Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Hematinics

All Drugs and Chemicals

Antineoplastic Agents

Liver Extracts

Sorafenib

Tepotinib

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.

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.

Medical Responsible

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.

c-Met Second-Line Hepatocellular Carcinoma

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose.

The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100

Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1.

Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1.

Merck KGaA, Darmstadt, Germany

Participants received a single oral dose of Tepotinib 300 milligram (mg) daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.

Phase 1b: Tepotinib 300 mg

Phase 1b: Tepotinib 500 mg

Phase 2: Tepotinib 500 mg

Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.

Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

Intent to Treat (ITT) set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Communication Center

DLT analysis set included all participants who completed Cycle 1 and who received 80 percent (%) or more of the planned cumulative dose of Tepotinib (MSC2156119J) in Cycle 1, and participants who experienced a DLT during Cycle 1.

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

Participants received a single oral dose of Tepotinib 500 mg daily in each 21 day treatment cycle until confirmed disease progression.

Intent to Treat (ITT) set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). The outcome measure was planned to be analyzed for Phase 2 only.

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

Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.

ITT set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC)

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, Overall number of participants analyzed signified those participants who had symptomatic progression. As per planned analysis, data for this outcome was analyzed for Phase 2 only.

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

Phase 1b and Phase 2: Overall Survival (OS) Time

Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1

Phase 1b and Phase 2: Percentage of Participants With Disease Control

Participants received a single oral dose of Tepotinib 300 mg daily in each 21 day treatment cycle until confirmed disease progression.

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, "Overall number of participants analyzed" signified the participants with baseline and post baseline AFP assessments.

Phase 1b and Phase 2: Percentage of Participants With Biological Response

Cycle 1 Day 1

Cycle 1 Day 15

Pharmacokinetic (PK) population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

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

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

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

Pharmacokinetic (PK) population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

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

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

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

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

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

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

Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib

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

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Spots Global Cancer Trial Database for c-Met Second-Line Hepatocellular Carcinoma

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