Patients With Solid Tumors, Either Refractory to Standard Therapy or for Which no Effective Standard Therapy is Available
Conditions
Keywords
Phase 1, advanced solid tumors, refractory to standard therapy
Brief summary
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)
Interventions
DRUGMSC2156119J
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject should read and fully understand the requirements of the trial, be willing to comply with all trial visits and assessments, and be willing and able to give informed consent 2. Histologically or cytologically confirmed solid tumor, either refractory to standard therapy or for which no effective standard therapy is available 3. Measurable or evaluable disease, as defined by RECIST 1.0 4. Estimated life expectancy greater than (\>) three months 5. Men or women aged greater than or equal to (\>=) 18 years 6. Women of childbearing potential must have a negative blood pregnancy test at the Screening Visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are post-menopausal for at least 12 months, are surgically sterile, or are sexually inactive. 7. Subjects and their partners must be willing to avoid pregnancy during the trial and until three months after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator, such as a two-barrier method or one-barrier method with spermicide or intrauterine device. This requirement begins two weeks before receiving the first trial treatment and ends one month after receiving the last treatment. 8. ECOG performance status of 0 to 2 9. Adequate hematological function: * Hemoglobin \>= 9.0 g/dL * Neutrophils \> 1.5 x 109/L * Platelets \>= 75 x 109/L 10. Adequate liver function: * Total bilirubin less than or equal to (\<=) 1.5 x ULN (upper limit to normal) * AST/ ALT ≤ 2.5 x ULN For subjects with liver metastases: * Total bilirubin ≤ 1.5 x ULN * AST/ ALT ≤ 5 x ULN 11. Adequate renal function: * Serum creatinine \< 1.5 x ULN, and/or * Calculated creatinine clearance \> 60 mL/min 12. Resolution of all acute chemotherapy, radiotherapy or surgery-related AEs to Grade \<= 2, except for alopecia 13. Recovery from any surgical intervention 14. Subjects enrolling after the MTD has been determined must present specific c Met alterations (mutation, overexpression, amplification
Exclusion criteria
1. Received chemotherapy, immunotherapy, hormonal therapy (except subjects with prostate cancer), biologic therapy, or any other investigational agent or anticancer therapy within 28 days (or five half-lives for non-cytotoxics, whichever is shorter), of Day 1 of trial treatment (six weeks for nitrosureas or mitomycin C) 2. Received extensive prior radiotherapy on more than 30% of bone marrow 3. Symptomatic primary tumors or metastasis of brain and/or central nervous system, uncontrolled with antiepileptics and requiring high doses of steroids 4. Known HIV positivity, active hepatitis C, or active hepatitis B 5. Medical history of liver fibrosis/ cirrhosis 6. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such 7. Medical history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product 8. Medical history of surgery within six weeks prior to enrollment 9. Impaired cardiac function (left ventricular ejection fraction \< 45% defined by echocardiograph, serious arrhythmia, unstable angina pectoris, congestive heart failure NYHA III and IV, myocardial infarction within the last 12 months prior to trial entry; signs of pericardial effusion) 10. Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mm Hg) 11. Peripheral neuropathy Grade \>= 2 12. Medical history of any other significant medical disease, major surgery, or psychiatric condition that might impair the subject's well being or preclude full participation in the trial 13. Women who are pregnant or nursing 14. Known drug abuse or alcohol abuse 15. Participation in another clinical trial within the past 28 days 16. Requires concurrent treatment with a non-permitted drug 17. Known hypersensitivity to any of the trial treatment ingredients 18. Legal incapacity or limited legal capacity 19. Any other reason that, in the opinion of the principal investigator, precludes the subject from participating in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Any Dose Limiting Toxicity (DLT) | Day 1, 3, 8, 14, 17 of Cycle 1 (for Regimen 1 and 3); Day 1, 3, 8, 15, 19 of Cycle 1 (for Regimen 2) | 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. |
| Recommended Phase 2 Dose (RP2D) | Cycle 1 (Day 1 to Day 21) | 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. |
| Number of Subjects With Treatment-Related Adverse Events | Baseline up to 158.01 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | — |
| Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | — |
| Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1 | — |
| Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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. |
| Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 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 Single Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48, 49.32 hours post-dose on Day 1 Cycle 1 | — |
| Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 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: Regimen 1 | 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 Multiple Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1 | — |
| Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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 ( t1/2) After Single Dose Of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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 ( t1/2) After Single Dose Of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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 ( t1/2) After Single Dose Of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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 (t1/2) After Multiple Dose Of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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 (t1/2) After Multiple Dose Of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1 | 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 (t1/2) After Multiple Dose Of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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 Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 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 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 Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 2 | 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 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 Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 3 | 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 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 Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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 Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1 | 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 Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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. |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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. |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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. |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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. |
| Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | — |
| Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 hours post-dose on Day 1 Cycle 1 | — |
| Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | — |
| Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | — |
| Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 hours post-dose on Day 19 Cycle 1 | — |
| Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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 Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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. |
| Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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. |
| Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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. |
| Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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 Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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 Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | 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 Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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 Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1 | 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 Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | 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 (λz) After Single Dose of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1 | Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 3 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1 | Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Baseline, Day 1 Cycle 2 | 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. |
| Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Baseline up to 158.01 weeks | 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. |
| Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | Day 1 Cycle 2 | 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. |
| Relative Percentage Change In Sum of Longest Diameter (SOLD) of Target Lesions to Post-Baseline Nadir | Baseline, On Treatment (up to 153.3 weeks) | 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 Best Overall Response (BOR) | Baseline up to 153.3 weeks | 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. |
| Progression-free Survival (PFS) | Baseline up to 153.3 weeks | 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. |
| Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Baseline, Day 1 Cycle 2 | 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 |
| Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | — |
| Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 | — |
Countries
United States
Participant flow
Pre-assignment details
First/last subject (informed consent): November 2009/December 2014. Last subject completed: October 2015. Clinical data cut-off: February 2016
Participants by arm
| Arm | Count |
|---|---|
| MSC2156119J Regimen 1 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. | 42 |
| MSC2156119J Regimen 2 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. | 45 |
| MSC2156119J Regimen 3 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. | 62 |
| Total | 149 |
Baseline characteristics
| Characteristic | MSC2156119J Regimen 1 | MSC2156119J Regimen 2 | MSC2156119J Regimen 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 59.97 years STANDARD_DEVIATION 13.496 | 59.29 years STANDARD_DEVIATION 14.656 | 56.49 years STANDARD_DEVIATION 13.986 | 58.32 years STANDARD_DEVIATION 14.05 |
| Sex: Female, Male Female | 18 Participants | 23 Participants | 25 Participants | 66 Participants |
| Sex: Female, Male Male | 24 Participants | 22 Participants | 37 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 41 / 42 | 45 / 45 | 59 / 62 |
| serious Total, serious adverse events | 14 / 42 | 17 / 45 | 22 / 62 |
Outcome results
Primary
Number of Subjects With Any Dose Limiting Toxicity (DLT)
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.
