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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Tepotinib 300 mg
* Drug: Tepotinib 500 mg
* Drug: Tepotinib 1000 mg
* Drug: Tepotinib
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Tepotinib 300 mg<br>Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Drug: Tepotinib 300 mg<br>* Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.<br>|
| Experimental: Phase 1b: Tepotinib 500 mg<br>Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Drug: Tepotinib 500 mg<br>* Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.<br>|
| Experimental: Phase 1b: Tepotinib 1000 mg<br>Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Drug: Tepotinib 1000 mg<br>* Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal<br>|
| Experimental: Phase 2: Tepotinib<br>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. | Drug: Tepotinib<br>* 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.<br>|
| Experimental: Phase 2 Sorafenib<br>Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Drug: Sorafenib<br>* Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 to Day 21 of Cycle 1 (each cycle is 21 days) | 
| 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. | Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks | 
| 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). | From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 2.8 years | 
| Phase 2: Overall Survival (OS) | Overall survival time was measured as time in months between the date of randomization and the date of death. | Time from randomization to the date of death or up to 6.9 years | 
| 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. | 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 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. | 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 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. | 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 | AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval. | 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: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve. | 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 | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. | 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: 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. | 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: 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. | 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 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). | 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 | 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). | 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 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. | 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 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. | 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 | 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. | 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) | 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. | Up to 6.9 years | 
| 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. | Time from randomization until the first occurrence of PD 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 | 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. | Time from randomization until the first occurrence of PD assessed up to 6.9 years | 
| 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. | 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: 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. | Time from randomization until the first occurrence of PD assessed up to 6.9 years | 
| 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 | 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. | Approximately up to 6.9 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, Hepatocellular, MSC2156119J, Sorafenib, Recommended Phase 2 dose