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Efficacy, Safety, and Pharmacokinetic of MSC2156119J in Asian Participants With Hepatocellular Carcinoma

Primary Purpose

Carcinoma, Hepatocellular

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Tepotinib 300 mg

Tepotinib 500 mg

Tepotinib 1000 mg

Tepotinib

Sorafenib

About this trial

This is an interventional treatment trial for Carcinoma, Hepatocellular focused on measuring Carcinoma, Hepatocellular, MSC2156119J, Sorafenib, Recommended Phase 2 dose

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

307 Hosptial of PLA
Peking University Cancer Hospital
Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA
Sun Yat-sen University, Cancer Center
Nanfang Hospital
Harbin Medical University Cancer Hospital
The Third Xiangya Hospital of Central South University
Nanjing Bayi Hospital
Nanjing First Hospital Affiliated to Nanjing Medical University
Jilin Cancer Hospital
Shanghai Cancer Hospital, Fudan University
Zhongshan Hospital Fudan University
Cancer Hospital, Tianjin Medical University
Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
Beijing Friendship Hospital, Capital Medical University
Dong-A University Hospital
Pusan National University Hospital
Keimyung University Dongsan Hospital
Kyungpook National University Hospital
National Cancer Center
CHA Bundang Medical Center, CHA University
Seoul National University Bundang Hospital
Kyung Hee University Hospital
Korea University Anam Hospital
Severance Hospital, Yonsei University
Asan Medical Center
Gangnam Severance Hospital, Yonsei University Health System
Samsung Medical Center
The Catholic University of Korea, Seoul St. Mary's Hospital
Korea University Guro Hospital
Seoul National University Hospital
Ajou University Hospital
Pusan National University Yangsan Hospital
Changhua Christian Hospital
Kaohsiung Medical University Chung-Ho Memorial Hospital
Kaohsiung Chang Gung Memorial Hospital
Taichung Veterans General Hospital
National Cheng Kung University Hospital
Chi Mei Medical Center, Liou Ying
National Taiwan University Hospital
Mackay Memorial Hospital
Taipei Veterans General Hospital
Chang Gung Memorial Hospital, Linkou

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Phase 1b: Tepotinib 300 mg

Phase 1b: Tepotinib 500 mg

Phase 1b: Tepotinib 1000 mg

Phase 2: Tepotinib

Phase 2 Sorafenib

Arm Description

Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

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.

Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Outcomes

Primary Outcome Measures

Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity

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

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)

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).

Secondary Outcome Measures

Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC)

Progression-free survival (PFS) time was defined as the time in months from randomization to either first observation of disease progression (based on RECIST v1.1) or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter(mm). PFS was measured using Kaplan-Meier (KM) estimates.

Phase 2: Overall Survival (OS)

Overall survival time was measured as time in months between the date of randomization and the date of death.

Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator

TTP was defined as the time in months from randomization to date of the observation of radiological PD (based on RECIST v1.1) assessed by the investigator. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm.

Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib

Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLLQ). AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule.

Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib

AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval.

Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib

Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.

Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib

Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.

Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib

Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.

Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib

Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.

Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib

The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z).

Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib

The CL/f is a measure of the rate at which it was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. The CL/F from plasma was calculated using the formula: Dose divided by area under the concentration time curve from time zero to infinity (AUC0-inf).

Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed.

Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib

Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib

Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.

Phase 2: Time-to-Symptomatic Progression (TTSP)

Time-to-symptomatic progression was defined as time (in months) from first study drug administration to the date of deterioration of symptoms assessed by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8) (defined as at least a 4-point increase, i.e., higher score, compared with baseline value), or deterioration to Eastern Cooperative Oncology Group (ECOG) performance score 4, or death. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms). ECOG assess participant's performance status on a scale of 0 to 5, where 0=fully active and 5=dead.

Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC

The objective response rate (ORR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR: Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.

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

Disease control was defined as CR, PR, or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. Percentage of participants with disease control were reported.

Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator

Progression-free survival (assessed by the Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease by the investigator or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. PFS was measured using Kaplan-Meier (KM) estimates.

Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator

The objective response rate was defined as the percentage of participants who had achieved CR or PR as the best overall response according to radiological assessments as adjudicated by the investigator from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.

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

Full Information

NCT ID

NCT01988493

First Posted

November 1, 2013

Last Updated

August 22, 2022

Sponsor

Merck KGaA, Darmstadt, Germany

1. Study Identification

Unique Protocol Identification Number

NCT01988493

Brief Title

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

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

January 6, 2014 (Actual)

Primary Completion Date

February 5, 2018 (Actual)

Study Completion Date

December 3, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck KGaA, Darmstadt, Germany

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Carcinoma, Hepatocellular

Keywords

Carcinoma, Hepatocellular, MSC2156119J, Sorafenib, Recommended Phase 2 dose

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

117 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phase 1b: Tepotinib 300 mg

Arm Type

Experimental

Arm Description

Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Arm Title

Phase 1b: Tepotinib 500 mg

Arm Type

Experimental

Arm Description

Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Arm Title

Phase 1b: Tepotinib 1000 mg

Arm Type

Experimental

Arm Description

Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Arm Title

Phase 2: Tepotinib

Arm Type

Experimental

Arm Description

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.

