Carcinoma, Hepatocellular
Conditions
Keywords
Carcinoma, Hepatocellular, MSC2156119J, Sorafenib, Recommended Phase 2 dose
Brief summary
This is an open-label, integrated, Phase 1b/2 trial to determine the recommended Phase 2 dose (RP2D) and to evaluate the efficacy, safety, and pharmacokinetic of MSC2156119J as first-line treatment versus sorafenib in subjects with MET+, Barcelona Clinic Liver Cancer (BCLC) Stage C, systemic treatment naive advanced hepatocellular carcinoma (HCC) and Child-Pugh class A liver function.
Interventions
DRUGTepotinib 300 mg
Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
DRUGTepotinib 500 mg
Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
DRUGTepotinib 1000 mg
Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal
DRUGTepotinib
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.
DRUGSorafenib
Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity | Day 1 to Day 21 of Cycle 1 (each cycle is 21 days) | Dose limiting toxicity (DLT) was defined as toxicities at any dose level and judged to be related to the study treatment by investigator and/or the sponsor. DLTs included Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (\>=) 3 febrile neutropenia for more than 1 day; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade \>= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade \>= 3 any non-hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia. Number of participants who experienced DLT during phase 1b were reported. |
| Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks | An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and assessed up to 94 weeks. TEAEs include both Serious TEAEs and non-serious TEAEs. |
| Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC) | From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years | TTP was defined as the time in months from randomization to date of the observation of radiological progressive disease (PD) (based on Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1) assessed by an IRC. PD is defined as at least 20 percent (%) increase in sum of diameters of target lesions, taking as reference as smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must demonstrate an absolute increase of at least 5 millimeter (mm). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib | 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) | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. |
| Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib | 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) | Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLLQ). AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule. |
| Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib | 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) | AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval. |
| Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | 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) | Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve. |
| Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib | 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) | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. |
| Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib | 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) | Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve. |
| Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | 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) | Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve. |
| Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | 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) | The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)\* Lambda(z). |
| Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | 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) | The CL/f is a measure of the rate at which it was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. The CL/F from plasma was calculated using the formula: Dose divided by area under the concentration time curve from time zero to infinity (AUC0-inf). |
| Phase 2: Overall Survival (OS) | Time from randomization to the date of death or up to 6.9 years | Overall survival time was measured as time in months between the date of randomization and the date of death. |
| Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib | 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) | Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | 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) | Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. |
| Phase 2: Time-to-Symptomatic Progression (TTSP) | Up to 6.9 years | Time-to-symptomatic progression was defined as time (in months) from first study drug administration to the date of deterioration of symptoms assessed by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8) (defined as at least a 4-point increase, i.e., higher score, compared with baseline value), or deterioration to Eastern Cooperative Oncology Group (ECOG) performance score 4, or death. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms). ECOG assess participant's performance status on a scale of 0 to 5, where 0=fully active and 5=dead. |
| Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC | Time from randomization until the first occurrence of PD assessed up to 6.9 years | The objective response rate (ORR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR: Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. |
| Phase 2: Percentage of Participants With Disease Control Based on Tumor Assessment by IRC According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | Time from randomization until the first occurrence of PD assessed up to 6.9 years | Disease control was defined as CR, PR, or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. Percentage of participants with disease control were reported. |
| Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator | 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 | Progression-free survival (assessed by the Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease by the investigator or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. PFS was measured using Kaplan-Meier (KM) estimates. |
| Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator | Time from randomization until the first occurrence of PD assessed up to 6.9 years | The objective response rate was defined as the percentage of participants who had achieved CR or PR as the best overall response according to radiological assessments as adjudicated by the investigator from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. |
| Phase 2: Percentage of Participants With Disease Control Based on Tumor Assessment by Investigator According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | Approximately up to 6.9 years | Disease control was defined as CR, PR, or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. Percentage of participants with disease control were reported. |
| Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | 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) | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed. |
| Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC) | Up to 2.8 years | Progression-free survival (PFS) time was defined as the time in months from randomization to either first observation of disease progression (based on RECIST v1.1) or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter(mm). PFS was measured using Kaplan-Meier (KM) estimates. |
| Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator | From randomization to date of the observation of radiological progressive disease, assessed up to maximum 2.8 years | 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. |
Countries
China, South Korea, Taiwan
Participant flow
Recruitment details
First participant enrolled 06 Jan 2014. Last participant last visit: 03 Dec 2020.
