Carcinoma, Hepatocellular
Conditions
Keywords
Hepatocellular Carcinoma, c-Met inhibitor, Phase 1b, Sorafenib, MSC2156119J
Brief summary
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.
Interventions
DRUGTepotinib
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.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Day 1 to Day 21 of Cycle 1 (each cycle was 21 days) | 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. |
| 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 | At 12 weeks post first-dose in Phase 2 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC) | From randomization up to first observation of PD or death, assessed maximum up to 1369 days | 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. |
| Phase 2: Time-to-symptomatic Progression (TTSP) | From date of randomization up to 1369 days | 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 1b and Phase 2: Overall Survival (OS) Time | From date of randomization up to the date of death, assessed maximum up to 1369 days | 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. |
| Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1 | From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days | 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. |
| Phase 1b and Phase 2: Percentage of Participants With Disease Control | From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days | 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. |
| Phase 1b and Phase 2: Percentage of Participants With Biological Response | Baseline up to Cycle 3 (each cycle is 21 days) | 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. |
| 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 | 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) | 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. |
| 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 | 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) | Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve. |
| Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) 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) | Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose. |
| Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 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) | 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. |
| 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 | 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) | The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100 |
| Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax)) | 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) | Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1. |
| Phase 1b: Accumulation Ratio of AUC (Racc (AUC) | 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) | Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1. |
| 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 and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | From randomization up to first observation of PD or death, assessed maximum up to 1369 days | 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. |
Countries
Germany
Participant flow
Recruitment details
First participant signed informed consent:18 May 2014, Last participant last visit: 14th Feb 2018
Pre-assignment details
In Phase 1b, 24 participants were screened of which, 17 started the treatment. In Phase 2 ,155 participants were screened, of which 49 participants started the treatment.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Tepotinib 300 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. | 4 |
| Phase 1b: Tepotinib 500 mg 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. | 13 |
| Phase 2: Tepotinib 500 mg 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. | 49 |
| Total | 66 |
Baseline characteristics
| Characteristic | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 2: Tepotinib 500 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 10 Participants | 28 Participants | 41 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 3 Participants | 21 Participants | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 20 Participants | 27 Participants |
| Race (NIH/OMB) White | 1 Participants | 8 Participants | 26 Participants | 35 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 11 Participants | 41 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 11 / 13 | 40 / 49 |
| other Total, other adverse events | 4 / 4 | 12 / 13 | 48 / 49 |
| serious Total, serious adverse events | 2 / 4 | 5 / 13 | 21 / 49 |
Outcome results
Primary
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.
Time frame: Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | 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 | 0 Participants |
| Phase 1b: Tepotinib 500 mg | 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 | 0 Participants |
Primary
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.
Time frame: At 12 weeks post first-dose in Phase 2
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | 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 | 31 Participants |
Secondary
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Accumulation Ratio of AUC (Racc (AUC) | 3.43 ratio | Geometric Coefficient of Variation 22.6 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Accumulation Ratio of AUC (Racc (AUC) | 2.51 ratio | Geometric Coefficient of Variation 22 |
Secondary
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax)) | 2.81 ratio | Geometric Coefficient of Variation 24.1 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax)) | 2.32 ratio | Geometric Coefficient of Variation 23 |
Secondary
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.
Time frame: From date of randomization up to the date of death, assessed maximum up to 1369 days
Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b and Phase 2: Overall Survival (OS) Time | 3 Participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b and Phase 2: Overall Survival (OS) Time | 11 Participants |
| Phase 2: Tepotinib 500 mg | Phase 1b and Phase 2: Overall Survival (OS) Time | 40 Participants |
90% CI: [3.68, 10.119]
90% CI: [5.092, 8.181]
Secondary
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.
Time frame: From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1 | 50.0 percentage of Participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1 | 0.0 percentage of Participants |
| Phase 2: Tepotinib 500 mg | Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1 | 8.2 percentage of Participants |
Secondary
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.
Time frame: Baseline up to Cycle 3 (each cycle is 21 days)
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b and Phase 2: Percentage of Participants With Biological Response | 66.7 percentage of participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b and Phase 2: Percentage of Participants With Biological Response | 45.5 percentage of participants |
| Phase 2: Tepotinib 500 mg | Phase 1b and Phase 2: Percentage of Participants With Biological Response | 31.1 percentage of participants |
Secondary
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.
Time frame: From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b and Phase 2: Percentage of Participants With Disease Control | 50.0 percentage of participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b and Phase 2: Percentage of Participants With Disease Control | 30.8 percentage of participants |
| Phase 2: Tepotinib 500 mg | Phase 1b and Phase 2: Percentage of Participants With Disease Control | 57.1 percentage of participants |
Secondary
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.