Arm Title

Phase 2 Sorafenib

Arm Type

Experimental

Arm Description

Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Intervention Type

Drug

Intervention Name(s)

Tepotinib 300 mg

Intervention Description

Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Intervention Type

Drug

Intervention Name(s)

Tepotinib 500 mg

Intervention Description

Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Intervention Type

Drug

Intervention Name(s)

Tepotinib 1000 mg

Intervention Description

Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal

Intervention Type

Drug

Intervention Name(s)

Tepotinib

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Sorafenib

Intervention Description

Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Primary Outcome Measure Information:

Title

Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity

Description

Time Frame

Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)

Title

Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

Description

Time Frame

Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks

Title

Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC)

Description

Time Frame

From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years

Secondary Outcome Measure Information:

Title

Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC)

Description

Time Frame

Up to 2.8 years

Title

Phase 2: Overall Survival (OS)

Description

Overall survival time was measured as time in months between the date of randomization and the date of death.

Time Frame

Time from randomization to the date of death or up to 6.9 years

Title

Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator

Description

Time Frame

From randomization to date of the observation of radiological progressive disease, assessed up to maximum 2.8 years

Title

Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib

Description

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

Time Frame

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)

Title

Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib

Description

Time Frame

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)

Title

Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib

Description

AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval.

Time Frame

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)

Title

Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib

Description

Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.

Time Frame

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)

Title

Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib

Description

Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.

Time Frame

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)

Title

Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib

Description

Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.

Time Frame

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)

Title

Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib

Description

Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.

Time Frame

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)

Title

Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib

Description

Time Frame

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)

Title

Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib

Description

Time Frame

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)

Title

Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib

Description

Time Frame

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)

Title

Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib

Description

Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Time Frame

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)

Title

Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib

Description

Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.

Time Frame

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)

Title

Phase 2: Time-to-Symptomatic Progression (TTSP)

Description

Time Frame

Up to 6.9 years

Title

Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC

Description

Time Frame

Time from randomization until the first occurrence of PD assessed up to 6.9 years

Title

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

Description

Time Frame

Time from randomization until the first occurrence of PD assessed up to 6.9 years

Title

Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator

Description

Time Frame

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

Title

Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator

Description

Time Frame

Time from randomization until the first occurrence of PD assessed up to 6.9 years

Title

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

Description

Time Frame

Approximately up to 6.9 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Responsible

Organizational Affiliation

Merck KGaA, Darmstadt, Germany

Official's Role

Study Director

Facility Information:

