Clinical trial NCT01988493: Efficacy, Safety, and Pharmacokinetic of MSC2156119J in Asian Participants With Hepatocellular Carcinoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Carcinoma, Hepatocellular
Keywords: Carcinoma, Hepatocellular
MSC2156119J
Sorafenib
Recommended Phase 2 dose
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2013-11-20
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity
timeFrame: Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)
measure: Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks
measure: Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC)
timeFrame: From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years
Secondary outcomes:
measure: Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC)
timeFrame: Up to 2.8 years
measure: Phase 2: Overall Survival (OS)
timeFrame: Time from randomization to the date of death or up to 6.9 years
measure: Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator
timeFrame: From randomization to date of the observation of radiological progressive disease, assessed up to maximum 2.8 years
measure: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib
timeFrame: 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)
measure: Phase 2: Time-to-Symptomatic Progression (TTSP)
timeFrame: Up to 6.9 years
measure: Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC
timeFrame: Time from randomization until the first occurrence of PD assessed up to 6.9 years
measure: 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
timeFrame: Time from randomization until the first occurrence of PD assessed up to 6.9 years
measure: Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator
timeFrame: 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
measure: Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator
timeFrame: Time from randomization until the first occurrence of PD assessed up to 6.9 years
measure: 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
timeFrame: Approximately up to 6.9 years
Other outcomes:
Locations:
city: Beijing
country: China
facility: 307 Hosptial of PLA
state: Beijing
city: Beijing
country: China
facility: Peking University Cancer Hospital
state: Beijing
city: Fuzhou
country: China
facility: Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA
state: Fujian
city: Guangzhou
country: China
facility: Sun Yat-sen University, Cancer Center
state: Guangdong
city: Guangzhou
country: China
facility: Nanfang Hospital
state: Guangdong
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Changsha
country: China
facility: The Third Xiangya Hospital of Central South University
state: Hunan
city: Nanjing
country: China
facility: Nanjing Bayi Hospital
state: Jiangsu
city: Nanjing
country: China
facility: Nanjing First Hospital Affiliated to Nanjing Medical University
state: Jiangsu
city: Changchun
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Shanghai
country: China
facility: Shanghai Cancer Hospital, Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
state: Shanghai
city: Tianjin
country: China
facility: Cancer Hospital, Tianjin Medical University
state: Zhejiang
city: Zhejiang
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
state: Zhejiang
city: Beijing
country: China
facility: Beijing Friendship Hospital, Capital Medical University
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Seongnam-si,
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
city: Yangsan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Tainan
country: Taiwan
facility: Chi Mei Medical Center, Liou Ying
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital, Linkou
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Ryoo BY, Cheng AL, Ren Z, Kim TY, Pan H, Rau KM, Choi HJ, Park JW, Kim JH, Yen CJ, Lim HY, Zhou D, Straub J, Scheele J, Berghoff K, Qin S. Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression. Br J Cancer. 2021 Jul;125(2):200-208. doi: 10.1038/s41416-021-01380-3. Epub 2021 May 10.
citation: Xiong W, Hietala SF, Nyberg J, Papasouliotis O, Johne A, Berghoff K, Goteti K, Dong J, Girard P, Venkatakrishnan K, Strotmann R. Exposure-response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations. Cancer Chemother Pharmacol. 2022 Jul;90(1):53-69. doi: 10.1007/s00280-022-04441-3. Epub 2022 Jun 30.