Time frame: From randomization up to first observation of PD or death, assessed maximum up to 1369 days
Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC) | 4 Participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC) | 9 Participants |
| Phase 2: Tepotinib 500 mg | Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC) | 37 Participants |
90% CI: [1.413, 3.844]
90% CI: [2.76, 4.172]
Secondary
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.
Time frame: From randomization up to first observation of PD or death, assessed maximum up to 1369 days
Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 4 Participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 12 Participants |
| Phase 2: Tepotinib 500 mg | Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 38 Participants |
90% CI: [1.413, 3.68]
90% CI: [0.03, 16.53]
Secondary
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 frame: 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)
Population: ITT set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 3 Participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 9 Participants |
| Phase 2: Tepotinib 500 mg | Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 36 Participants |
90% CI: [1.446, 7.195]
90% CI: [2.858, 4.238]
Secondary
Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib | Cycle 1 Day 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib | Cycle 1 Day 15 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib | Cycle 1 Day 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib | Cycle 1 Day 15 | NA 1 per hour |
Secondary
Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Cycle 1 Day 1 | NA hours |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Cycle 1 Day 15 | NA hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Cycle 1 Day 1 | NA hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Cycle 1 Day 15 | NA hours |
Secondary
Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | 17.7 Liter per hour (L/h) | Geometric Coefficient of Variation 18.2 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | 34.9 Liter per hour (L/h) | Geometric Coefficient of Variation 50.4 |
Secondary
Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Cycle 1 Day 1 | NA liter |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Cycle 1 Day 15 | NA liter |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Cycle 1 Day 1 | NA liter |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Cycle 1 Day 15 | NA liter |
Secondary
Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Cycle 1 Day 1 | NA liter |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Cycle 1 Day 15 | NA liter |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Cycle 1 Day 1 | NA liter |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Cycle 1 Day 15 | NA liter |
Secondary
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib | Cycle 1 Day 1 | NA nanogram hour per milliliter (ng*h/mL) |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib | Cycle 1 Day 15 | NA nanogram hour per milliliter (ng*h/mL) |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib | Cycle 1 Day 1 | NA nanogram hour per milliliter (ng*h/mL) |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib | Cycle 1 Day 15 | NA nanogram hour per milliliter (ng*h/mL) |
Secondary
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
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | 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 | Cycle 1 Day 1 | 4440 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 6.7 |
| Phase 1b: Tepotinib 300 mg | 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 | Cycle 1 Day 15 | 15200 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 18.2 |
| Phase 1b: Tepotinib 500 mg | 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 | Cycle 1 Day 1 | 5060 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 38.9 |
| Phase 1b: Tepotinib 500 mg | 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 | Cycle 1 Day 15 | 12900 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 50.4 |
Secondary
Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib | 635 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 18.2 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib | 542 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 50.7 |
Secondary
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | 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 | Cycle 1 Day 1 | 14.8 ng*h/mL/mg | Geometric Coefficient of Variation 6.7 |
| Phase 1b: Tepotinib 300 mg | 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 | Cycle 1 Day 15 | 50.7 ng*h/mL/mg | Geometric Coefficient of Variation 18.2 |
| Phase 1b: Tepotinib 500 mg | 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 | Cycle 1 Day 1 | 10.1 ng*h/mL/mg | Geometric Coefficient of Variation 38.9 |
| Phase 1b: Tepotinib 500 mg | 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 | Cycle 1 Day 15 | 25.8 ng*h/mL/mg | Geometric Coefficient of Variation 50.4 |
Secondary
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cycle 1 Day 1 | 0.871 ng/mL/mg | Geometric Coefficient of Variation 8.4 |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cycle 1 Day 15 | 2.45 ng/mL/mg | Geometric Coefficient of Variation 19.6 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cycle 1 Day 1 | 0.556 ng/mL/mg | Geometric Coefficient of Variation 39.3 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cycle 1 Day 15 | 1.35 ng/mL/mg | Geometric Coefficient of Variation 44.6 |
Secondary
Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib
Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cycle 1 Day 1 | 261 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 8.4 |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cycle 1 Day 15 | 734 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 19.6 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cycle 1 Day 1 | 278 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 39.3 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Cycle 1 Day 15 | 677 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 44.6 |
Secondary
Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib | 526 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 28 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib | 435 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 57.9 |
Secondary
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
Time frame: 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)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib | 31.5 percentage fluctuation | Geometric Coefficient of Variation 30.5 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib | 35.9 percentage fluctuation | Geometric Coefficient of Variation 44.1 |
Secondary
Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib | 0.53 hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib | 0.50 hours |
Secondary
Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Cycle 1 Day 1 | 10.0 hours |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Cycle 1 Day 15 | 8.0 hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Cycle 1 Day 1 | 8.0 hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Cycle 1 Day 15 | 6.1 hours |
Secondary
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.
Time frame: From date of randomization up to 1369 days
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Time-to-symptomatic Progression (TTSP) | 4.86 months |