Subjects will be administered with MSC2156119J 215 mg, 300 mg and 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

MSC2156119J

Medical Responsible

This is a Japanese multicenter, open-label, Phase 1 study to evaluate safety and efficacy of MSC2156119J in subjects with malignant solid tumor which is refractory to standard therapy or to which no effective standard therapy is applicable.

A Japanese Phase 1 Trial of c-Met Inhibitor MSC2156119J in Subjects With Solid Tumors

A Japanese Multicenter, Open Label, Phase I Trial of c-Met Inhibitor MSC2156119J Given Orally as Monotherapy to Subjects With Solid Tumors

DLT: defined using National Cancer Institute Common Toxicity Criteria for Adverse Events 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; Grade 4 or Grade 3 thrombocytopenia with bleeding; \>=Grade 3 nausea despite adequate treatment; \>=Grade 3 any non-hematological AE (DLT defined specifically for following cases: \>=Grade 3 liver adverse event \[AE\] requiring recovery period of more than 7 days or to Grade 1 without liver metastases 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 \>=Grade 2 any AE not otherwise defined as DLT that, due to prolonged recovery to Grade 1 (or less) or baseline status, led to delay of treatment with IMP for more than 21 days.

An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with 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 or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) 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 30 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.

ECOG PS score is widely used by doctors and researchers to assess how a subjects' disease is progressing, and is used to assess how the disease affects the daily living abilities of the subject, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 4, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.

Terminal half-life is the time measured for the plasma concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base 2 (Ln2) divided by elimination rate constant (λz), where 'λz' is calculated by a linear regression of the log-linear concentration-time curve.

AUC(inf) was calculated by combining AUC0-t and AUCextra. AUCextra represented an extrapolated value obtained by Clast/λz, where Clast was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and λz is the terminal elimination rate constant.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. CL/F = Dose/AUC(inf), where AUC(inf) =AUC0-t + AUCextra. AUCextra represented an extrapolated value obtained by Clast/λz, where Clast was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and λz is the terminal elimination rate constant.

Volume of distribution is 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed and is calculated by Dose/(AUC(inf)\*λz).

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) AUC0-t was calculated according to the mixed log-linear trapezoidal rule

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 LLQ. AUC0-t was calculated according to the mixed log-linear trapezoidal rule

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.

Clinical Benefit was defined as CR or PR at any time point or SD at week 12 or later, based on tumor assessment as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). 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. 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. 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.

PFS was defined as the time in months from the first administration of trial treatment until first observation of progressive disease (PD), or death due to any cause when death occurs within 12 weeks of the last tumor assessment or first administration of trial treatment (whichever is later). 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. PFS was planned to be presented for "MSC2156119J Combined" reporting arm.

Merck KGaA, Darmstadt, Germany

Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

MSC2156119J 215 mg

Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

MSC2156119J 300 mg

Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

MSC2156119J 500 mg

Total

Age, Continuous

Sex: Female, Male

Safety analysis set included all subjects who had received at least 1 dose of the investigational medicinal product (IMP).

Merck KGaA Communication Center

Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

DLT analysis set included all subjects who completed Cycle 1 (having received 80% or more of planned cumulative dose of IMP for Cycle 1) or who stopped treatment with IMP during Cycle 1 because of DLT.

Number of Subjects Experiencing Dose Limiting Toxicity (DLT)

TEAEs

Serious TEAEs

TEAEs Leading To Death

Safety analysis set included all subjects who had received at least 1 dose of the IMP.

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs or TEAEs Leading To Death

Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score of 2 or Higher

Pharmacokinetic (PK) analysis set included all subjects who had completed Cycle 1 without any relevant protocol violations with respect to factors that were likely to affect PK results and who received at least first dose of study drug according to protocol providing sufficient concentration time data to determine PK endpoints for the study drug.

Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J

PK analysis set. Here "Number of participants analyzed" signifies those subjects who were evaluable for this outcome at the specified time point for each arm, respectively.

Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J

PK analysis set included all subjects who had completed Cycle 1 without any relevant protocol violations with respect to factors that were likely to affect the PK results and who received at least first dose of study drug according to the protocol providing sufficient concentration time data to determine the PK endpoints for the study drug.

Time to Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J

Time to Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J

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) of MSC2156119J

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 AUCinf.

Area Under the Concentration Time Curve From Time Zero to Extrapolated Infinite Time (AUC[Inf]) of MSC2156119J

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) of MSC2156119J

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 the Vz/f.

Apparent Volume of Distribution Associated To The Terminal Phase (Vz/f) of MSC2156119J

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

MSC2156119J 200 mg

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

Not Evaluable

Number of Subjects With Best Overall Response (BOR)

Number of Subjects With Clinical Benefit

All subjects who were administered with MSC2156119J 215 mg, 300mg or 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

MSC2156119J Combined

Progression-free Survival (PFS)

Subjects were administered with MSC2156119J 215 milligram (mg) orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

Spots Global Cancer Trial Database for A Japanese Phase 1 Trial of c-Met Inhibitor MSC2156119J in Subjects With Solid Tumors

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

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