c-Met Second-Line Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This is a Phase 1b/2, multicenter, single arm trial to assess the efficacy, safety, and pharmacokinetics (PK) of MSC2156119J as monotherapy in subjects with MET+ advanced hepatocellular carcinoma (HCC) with child Pugh Class A liver function who have failed sorafenib treatment.

Official Title
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A Multicenter, Single Arm, Phase Ib/II Study to Evaluate Efficacy, Safety, and PK of MSC2156119J as Monotherapy in Subjects With MET+ Advanced Hepatocellular Carcinoma With Child Pugh Class A Liver Function Who Have Failed Sorafenib Treatment

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Tepotinib
* Drug: Tepotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed HCC Child Pugh Class A liver function score For Phase 2 only: MET+ status Male or female, 18 years of age or older Measurable disease in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (inclusive) Availability of a pretreatment tumor biopsy (excluding fine needle aspiration and cytology samples) taken after the subject has discontinued sorafenib and within 28 days before the day of first dosing with MSC2156119J. From the pretreatment biopsy either a formalin-fixed (formalin fixation is mandatory) paraffin-embedded block with tumor tissue (preferred) or at least 15 unstained slides must be sent to the central laboratory prior to enrollment. An associated pathology report must also be sent with the sample Previously treated with sorafenib for greater than or equal to 4 weeks and discontinued sorafenib treatment at least 14 days prior to Day 1 due to either intolerance or radiographic progression Signed and dated informed consent indicating that the subject (or legally acceptable representative if applicable by local laws) has 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 of at least 3 months as judged by the investigator Exclusion Criteria: Prior systemic anticancer treatment for advanced HCC (except for sorafenib as described in the inclusion criteria) Prior treatment with any agent targeting the hepatocyte growth factor (HGF)/c-Met pathway Local-regional therapy within 4 weeks before Day 1 Impaired cardiac function Other protocol defined exclusion criteria could apply

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Tepotinib 300 mg<br> | Drug: Tepotinib<br>* Participants received a single oral dose of Tepotinib 300 milligram (mg) in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.<br>* Other names: MSC2156119J;|
| Experimental: Phase 1b: Tepotinib 500 mg<br> | Drug: Tepotinib<br>* Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.<br>* Other names: MSC2156119J;|
| Experimental: Phase 2: Tepotinib 500 mg<br> | Drug: Tepotinib<br>* Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.<br>* Other names: MSC2156119J;|

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 (DLT) According to National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) for Adverse Events (AEs) Version 4.0 | DLT: defined using NCI-CTCAE for AEs Version 4.0, as any of following toxicities: Grade 4 neutropenia for more than 7 days; greater than or equal to (>=) Grade 3 febrile neutropenia for more than 1 day; Grade 4 or Grade 3 thrombocytopenia with nontraumatic bleeding; >=Grade 3 uncontrolled nausea/vomiting and/or diarrhoea despite adequate treatment for more than 3 days; >=Grade 3 any non-hematological AE. (DLT defined specifically for following cases: >=Grade 3 liver AE requiring recovery period of more than 7 days or to Grade 1 or less or Grade 2 with liver metastases ; >=Grade 3 lipase and/or amylase elevation with confirmation of pancreatitis. An isolated lipase and/or amylase elevation of >=Grade 3 without clinical/radiological evidence of pancreatitis was not classified as DLT); and AEs assessed by investigators to be exclusively related to the participant's underlying disease or medical condition/concomitant treatment are not considered as DLTs. | Day 1 to Day 21 of Cycle 1 (each cycle was 21 days) | 
| Phase 2: Number of Participants Who Were Progression-free at 12 Weeks (PFS Status) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | PFS status was evaluated by the number of participants who were progression-free at 12 weeks according to RECIST Version 1.1. Participants were considered to be progression-free if the participant had a tumor assessment of 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 millimeter (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, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (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)12 weeks after start of treatment or later. | At 12 weeks post first-dose in Phase 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | TTP was the time (in months) from the date of first study drug administration to the date of radiological confirmation of PD performed according to RECIST Version 1.1. 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. The descriptive data represents the number of participants with progression. | Time from first study drug administration to the date of first occurrence of radiological progressive disease (PD), assessed up to 12 months after last participant's first dose (assessed maximum up to 1369 days) | 
| Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PFS was assessed as per RECIST v1.1 as adjudicated by independent endpoint review committee (IERC). 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. The descriptive data represents number of participants with death or progressive disease. | From randomization up to first observation of PD or death, assessed maximum up to 1369 days | 
| Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC) | PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PFS was assessed as per mRECIST for HCC as adjudicated by independent endpoint review committee (IERC). PD was defined as an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents number of participants with death or progressive disease. | From randomization up to first observation of PD or death, assessed maximum up to 1369 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. | From date of randomization up to 1369 days | 
| Phase 1b and Phase 2: Overall Survival (OS) Time | The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. The descriptive data represents number of participants who had an event of death. | From date of randomization up to the date of death, assessed maximum up to 1369 days | 
| Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1 | Percentage of participants with best overall tumor assessment of (CR or PR) according to RECIST Version 1.1 was reported. 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. | From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days | 
| Phase 1b and Phase 2: Percentage of Participants With Disease Control | Disease control was defined as CR, PR, or SD as the best overall response according to RECIST Version 1.1. 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, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (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)12 weeks after start of treatment or later. Percentage of Participants With Disease Control were reported. | From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days | 
| Phase 1b and Phase 2: Percentage of Participants With Biological Response | Percentage of participants with biological response was measured by serum Alpha-Fetoprotein (AFP), defined as a greater than 20% decrease in AFP level by Cycle 3 (each cycle is of 21 days) compared with baseline. | Baseline up to Cycle 3 (each cycle is 21 days) | 
| Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib |  | Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days) | 
| Phase 1b: Dose Normalized Area Under the Plasma Concentration-Time Curve From Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib | Dose normalized was calculated as 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 (LLQ) divided by the dose. | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; 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 Infinity (AUC0-inf) of Tepotinib |  | Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 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. | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose. | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; 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 |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib |  | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib | The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav ) multiplied by 100 | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax)) | Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1. | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days) | 
| Phase 1b: Accumulation Ratio of AUC (Racc (AUC) | Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1. | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma, c-Met inhibitor, Phase 1b, Sorafenib, MSC2156119J