Facility Name

307 Hosptial of PLA

City

Beijing

State/Province

Beijing

ZIP/Postal Code

100071

Country

China

Facility Name

Peking University Cancer Hospital

City

Beijing

State/Province

Beijing

ZIP/Postal Code

100142

Country

China

Facility Name

Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA

City

Fuzhou

State/Province

Fujian

ZIP/Postal Code

350025

Country

China

Facility Name

Sun Yat-sen University, Cancer Center

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510060

Country

China

Facility Name

Nanfang Hospital

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510515

Country

China

Facility Name

Harbin Medical University Cancer Hospital

City

Harbin

State/Province

Heilongjiang

ZIP/Postal Code

150081

Country

China

Facility Name

The Third Xiangya Hospital of Central South University

City

Changsha

State/Province

Hunan

ZIP/Postal Code

410013

Country

China

Facility Name

Nanjing Bayi Hospital

City

Nanjing

State/Province

Jiangsu

ZIP/Postal Code

210002

Country

China

Facility Name

Nanjing First Hospital Affiliated to Nanjing Medical University

City

Nanjing

State/Province

Jiangsu

ZIP/Postal Code

210029

Country

China

Facility Name

Jilin Cancer Hospital

City

Changchun

State/Province

Jilin

ZIP/Postal Code

130012

Country

China

Facility Name

Shanghai Cancer Hospital, Fudan University

City

Shanghai

State/Province

Shanghai

ZIP/Postal Code

200032

Country

China

Facility Name

Zhongshan Hospital Fudan University

City

Shanghai

State/Province

Shanghai

ZIP/Postal Code

200032

Country

China

Facility Name

Cancer Hospital, Tianjin Medical University

City

Tianjin

State/Province

Zhejiang

ZIP/Postal Code

300060

Country

China

Facility Name

Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine

City

Zhejiang

State/Province

Zhejiang

ZIP/Postal Code

310016

Country

China

Facility Name

Beijing Friendship Hospital, Capital Medical University

City

Beijing

ZIP/Postal Code

100050

Country

China

Facility Name

Dong-A University Hospital

City

Busan

ZIP/Postal Code

602-715

Country

Korea, Republic of

Facility Name

Pusan National University Hospital

City

Busan

ZIP/Postal Code

602-739

Country

Korea, Republic of

Facility Name

Keimyung University Dongsan Hospital

City

Daegu

ZIP/Postal Code

41931

Country

Korea, Republic of

Facility Name

Kyungpook National University Hospital

City

Daegu

ZIP/Postal Code

700-721

Country

Korea, Republic of

Facility Name

National Cancer Center

City

Goyang-si

ZIP/Postal Code

10408

Country

Korea, Republic of

Facility Name

CHA Bundang Medical Center, CHA University

City

Seongnam-si,

ZIP/Postal Code

13496

Country

Korea, Republic of

Facility Name

Seoul National University Bundang Hospital

City

Seongnam-si

ZIP/Postal Code

13620

Country

Korea, Republic of

Facility Name

Kyung Hee University Hospital

City

Seoul

ZIP/Postal Code

02447

Country

Korea, Republic of

Facility Name

Korea University Anam Hospital

City

Seoul

ZIP/Postal Code

02841

Country

Korea, Republic of

Facility Name

Severance Hospital, Yonsei University

City

Seoul

ZIP/Postal Code

03722

Country

Korea, Republic of

Facility Name

Asan Medical Center

City

Seoul

ZIP/Postal Code

05505

Country

Korea, Republic of

Facility Name

Gangnam Severance Hospital, Yonsei University Health System

City

Seoul

ZIP/Postal Code

06273

Country

Korea, Republic of

Facility Name

Samsung Medical Center

City

Seoul

ZIP/Postal Code

06351

Country

Korea, Republic of

Facility Name

The Catholic University of Korea, Seoul St. Mary's Hospital

City

Seoul

ZIP/Postal Code

06591

Country

Korea, Republic of

Facility Name

Korea University Guro Hospital

City

Seoul

ZIP/Postal Code

08308

Country

Korea, Republic of

Facility Name

Seoul National University Hospital

City

Seoul

ZIP/Postal Code

110744

Country

Korea, Republic of

Facility Name

Ajou University Hospital

City

Suwon-si

ZIP/Postal Code

443-380

Country

Korea, Republic of

Facility Name

Pusan National University Yangsan Hospital

City

Yangsan

ZIP/Postal Code

626-770

Country

Korea, Republic of

Facility Name

Changhua Christian Hospital

City

Changhua

ZIP/Postal Code

50004

Country

Taiwan

Facility Name

Kaohsiung Medical University Chung-Ho Memorial Hospital

City

Kaohsiung

ZIP/Postal Code

807

Country

Taiwan

Facility Name

Kaohsiung Chang Gung Memorial Hospital

City

Kaohsiung

ZIP/Postal Code

83301

Country

Taiwan

Facility Name

Taichung Veterans General Hospital

City

Taichung

ZIP/Postal Code

40705

Country

Taiwan

Facility Name

National Cheng Kung University Hospital

City

Tainan

ZIP/Postal Code

704

Country

Taiwan

Facility Name

Chi Mei Medical Center, Liou Ying

City

Tainan

ZIP/Postal Code

736

Country

Taiwan

Facility Name

National Taiwan University Hospital

City

Taipei

ZIP/Postal Code

100

Country

Taiwan

Facility Name

Mackay Memorial Hospital

City

Taipei

ZIP/Postal Code

10449

Country

Taiwan

Facility Name

Taipei Veterans General Hospital

City

Taipei

ZIP/Postal Code

11217

Country

Taiwan

Facility Name

Chang Gung Memorial Hospital, Linkou

City

Taoyuan

ZIP/Postal Code

333

Country

Taiwan

12. IPD Sharing Statement

Citations:

PubMed Identifier

33972742

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.

Results Reference

result

PubMed Identifier

35771259

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.

Results Reference

derived

Links:

URL

https://clinicaltrials.emdgroup.com/en/trial-details/?id=200095-004

Description

Trial Awareness and Transparency website

URL

https://clinical-information.canada.ca/ci-rc/item/242300

Description

Redacted Clinical study report, redacted clinical study protocol and redacted statistical analysis plan for this study is also available at the HC-PRCI portal (Health Canada-Public release of clinical information)

Learn more about this trial

Efficacy, Safety, and Pharmacokinetic of MSC2156119J in Asian Participants With Hepatocellular Carcinoma

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