Pre-assignment details
A total of 27 participants were enrolled in Phase 1b part of the study and a total of 90 participants were enrolled in phase 2 part of the study. Participants enrolled in phase 1b were not eligible for randomization in phase 2.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Tepotinib 300 mg Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | 7 |
| Phase 1b: Tepotinib 500 mg Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | 14 |
| Phase 1b: Tepotinib 1000 mg Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | 6 |
| Phase 2: Tepotinib 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. | 45 |
| Phase 2 Sorafenib Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | 44 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Randomized but not treated | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg | Phase 2: Tepotinib | Phase 1b: Tepotinib 300 mg | Phase 2 Sorafenib | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 11 Participants | 1 Participants | 7 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 5 Participants | 34 Participants | 6 Participants | 37 Participants | 93 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 6 Participants | 45 Participants | 7 Participants | 44 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 6 Participants | 45 Participants | 7 Participants | 44 Participants | 116 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 12 Participants | 5 Participants | 41 Participants | 6 Participants | 41 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 7 | 11 / 14 | 3 / 6 | 24 / 45 | 30 / 44 |
| other Total, other adverse events | 7 / 7 | 14 / 14 | 6 / 6 | 43 / 45 | 43 / 44 |
| serious Total, serious adverse events | 2 / 7 | 9 / 14 | 4 / 6 | 23 / 45 | 12 / 44 |
Outcome results
Primary
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.
Time frame: Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)
Population: Dose Limiting Toxicity (DLT) set included all participants who experienced a DLT during Cycle 1, or received at least 80 percent of all planned doses of treatment during Cycle.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity | 0 Participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity | 0 Participants |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity | 0 Participants |
Primary
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.
Time frame: Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 7 Participants |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any Serious TEAE | 2 Participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 14 Participants |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any Serious TEAE | 9 Participants |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 6 Participants |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any Serious TEAE | 4 Participants |
Primary
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).
Time frame: From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years
Population: The modified intent-to treat (mITT) analysis set in the Phase 2 part of this study included all participants with Mesenchymal-epithelial transition (MET)+ hepatocelluar carcinoma (HCC) who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC) | 2.9 Months |
| Phase 1b: Tepotinib 500 mg | Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC) | 1.4 Months |
p-value: 0.008790% CI: [0.28, 0.76]Log Rank
Secondary
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.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib | Day 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib | Day 15 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib | Day 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib | Day 15 | NA 1 per hour |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib | Day 1 | NA 1 per hour |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib | Day 15 | NA 1 per hour |
Secondary
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.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Day 15 | NA Hours |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Day 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Day 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Day 15 | NA Hours |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Day 1 | NA Hours |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib | Day 15 | NA Hours |
Secondary
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).
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | Day 1 | NA liter per hour (L/h) |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | Day 15 | NA liter per hour (L/h) |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | Day 1 | NA liter per hour (L/h) |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | Day 15 | NA liter per hour (L/h) |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | Day 15 | NA liter per hour (L/h) |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib | Day 1 | NA liter per hour (L/h) |
Secondary
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.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose.
| 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 | Day 1 | NA liter |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Day 15 | NA liter |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Day 1 | NA liter |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Day 15 | NA liter |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Day 1 | NA liter |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib | Day 15 | NA liter |
Secondary
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).
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose.
| 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 | Day 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Day 15 | NA Liter |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Day 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Day 15 | NA Liter |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Day 15 | NA Liter |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib | Day 1 | NA Liter |
Secondary
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.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose.
| 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-infinity) of Tepotinib | 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-infinity) of Tepotinib | 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-infinity) of Tepotinib | 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-infinity) of Tepotinib | Day 15 | NA nanogram hour per milliliter (ng*h/mL) |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib | Day 1 | NA nanogram hour per milliliter (ng*h/mL) |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib | Day 15 | NA nanogram hour per milliliter (ng*h/mL) |
Secondary
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.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis set was used. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable at each specified time point.
