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

Study Overview
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Brief Summary
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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.

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

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: MSC2156119J


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject with a histologically or cytologically confirmed diagnosis of malignant solid tumor which is refractory to standard therapy or to which no effective standard therapy is applicable An archived tumor tissue is available or biopsy of tumor tissues can be newly performed A Japanese male or female, age greater than or equal to (>=) 20 years A subject who has read the Subject Information Sheet and understood the details of this clinical trial, and is willing and able to give his/her informed consent. A female of child-bearing potential must have a negative blood pregnancy test result at her screening period. A female subject of child-bearing potential must be willing to avoid pregnancy by using an adequate method of contraception Life expectancy is at least 3 months Other inclusion criteria apply Exclusion Criteria: Known Human immunodeficiency virus (HIV) positivity, active hepatitis C, or active hepatitis B Presence of liver fibrosis or liver cirrhosis that has been histologically diagnosed Signs or symptoms that suggest transmissible spongiform encephalopathy Received major surgery within 6 weeks before Day 1 in Cycle 1 Known drug abuse or alcohol abuse Known hypersensitivity to any of the trial treatment ingredients Hematological test abnormalities Renal impairment as defined in the protocol Liver dysfunction as defined in the protocol History or presence of central nervous system metastasis History or presence of disease or condition that may hamper compliance or absorption of the investigational medicinal product (IMP) due to difficulty in swallowing or absorption Poor performance status of Eastern Cooperative Oncology Group Performance status (ECOG PS) >= 2 Received any anti-cancer therapy days Received extensive prior radiotherapy that irradiates more than 30 percent of bone marrow Received any radiotherapy within 4 weeks before Day 1 in Cycle 1 Pregnancy and lactation period History of receiving treatment with any c-Met signaling pathway inhibitor Participation in another interventional clinical trial within the past 30 days from Day 1 in Cycle 1 Other significant disease that in the Investigator's opinion would exclude the subject from the trial Legal incapacity or limited legal capacity Other exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSC2156119J<br> | Drug: MSC2156119J<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Experiencing Dose Limiting Toxicity (DLT) | 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. | Cycle 1 (Day 1 up to 21) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs or TEAEs Leading To Death | 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. | Baseline Up to 30 days after last dose of study drug administration (55.1 weeks) | 
| Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score of 2 or Higher | 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. | Baseline up to 30 days after last dose of study drug administration (55.1 weeks) | 
| Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J |  | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 
| Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J |  | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 
| Time to Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J |  | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 
| Time to Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J |  | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 
| Apparent Terminal Half-life (t1/2) of MSC2156119J | 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. | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1 | 
| Area Under the Concentration Time Curve From Time Zero to Extrapolated Infinite Time (AUC[Inf]) of MSC2156119J | 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. | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1 | 
| Apparent Body Clearance (CL/f) of MSC2156119J | 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. | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1 | 
| Apparent Volume of Distribution Associated To The Terminal Phase (Vz/f) of MSC2156119J | 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). | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1 | 
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time t (AUC0-t) After Single Dose of MSC2156119J | 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 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time t (AUC0-t) After Multiple Dose of MSC2156119J | 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 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 
| Number of Subjects With Best Overall Response (BOR) | 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. | Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks | 
| Number of Subjects With Clinical Benefit | 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. | Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks | 
| Progression-free Survival (PFS) | 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. | Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumors, MSC2156119J, c-Met inhibitor, Japanese, Phase 1