Antineoplastic Agents

All Drugs and Chemicals

Tepotinib

Subjects will be administered with micronized or non-micronized MSC2156119J in dose ranging from 30 mg to 400 mg (capsule formulation) once daily for 14 days, followed by 7 days with no treatment (21-day cycle) in Regimen 1.

Subjects will be administered with micronized or non-micronized MSC2156119J in dose ranging from 60 mg to 315 mg (capsule formulation) once daily 3 times per week for 3 weeks (21-day cycle) in Regimen 2.

Subjects will be administered with micronized MSC2156119J in dose ranging from 300 mg to 1400 mg (capsule or tablet formulation) once daily for 21 days (21-day cycle) in Regimen 3.

MSC2156119J

Medical Responsible

This is a an open-label, dose-escalation, first-in-man (FIM) study designed to explore MSC2156119J, in subjects with advanced solid tumors who have not responded to previous therapies or for whom no other therapies are available.

Subjects will be assigned one of the dosing regimens:

* Regimen 1: MSC2156119J once daily for 14 days, followed by 7 days with no treatment (21-day cycle)
* Regimen 2: MSC2156119J three times per week (e.g., Days 1, 3, and 5) for three weeks (21-day cycle)
* Regimen 3: MSC2156119J every day for three weeks (21-day cycle)

First-in-Man, Dose-escalation Trial of C-met Kinase Inhibitor MSC2156119J in Subjects With Advanced Solid Tumors

A Phase I Open-label, Non-randomized, Dose-escalation First-in-man Trial to Investigate the c-Met Kinase Inhibitor MSC2156119J Under Three Different Regimens in Subjects With Advanced Solid Tumors

DLT was defined as one of the following adverse events (AEs) observed during Cycle1, regardless of MSC2156119J relationship, excluding AEs assessed by investigator exclusively related to subject's underlying disease or medical condition: Grade 4 neutropenia for \>7 days; Grade \>=3 febrile neutropenia for \>1 day; Grade 4 thrombocytopenia/Grade 3 with bleeding; Grade \>=3 nausea and emesis, despite optimal treatment; Grade \>=3 non-hematological AE, except emesis and nausea with no adequate therapy and alopecia, Grade \>= 3 liver AE with a recovery period of \>7 days or to Grade \<=1 for subjects without liver metastases or to \<=2 for subjects with liver metastases; Grade \>=3 lipase and/or amylase rise with pancreatitis confirmation, either based on clinical or radiological signs. Any AE not otherwise defined as a DLT that, due to prolonged recovery to Grade \<=1 or baseline status, leads to delay of above 21 days in planned administration of study drug.

MTD was defined as the dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a DLT. The primary endpoint was to determine MTD of MSC2156119J for each of the 3 treatment regimens in subjects with advanced solid tumors. However, during the course of the trial it was established that the MTD could not be determined and instead, RP2D was to be determined.

Related AE was defined as any untoward medical occurrence which was considered to have a relationship with the study drug (suspected to be reasonably related to the study drug or AE was medically (pharmacologically/clinically) attributed to the study drug as per Investigator's assessment.

AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. 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 up to 33 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs.

Reporting group "MSC2156119J 1200 mg: Fasted" is not applicable for Multiple Dosing because only one subject was erroneously dosed with 1200 mg in fasted state as a single dose in Regimen 3. For multiple dose PK profile (Study Day 14), this subject was included in reporting group "MSC2156119J 1400 mg: Fed".

Apparent Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz.

Apparent terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz.

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the LLQ. AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the LLQ. AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. Reporting group "MSC2156119J 1200 mg: Fasted" is not applicable for Multiple Dosing because only one subject was erroneously dosed with 1200 mg in fasted state as a single dose in Regimen 3. For multiple dose PK profile (Study Day 14), this subject was included in reporting group "MSC2156119J 1400 mg: Fed".

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the LLQ and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf.

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 serum concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz.

Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.

Histo score (H-score) is a composite score that comprises of intensity and percentage of staining and is used for assessing the amount of protein or phospho-protein present in a biopsy sample. The composite score obtained by H-score is derived by summing the percentages of cell staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+; where 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). The composite H-score ranges from 0 to 300, with a score of 0 representing the absence of any of the target protein and an H-score of 300 representing maximum staining and intensity of the target protein.

Histo score (H-score) is a composite score that comprises of intensity and percentage of staining and is used for assessing the amount of protein or phospho-protein present in a biopsy sample. The composite score obtained by H-score is derived by summing the percentages of cell staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+; where 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). The composite H-score ranges from 0 to 300, with a score of 0 representing the absence of any of the target protein and an H-score of 300 representing maximum staining and intensity of the target protein. Fold change = on-treatment value/ baseline value

MetMAb score was used to assess the tumor c-Met expression and ranged from 0 to 3, where a score of 0 corresponds to the lowest c-Met expression and a score of 3 corresponds to the highest c-Met expression in tumor tissue by immunohistochemistry.

