <= 2, except for alopecia
  • •Recovery from any surgical intervention
  • •Subjects enrolling after the MTD has been determined must present specific c Met alterations (mutation, overexpression, amplification

排除标准

  • •Received chemotherapy, immunotherapy, hormonal therapy (except subjects with prostate cancer), biologic therapy, or any other investigational agent or anticancer therapy within 28 days (or five half-lives for non-cytotoxics, whichever is shorter), of Day 1 of trial treatment (six weeks for nitrosureas or mitomycin C)
  • •Received extensive prior radiotherapy on more than 30% of bone marrow
  • •Symptomatic primary tumors or metastasis of brain and/or central nervous system, uncontrolled with antiepileptics and requiring high doses of steroids
  • •Known HIV positivity, active hepatitis C, or active hepatitis B
  • •Medical history of liver fibrosis/ cirrhosis
  • •Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such
  • •Medical history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product
  • •Medical history of surgery within six weeks prior to enrollment
  • •Impaired cardiac function (left ventricular ejection fraction < 45% defined by echocardiograph, serious arrhythmia, unstable angina pectoris, congestive heart failure NYHA III and IV, myocardial infarction within the last 12 months prior to trial entry; signs of pericardial effusion)
  • •Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mm Hg)
  • •Peripheral neuropathy Grade >= 2
  • •Medical history of any other significant medical disease, major surgery, or psychiatric condition that might impair the subject's well being or preclude full participation in the trial
  • •Women who are pregnant or nursing
  • •Known drug abuse or alcohol abuse
  • •Participation in another clinical trial within the past 28 days
  • •Requires concurrent treatment with a non-permitted drug
  • •Known hypersensitivity to any of the trial treatment ingredients
  • •Legal incapacity or limited legal capacity
  • •Any other reason that, in the opinion of the principal investigator, precludes the subject from participating in the trial

研究组 & 干预措施

MSC2156119J Regimen 1

Experimental

Subjects will be administered with micronized or non-micronized MSC2156119J in dose ranging from 30 mg to 400 mg (capsule formulation) once daily for 14 days, followed by 7 days with no treatment (21-day cycle) in Regimen 1.

干预措施: MSC2156119J (Drug)

MSC2156119J Regimen 2

Experimental

Subjects will be administered with micronized or non-micronized MSC2156119J in dose ranging from 60 mg to 315 mg (capsule formulation) once daily 3 times per week for 3 weeks (21-day cycle) in Regimen 2.

干预措施: MSC2156119J (Drug)

MSC2156119J Regimen 3

Experimental

Subjects will be administered with micronized MSC2156119J in dose ranging from 300 mg to 1400 mg (capsule or tablet formulation) once daily for 21 days (21-day cycle) in Regimen 3.

干预措施: MSC2156119J (Drug)

结局指标

主要结局

Recommended Phase 2 Dose (RP2D)

时间窗: Cycle 1 (Day 1 to Day 21)

MTD was defined as the dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a DLT. The primary endpoint was to determine MTD of MSC2156119J for each of the 3 treatment regimens in subjects with advanced solid tumors. However, during the course of the trial it was established that the MTD could not be determined and instead, RP2D was to be determined.

Number of Subjects With Any Dose Limiting Toxicity (DLT)

时间窗: Day 1, 3, 8, 14, 17 of Cycle 1 (for Regimen 1 and 3); Day 1, 3, 8, 15, 19 of Cycle 1 (for Regimen 2)

DLT was defined as one of the following adverse events (AEs) observed during Cycle1, regardless of MSC2156119J relationship, excluding AEs assessed by investigator exclusively related to subject's underlying disease or medical condition: Grade 4 neutropenia for \>7 days; Grade \>=3 febrile neutropenia for \>1 day; Grade 4 thrombocytopenia/Grade 3 with bleeding; Grade \>=3 nausea and emesis, despite optimal treatment; Grade \>=3 non-hematological AE, except emesis and nausea with no adequate therapy and alopecia, Grade \>= 3 liver AE with a recovery period of \>7 days or to Grade \<=1 for subjects without liver metastases or to \<=2 for subjects with liver metastases; Grade \>=3 lipase and/or amylase rise with pancreatitis confirmation, either based on clinical or radiological signs. Any AE not otherwise defined as a DLT that, due to prolonged recovery to Grade \<=1 or baseline status, leads to delay of above 21 days in planned administration of study drug.

Number of Subjects With Treatment-Related Adverse Events

时间窗: Baseline up to 158.01 weeks

Related AE was defined as any untoward medical occurrence which was considered to have a relationship with the study drug (suspected to be reasonably related to the study drug or AE was medically (pharmacologically/clinically) attributed to the study drug as per Investigator's assessment.

次要结局

  • Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death(Baseline up to 158.01 weeks)
  • Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48, 49.32 hours post-dose on Day 1 Cycle 1)
  • Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 hours post-dose on Day 19 Cycle 1)
  • Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1)
  • Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1)
  • Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1)
  • Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1)
  • Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1)
  • Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2(Baseline, Day 1 Cycle 2)
  • Relative Percentage Change In Sum of Longest Diameter (SOLD) of Target Lesions to Post-Baseline Nadir(Baseline, On Treatment (up to 153.3 weeks))
  • Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 hours post-dose on Day 1 Cycle 1)
  • Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 2(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1)
  • Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2(Baseline, Day 1 Cycle 2)
  • Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS)(Day 1 Cycle 2)
  • Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1)
  • Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 1(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 3(pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1)
  • Number of Subjects With Best Overall Response (BOR)(Baseline up to 153.3 weeks)
  • Progression-free Survival (PFS)(Baseline up to 153.3 weeks)

研究者

发起方
EMD Serono
申办方类型
Industry
责任方
Sponsor

研究点 (1)

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