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临床试验/NCT01668017
NCT01668017终止1 期

A Multicentre, Open Label, Phase I Trial in Japan of the MEK Inhibitor Pimasertib Given Orally to Subjects With Solid Tumors as Monotherapy

Merck KGaA, Darmstadt, Germany1 个研究点 分布在 1 个国家目标入组 26 人开始时间: 2012年9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
终止
入组人数
26
试验地点
1
主要终点
Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT)
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 two-part trial. "Solid tumor" in this protocol means solid tumor excluding hepatocellular carcinoma (HCC).

Part 1: Dose Escalation Phase in subjects with solid tumor (Cohort A) and HCC (Cohort B). The dose will be increased from 45 mg twice a day (BID) with 3+3 cohort method up to the recommended phase 2 dose (RP2D) of pimasertib established as single agent in the global studies for each arm independently.

Part 2: The Maximum Tolerated Dose (MTD) defined in Part 1 will be confirmed in more subjects in Cohort A (N=18) and Cohort B (N=6) separately.

Following the recommendation by the Safety Monitoring Committee, Cohort B was discontinued due to hepatocellular carcinoma (HCC) and there will be no further enrollment of subjects to this cohort. This decision is based upon review of safety and efficacy information.

研究设计

研究类型
Interventional
分配方式
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

  • •Cohort A: A histologically or cytologically confirmed diagnosis of advanced solid tumors which is either refractory after standard therapy for the disease or for which no effective standard therapy is available. Archived tumor tissue available or biopsy of tumor tissue needs to be performed.
  • •Cohort B: A histologically or cytologically confirmed diagnosis of advanced hepatocellular carcinoma (HCC) which is either refractory after standard therapy for the disease or for which no effective standard therapy is available. Archived tumor tissue available or biopsy of tumor tissue needs to be performed. Subjects with Child Pugh A.
  • •Male or female Japanese, age greater than or equal to (>=) 18 years.
  • •Subject has read and understands the informed consent form and is willing and able to give informed consent. The subject fully understands requirements of the trial and is willing to comply with all trial visits and assessments.
  • •Women of childbearing potential must have a negative blood pregnancy test at the screening visit.
  • •Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose investigational medicinal product (IMP).
  • •Life expectancy of at least 3 months

排除标准

  • •Hematological abnormality Cohort A: Hematological test abnormalities of Hemoglobin < 9.0 g/dL, Neutrophil count < 1.0*10^9/L and Platelet count < 100*10^9/L.
  • •Cohort B: Hematological test abnormalities of Hemoglobin < 9.0 g/dL, Neutrophil count < 1.0*10^9/L, Platelet count < 75*10^9/L, subjects with hepatic encephalopathy
  • •Renal impairment as evidenced by serum creatinine > 1.5*upper limit of normal (ULN), and calculated creatinine clearance < 60 mL/min by Cockcroft-Gault formula.
  • •Liver function abnormality of Total Bilirubin > 1.5*ULN, or aspartate transaminase 9AST) or alkaline phosphatase (ALT)> 2.5*ULN. For subjects with HCC or liver involvement AST/ALT > 5*ULN.
  • •History of central nervous system (CNS) metastases, unless subject has been previously treated for CNS metastases
  • •History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions
  • •Eastern Cooperative Oncology Group Performance status (ECOG PS) greater than
  • •Has received chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy (including any investigational agent) or surgical intervention within 28 days or 5 half lives for non-cytotoxics of registration.
  • •Baseline corrected QT interval on screening ECG (QTc) >= 480 ms or left ventricular ejection fraction (LVEF) < 40% on screening echocardiogram
  • •Cohort B: Subjects with hepatic encephalopathy, remarkable ascites and subjects with history of esophageal varices rupture within 6 months (subjects with symptom improvement after treatment are eligible)
  • •Other serious illness or medical conditions.
  • •Retinal degenerative disease.
  • •Previous treatment with MEK inhibitors.
  • •Legal incapacity or limited legal capacity.

研究组 & 干预措施

Part 1: Pimasertib 30mg in Solid Tumor

Experimental

干预措施: Pimasertib (Drug)

Part 1: Pimasertib 45 mg in Solid Tumor

Experimental

干预措施: Pimasertib (Drug)

Part 1: Pimasertib 60 mg in Solid Tumor

Experimental

干预措施: Pimasertib (Drug)

Part 1: Pimasertib 30 mg in Hepatocellular Carcinoma (HCC)

Experimental

干预措施: Pimasertib (Drug)

Part 1: Pimasertib 45 mg in HCC

Experimental

干预措施: Pimasertib (Drug)

结局指标

主要结局

Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT)

时间窗: During Treatment Cycle 1 (Day 1 to 21)

DLT defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0): any of following toxicities possibly/probably related to study drug: Any non-hematological toxicity of Grade 3 or higher (excluding Grade 3 asymptomatic rise in liver function tests (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], alkaline phosphatase \[ALP\], gamma-glutamyl transferase \[GGT\] reversible in 7 days for subjects with solid tumor and without liver involvement, or Grade 4 for subjects with HCC or with liver involvement; Grade 3 or 4 asymptomatic rise in creatinine phosphokinase (CPK) reversible in 7 days, deniable for myocardial infarction and rhabdomyolysis; Grade 3 vomiting/diarrhea encountered without optimal therapy). Any Grade 4 neutropenia \>5 days duration, any Grade 3 or above febrile neutropenia. Grade 4 thrombocytopenia \>1 day or Grade 3 with bleeding. Any treatment delay \>2 weeks due to drug-related adverse effects.

次要结局

  • Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Area Under the Concentration Over Time (AUCt) at Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Area Under the Concentration Over Time (AUCt) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib of 1 Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Accumulation Ratio for Cmax Racc(Cmax) of Part 1: Pimasertib 30 mg In HCC Arm(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15)
  • Percentage of Subjects With Best Overall Response(Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks))
  • Percentage of Subjects With Objective Response(Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks))
  • Percentage of Subjects With Disease Control(Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks))
  • Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs(Baseline up to 30 days post last dose of study drug; assessed maximum up to 39.4 weeks)
  • Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Apparent Clearance (CL/f) of Pimasertib on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Apparent Clearance (CL/f) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Apparent Clearance at Steady-state (CLss/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Apparent Volume of Distribution at Terminal Phase (Vz/f) Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)
  • Apparent Clearance at Steady-state (CLss/f) of Pimasertib on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Apparent Volume of Distribution at Terminal Phase (Vz/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15)
  • Accumulation Ratio for AUC Racc(AUC) of Pimasertib(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15)
  • Accumulation Ratio for AUC Racc(AUC) of Part 1: Pimasertib 30 mg In HCC Arm(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15)
  • Accumulation Ratio for Cmax Racc(Cmax) of Pimasertib(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15)
  • Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1(Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (1)

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