The post-baseline nadir was defined as the the smallest SOLD recorded after baseline. The relative change (%) was derived based on the SOLD of target lesions as follows: 100\* (SOLD at post-baseline nadir - baseline SOLD) / baseline SOLD.

Number of subjects with BOR in each category (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) was reported. CR: defined as disappearance of all target and all non-target lesions. 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 sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD:defined as at least a 20% increase in sum of longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter while on study.

PFS was defined as the time (in months) between the first dosing day and radiographic PD or clinical PD (as recorded on the study termination form) or death, if death occurred within 12 weeks (84 days) after the last tumor assessment without documented progressive disease, whichever occurred first. Any subject with neither assessment of tumor progression, nor death within 12 weeks after last tumor assessment date was censored on the date of last tumor assessment.

Merck KGaA, Darmstadt, Germany

EMD Serono

Subjects were administered with micronized or non-micronized MSC2156119J in dose ranging from 30 mg to 400 mg (capsule formulation) once daily for 14 days, followed by 7 days with no treatment (21-day cycle) in Regimen 1.

MSC2156119J Regimen 1

Subjects were administered with micronized or non-micronized MSC2156119J in dose ranging from 60 mg to 315 mg (capsule formulation) once daily 3 times per week for 3 weeks (21-day cycle) in Regimen 2.

MSC2156119J Regimen 2

Subjects were administered with micronized MSC2156119J in dose ranging from 300 mg to 1400 mg (capsule or tablet formulation) once daily for 21 days (21-day cycle) in Regimen 3.

MSC2156119J Regimen 3

Total

Age, Continuous

Sex: Female, Male

Safety set included all subjects who had received at least 1 dose of MSC2156119J treatment.

It was not possible to calculate data for PK parameters such as t1/2, AUC0-inf, CL/f, Vz/f, λz because dosing interval was too small compared to the long half-life to characterize terminal phase rate constant, which is needed for the calculation.

Merck KGaA Communication Center

DLT analysis set comprised of subjects who had either completed Cycle 1 or had stopped treatment because of a DLT during Cycle 1.

Number of Subjects With Any Dose Limiting Toxicity (DLT)

All subjects who were administered with micronized or non-micronized MSC2156119J (capsule or tablet formulation) in any of the three regimens.

MSC2156119J Combined

Recommended Phase 2 Dose (RP2D)

Number of Subjects With Treatment-Related Adverse Events

TEAEs

Serious TEAEs

TEAEs Leading to Discontinuation

TEAEs Leading To Death

Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death

Subjects were administered with micronized MSC2156119J 30 mg (capsule formulation) with food.

MSC2156119J 30 mg: Fed

Subjects were administered with micronized MSC2156119J 60 mg (capsule formulation) with food.

MSC2156119J 60 mg: Fed

Subjects were administered with micronized MSC2156119J 100 mg (capsule formulation) with food.

MSC2156119J 100 mg: Fed

Subjects were administered with micronized MSC2156119J 145 mg (capsule formulation) with food.

MSC2156119J 145 mg: Fed

Subjects were administered with micronized MSC2156119J 215 mg (capsule formulation) with food.

MSC2156119J 215 mg: Fed

Subjects were administered with micronized MSC2156119J 300 mg (capsule formulation) with food.

MSC2156119J 300 mg: Fed

Subjects were administered with micronized MSC2156119J 400 mg (capsule formulation) with food.

MSC2156119J 400 mg: Fed

Subjects were administered with non-micronized MSC2156119J 30 mg (capsule formulation) in the fasted state.

MSC2156119J 30 mg: Fasted

Subjects were administered with non-micronized MSC2156119J 60 mg (capsule formulation) in the fasted state.

MSC2156119J 60 mg: Fasted

Subjects were administered with non-micronized MSC2156119J 115 mg (capsule formulation) in the fasted state.

MSC2156119J 115 mg: Fasted

Subjects were administered with non-micronized MSC2156119J 115 mg (capsule formulation) with food.

MSC2156119J 115 mg: Fed

Subjects were administered with non-micronized MSC2156119J 230 mg (capsule formulation) in the fasted state.

MSC2156119J 230 mg: Fasted

Pharmacokinetic (PK) analysis set included all subjects who had received at least 1 dose of MSC2156119J and who had provided at least 1 concentration of MSC2156119J measurement after the first dose.

Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1

Subjects were administered with micronized MSC2156119J 130 mg (capsule formulation) with food.

MSC2156119J 130 mg: Fed

Subjects were administered with micronized MSC2156119J 175 mg (capsule formulation) with food.

MSC2156119J 175 mg: Fed

Subjects were administered with micronized MSC2156119J 315 mg (capsule formulation) with food.

MSC2156119J 315 mg: Fed

PK analysis set included all subjects who had received at least 1 dose of MSC2156119J and who had provided at least 1 concentration of MSC2156119J measurement after the first dose.

Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2

Subjects were administered with micronized MSC2156119J 500 mg (capsule formulation) in the fasted state.

MSC2156119J 500 mg: Fasted

Subjects were administered with micronized MSC2156119J 500 mg (capsule formulation) with food.