| 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 the Last Sampling Time (AUC 0-t) of Tepotinib | Day 1 of Cycle 1 | 4700 ng*h/mL | Geometric Coefficient of Variation 12.1 |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib | Day 15 of Cycle 1 | 11800 ng*h/mL | Geometric Coefficient of Variation 35.7 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib | Day 1 of Cycle 1 | 6760 ng*h/mL | Geometric Coefficient of Variation 28 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib | Day 15 of Cycle 1 | 16700 ng*h/mL | Geometric Coefficient of Variation 29.7 |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib | Day 1 of Cycle 1 | 11900 ng*h/mL | Geometric Coefficient of Variation 40.3 |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib | Day 15 of Cycle 1 | 28600 ng*h/mL | Geometric Coefficient of Variation 38.8 |
Secondary
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.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis set was used. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable at each specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib | Day 1 of Cycle 1 | 4700 ng*h/mL | Geometric Coefficient of Variation 12.1 |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib | Day 15 of Cycle 1 | 11800 ng*h/mL | Geometric Coefficient of Variation 35.7 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib | Day 1 of Cycle 1 | 6760 ng*h/mL | Geometric Coefficient of Variation 28 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib | Day 15 of Cycle 1 | 16700 ng*h/mL | Geometric Coefficient of Variation 29.7 |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib | Day 1 of Cycle 1 | 11900 ng*h/mL | Geometric Coefficient of Variation 40.3 |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib | Day 15 of Cycle 1 | 28600 ng*h/mL | Geometric Coefficient of Variation 38.8 |
Secondary
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.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis set was used. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib | 494 ng/mL | Geometric Coefficient of Variation 35.7 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib | 696 ng/mL | Geometric Coefficient of Variation 29.7 |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib | 1190 ng/mL | Geometric Coefficient of Variation 38.8 |
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: 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)
Population: The PK analysis set was used. Here Number Analyzed signifies those participants who were evaluable for specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Day 1 of Cycle 1 | 266 ng/mL | Geometric Coefficient of Variation 24.7 |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Day 15 of Cycle 1 | 585 ng/mL | Geometric Coefficient of Variation 30.8 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Day 1 of Cycle 1 | 394 ng/mL | Geometric Coefficient of Variation 30.4 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Day 15 of Cycle 1 | 815 ng/mL | Geometric Coefficient of Variation 31.6 |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Day 1 of Cycle 1 | 680 ng/mL | Geometric Coefficient of Variation 44 |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Day 15 of Cycle 1 | 1370 ng/mL | Geometric Coefficient of Variation 36.3 |
Secondary
Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib
Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis set was used. Here, Number of participants analyzed signifies those 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 | 398 ng/mL | Geometric Coefficient of Variation 39 |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib | 529 ng/mL | Geometric Coefficient of Variation 43.6 |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib | 1010 ng/mL | Geometric Coefficient of Variation 38.8 |
Secondary
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.
Time frame: Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis set was used. Here Number Analyzed signifies those participants who were evaluable for specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Day 1 of Cycle 1 | 8.00 Hours |
| Phase 1b: Tepotinib 300 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Day 15 of Cycle 1 | 6.00 Hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Day 1 of Cycle 1 | 8.00 Hours |
| Phase 1b: Tepotinib 500 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Day 15 of Cycle 1 | 8.00 Hours |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Day 1 of Cycle 1 | 10.00 Hours |
| Phase 1b: Tepotinib 1000 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib | Day 15 of Cycle 1 | 8.00 Hours |
Secondary
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 frame: Time from randomization until the first occurrence of PD assessed up to 6.9 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator | 15.8 Percentage of participants |
| Phase 1b: Tepotinib 500 mg | Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator | 2.7 Percentage of participants |
p-value: 0.0527Cochran-Mantel-Haenszel
Secondary
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 frame: Time from randomization until the first occurrence of PD assessed up to 6.9 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC | 10.5 Percentage of participants |
| Phase 1b: Tepotinib 500 mg | Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC | 0 Percentage of participants |
p-value: 0.0438Cochran-Mantel-Haenszel
Secondary
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 frame: Time from randomization to the date of death or up to 6.9 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Overall Survival (OS) | 9.3 Months |
| Phase 1b: Tepotinib 500 mg | Phase 2: Overall Survival (OS) | 8.6 Months |
p-value: 0.233390% CI: [0.45, 1.14]Log Rank
Secondary
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.
Time frame: Approximately up to 6.9 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | 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 | 60.5 Percentage of Participants |
| Phase 1b: Tepotinib 500 mg | 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 | 45.9 Percentage of Participants |
Secondary
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 frame: Time from randomization until the first occurrence of PD assessed up to 6.9 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | 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 | 50 Percentage of participants |
| Phase 1b: Tepotinib 500 mg | 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 | 21.6 Percentage of participants |
Secondary
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 frame: Time from randomization to disease progression or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment, assessed up to 6.9 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator | 3.2 Months |
| Phase 1b: Tepotinib 500 mg | Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator | 2.8 Months |
p-value: 0.049690% CI: [0.38, 0.92]Log Rank
Secondary
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.
Time frame: Up to 2.8 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC) | 2.8 Months |
| Phase 1b: Tepotinib 500 mg | Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC) | 1.4 Months |
p-value: 0.022990% CI: [0.33, 0.84]Log Rank
Secondary
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.
Time frame: From randomization to date of the observation of radiological progressive disease, assessed up to maximum 2.8 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator | 5.6 Months |
| Phase 1b: Tepotinib 500 mg | Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator | 2.8 Months |
p-value: 0.005990% CI: [0.28, 0.73]Log Rank
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: Up to 6.9 years
Population: The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. As per planned analysis, data for this outcome was analyzed only for phase 2 based on combined analysis of both FHSI-8 and ECOG.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg | Phase 2: Time-to-Symptomatic Progression (TTSP) | 2.2 Months |
| Phase 1b: Tepotinib 500 mg | Phase 2: Time-to-Symptomatic Progression (TTSP) | 2.7 Months |
p-value: 0.891590% CI: [0.62, 1.77]Log Rank