A Multicenter, Randomized, Phase Ib/II Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of MSC2156119J as Monotherapy Versus Sorafenib in Asian Subjects With MET+ Advanced Hepatocellular Carcinoma and Child-Pugh Class A Liver Function
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 117
- 试验地点
- 43
- 主要终点
- Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity
研究概览
简要总结
This is an open-label, integrated, Phase 1b/2 trial to determine the recommended Phase 2 dose (RP2D) and to evaluate the efficacy, safety, and pharmacokinetic of MSC2156119J as first-line treatment versus sorafenib in subjects with MET+, Barcelona Clinic Liver Cancer (BCLC) Stage C, systemic treatment naive advanced hepatocellular carcinoma (HCC) and Child-Pugh class A liver function.
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
- •Histologically or cytologically confirmed HCC
- •Participants were either intermediate HCC of BCLC Stage B, who were not eligible for surgical and/or local-regional therapies or who had progressive disease (PD) after surgical and/or local-regional therapies (note: the local-regional therapy must not contain sorafenib), or advanced HCC of BCLC Stage C
- •Participants who had disease progression on or were intolerant to the prior standard treatment for advanced HCC (phase Ib Korean subjects only)
- •A tumor biopsy was required for determining MET status
- •MET+ status (Phase 2 only), as determined by the central laboratory (Phase 1b retrospectively, Phase 2 for participant selection) were defined in the protocol
- •Child-Pugh class A with no encephalopathy according to the screening assessment
- •Asian male or female, 18 years of age or older
- •Measurable disease in accordance with RECIST v1.1 (Phase 2 only)
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2
- •Eligible for treatment with sorafenib, was assessed by investigators according to the Package Insert and clinical judgment (Phase 2 only)
- •Signed and dated informed consent indicating that the participants had been informed of all the pertinent aspects of the trial prior to enrollment
- •Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures
- •Life expectancy was judged by the investigator of at least 3 months
排除标准
- •Prior systemic anticancer treatment for advanced HCC, included targeted therapy (for example, sorafenib), chemotherapy, or any other investigational agent (Phase 2 only)
- •Prior treatment with any agent targeting the hepatocyte growth factor (HGF)/c-Met pathway
- •Prior local-regional therapy within 4 weeks prior to Day 1 of trial treatment
- •Prior history of liver transplant
- •Laboratory index at baseline were defined in the protocol
- •Past or current history of neoplasm other than HCC, except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years
- •Known central nervous system (CNS) or brain metastasis that is either symptomatic or untreated
- •Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested products
- •Clinically significant gastrointestinal bleeding within 4 weeks before trial entry
- •Peripheral neuropathy Grade greater than or equal to 2 (Common Terminology Criteria for Adverse Events [CTCAE] v4.0)
- •Impaired cardiac function was defined in the protocol
- •Hypertension uncontrolled by standard therapies
- •Participants with a family history of long QT syndrome or who take any agent that is known to prolong QT/QTc interval
- •Known human immunodeficiency virus (HIV) infection
- •Particpants who had acute pancreatitis and/or chronic pancreatitis, with elevated lipase and/or amylase, clinical symptoms, and/or imaging studies that are indicative of the diagnosis (Mainland Chinese participants only)
- •Known or suspected drug hypersensitivity to any ingredients of sorafenib (Phase 2 only) and MSC2156119J
- •Female participants who were pregnant or lactating, or males and females of reproductive potential not willing or not able to employ a highly effective method of birth control/contraception to prevent pregnancy from 2 weeks before receiving study drug until 3 months after receiving the last dose of study drug
- •Concurrent treatment with a non-permitted drug
- •Substance abuse, other acute or chronic medical or psychiatric condition, or laboratory abnormalities that may increase the risk associated with trial participation in the opinion of the investigator
- •Participation in another clinical trial within the past 28 days
- •Previous anticancer treatment-related toxicities not recovered to baseline or Grade 0-1 (except alopecia and peripheral neuropathy)
- •Participants with any concurrent medical condition or disease that will potentially compromise the conduct of the study at the discretion of the investigators
研究组 & 干预措施
Phase 1b: Tepotinib 300 mg
Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
干预措施: Tepotinib 300 mg (Drug)
Phase 1b: Tepotinib 500 mg
Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
干预措施: Tepotinib 500 mg (Drug)
Phase 1b: Tepotinib 1000 mg
Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
干预措施: Tepotinib 1000 mg (Drug)
Phase 2: Tepotinib
Participants randomized to receive Tepotinib recommended Phase 2 dose (RP2D) determined from Phase 1b over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
干预措施: Tepotinib (Drug)
Phase 2 Sorafenib
Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
干预措施: Sorafenib (Drug)
结局指标
主要结局
Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity
时间窗: Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)
Dose limiting toxicity (DLT) was defined as toxicities at any dose level and judged to be related to the study treatment by investigator and/or the sponsor. DLTs included Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (\>=) 3 febrile neutropenia for more than 1 day; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade \>= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade \>= 3 any non-hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia. Number of participants who experienced DLT during phase 1b were reported.
Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
时间窗: Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks
An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and assessed up to 94 weeks. TEAEs include both Serious TEAEs and non-serious TEAEs.
Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC)
时间窗: From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years
TTP was defined as the time in months from randomization to date of the observation of radiological progressive disease (PD) (based on Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1) assessed by an IRC. PD is defined as at least 20 percent (%) increase in sum of diameters of target lesions, taking as reference as smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must demonstrate an absolute increase of at least 5 millimeter (mm).
次要结局
- Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC)(Up to 2.8 years)
- Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator(From randomization to date of the observation of radiological progressive disease, assessed up to maximum 2.8 years)
- Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 2: Overall Survival (OS)(Time from randomization to the date of death or up to 6.9 years)
- Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 2: Time-to-Symptomatic Progression (TTSP)(Up to 6.9 years)
- Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC(Time from randomization until the first occurrence of PD assessed up to 6.9 years)
- Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 2: Percentage of Participants With Disease Control Based on Tumor Assessment by Investigator According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria(Approximately up to 6.9 years)
- Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator(Time from randomization until the first occurrence of PD assessed up to 6.9 years)
- Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib(Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days))
- Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator(Time from randomization to disease progression or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment, assessed up to 6.9 years)
- Phase 2: Percentage of Participants With Disease Control Based on Tumor Assessment by IRC According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria(Time from randomization until the first occurrence of PD assessed up to 6.9 years)