MSC2156119J 500 mg: Fed

Subjects were administered with micronized MSC2156119J 700 mg (capsule formulation) with food.

MSC2156119J 700 mg: Fed

Subjects were administered with micronized MSC2156119J 1000 mg (capsule formulation) with food.

MSC2156119J 1000 mg: Fed

Subjects were administered with micronized MSC2156119J 1200 mg (capsule formulation) in the fasted state.

MSC2156119J 1200 mg: Fasted

Subjects were administered with micronized MSC2156119J 1400 mg (capsule formulation) with food.

MSC2156119J 1400 mg: Fed

Subjects were administered with micronized MSC2156119J 500 mg (tablet formulation) with food.

MSC2156119J 500 mg: Fed (Tablet)

Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3

PK analysis set included all subjects who had received at least 1 dose of MSC2156119J and who had provided at least 1 concentration of MSC2156119J measurement after the first dose. Here, "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure.

Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1

Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2

Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3

Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1

Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2

MSC2156119J 500 mg Fed (Tablet)

Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3

Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1

MSC2156119J 130 mg Fed

PK analysis set included all subjects who had received at least 1 dose of MSC2156119J and who had provided at least 1 concentration of MSC2156119J measurement after the first dose. Here, "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure

Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2

Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3

Subjects were administered with non-micronized MSC2156119J 30 mg (capsule formulation) in the fasted state

It was not possible to calculate data for this outcome measure because dosing interval was too small compared to the long half-life to characterize the terminal phase rate constant, which is needed for the calculation of t1/2.

Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 1

Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 2

Subjects were administered with micronized MSC2156119J 300 mg with food.

MSC2156119J 300 mg Fed

Subjects were administered with micronized MSC2156119J 500 mg in the fasted state.

MSC2156119J 500 mg Fasted

Subjects were administered with micronized MSC2156119J 500 mg with food.

MSC2156119J 500 mg Fed

Subjects were administered with micronized MSC2156119J 700 mg with food.

MSC2156119J 700 mg Fed

Subjects were administered with micronized MSC2156119J 1000 mg with food.

MSC2156119J 1000 mg Fed

Subjects were administered with micronized MSC2156119J 1200 mg in the fasted state.

MSC2156119J 1200 mg Fasted

Subjects were administered with micronized MSC2156119J 1400 mg with food.

MSC2156119J 1400 mg Fed

Subjects were administered with micronized MSC2156119J 500 mg (tablet) with food.

Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 3

Subjects were administered with micronized MSC2156119J 30 mg (capsule formulation) with food

Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 1

Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 2

Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 3

Subjects were administered with non-micronized MSC2156119J 60 mg in the fasted state.

MSC2156119J 60 mg Fasted

Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1

Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 2

Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 3

Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 1

Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 2

Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 3

MSC2156119J 145 mg Fed

Subjects were administered with micronized MSC2156119J 215 mg with food.

MSC2156119J 215 mg Fed

MSC2156119J 400 mg Fed

MSC2156119J 115 mg Fasted

It was not possible to calculate data for this outcome measure because dosing interval was too small compared to the long half-life to characterize the terminal phase rate constant, which is needed for the calculation of AUC0-inf.

Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 1

Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 2

Subjects were administered with micronized MSC2156119J 300 mg with food

Subjects were administered with micronized MSC2156119J 500 mg with food

Subjects were administered with micronized MSC2156119J 500 mg (Tablet) with food.

Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 3

Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1

PK analysis set included all subjects who had received at least 1 dose of MSC2156119J and who had provided at least 1 concentration of MSC2156119J measurement after the first dose. Here, "Number Participants Analyzed" signifies those subjects who were evaluable for this outcome measure.

Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2

Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3

Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1

Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2

Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3

It was not possible to calculate data for this outcome measure because dosing interval was too small compared to the long half-life to characterize the terminal phase rate constant, which is needed for the calculation of CL/f.

Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 1

Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 2

Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 3

It was not possible to calculate data for this outcome measure because dosing interval was too small compared to the long half-life to characterize the terminal phase rate constant, which is needed for the calculation of Vz/f.

Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 1

Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 2

Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 3

Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 1

Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 2

Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 3

It was not possible to calculate data for this outcome measure because dosing interval was too small compared to the long half-life to characterize the terminal phase rate constant.

Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 1

MSC2156119J 115 mg Fed

Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 2

Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 3

Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 1

Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 2

Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 3

Cytoplasm H-Score

Membrane H-Score

Safety set included all subjects who had received at least 1 dose of MSC2156119J treatment. Here, "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure.

Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2

Cytoplasm H-Score (n=16, 17, 30)

Membrane H-Score (n= 0, 4, 5)

Safety set included all subjects who had received at least 1 dose of MSC2156119J treatment. Here "Number of Participants analyzed" signifies those subjects who were evaluable for this outcome and "n" signifies those subjects who were evaluable in the specified category for each arm, respectively.

Spots Global Cancer Trial Database for First-in-Man, Dose-escalation Trial of C-met Kinase Inhibitor MSC2156119J in Subjects With Advanced Solid Tumors

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