Time frame: Day 1, 3, 8, 14, 17 of Cycle 1 (for Regimen 1 and 3); Day 1, 3, 8, 15, 19 of Cycle 1 (for Regimen 2)
Population: DLT analysis set comprised of subjects who had either completed Cycle 1 or had stopped treatment because of a DLT during Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSC2156119J Regimen 1 | Number of Subjects With Any Dose Limiting Toxicity (DLT) | 1 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Any Dose Limiting Toxicity (DLT) | 3 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Any Dose Limiting Toxicity (DLT) | 2 subjects |
Primary
Number of Subjects With Treatment-Related Adverse Events
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.
Time frame: Baseline up to 158.01 weeks
Population: Safety set included all subjects who had received at least 1 dose of MSC2156119J treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSC2156119J Regimen 1 | Number of Subjects With Treatment-Related Adverse Events | 14 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Treatment-Related Adverse Events | 23 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Treatment-Related Adverse Events | 39 subjects |
Primary
Recommended Phase 2 Dose (RP2D)
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.
Time frame: Cycle 1 (Day 1 to Day 21)
Population: DLT analysis set comprised of subjects who had either completed Cycle 1 or had stopped treatment because of a DLT during Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSC2156119J Regimen 1 | Recommended Phase 2 Dose (RP2D) | 500 milligram |
Secondary
Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2
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.
Time frame: Baseline, Day 1 Cycle 2
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MSC2156119J Regimen 1 | Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Cytoplasm H-Score | -12.94 units on a scale | Standard Deviation 84.614 |
| MSC2156119J Regimen 1 | Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Membrane H-Score | 3.53 units on a scale | Standard Deviation 123.184 |
| MSC2156119J Regimen 2 | Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Cytoplasm H-Score | -31.43 units on a scale | Standard Deviation 92.967 |
| MSC2156119J Regimen 2 | Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Membrane H-Score | 28.10 units on a scale | Standard Deviation 75.407 |
| MSC2156119J Regimen 3 | Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Cytoplasm H-Score | 5.00 units on a scale | Standard Deviation 72.513 |
| MSC2156119J Regimen 3 | Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Membrane H-Score | -10.00 units on a scale | Standard Deviation 75.818 |
Secondary
Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 1
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 2
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 1
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
Secondary
Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 2
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
Population: 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.
Secondary
Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
Secondary
Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 1
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 2
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 1
Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
Secondary
Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 2
Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
Population: 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.
Secondary
Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 3
Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
Secondary
Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 1
Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 2
Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 3
Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 1
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 2
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 1
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
Secondary
Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 2
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
Population: 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.
Secondary
Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
Secondary
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 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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 849.4 h*ng/mL | Geometric Coefficient of Variation 24.5 |
| MSC2156119J Regimen 2 | Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 1283.0 h*ng/mL | Geometric Coefficient of Variation 23.9 |
| MSC2156119J Regimen 3 | Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 1433.5 h*ng/mL | Geometric Coefficient of Variation 35.5 |
| MSC2156119J 145 mg: Fed | Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 2532.7 h*ng/mL | Geometric Coefficient of Variation 12.6 |
| MSC2156119J 215 mg: Fed | Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 3105.5 h*ng/mL | Geometric Coefficient of Variation 60.3 |
| MSC2156119J 300 mg: Fed | Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 5467.9 h*ng/mL | Geometric Coefficient of Variation 49.9 |
| MSC2156119J 400 mg: Fed | Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 6176.3 h*ng/mL | Geometric Coefficient of Variation 17.8 |
| MSC2156119J 30 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 | 41.6 h*ng/mL | Geometric Coefficient of Variation 288.7 |
| 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 | 218.8 h*ng/mL | Geometric Coefficient of Variation 38.5 |
| MSC2156119J 115 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 | 215.0 h*ng/mL | Geometric Coefficient of Variation 163.5 |
| MSC2156119J 115 mg: Fed | Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 | 225.6 h*ng/mL | Geometric Coefficient of Variation 88.7 |
| MSC2156119J 230 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 | 516.5 h*ng/mL | Geometric Coefficient of Variation 74.3 |
Secondary
Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 2266.7 h*ng/mL | Geometric Coefficient of Variation 29.5 |
| MSC2156119J Regimen 2 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 4443.1 h*ng/mL | Geometric Coefficient of Variation 28.1 |
| MSC2156119J Regimen 3 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 5499.6 h*ng/mL | Geometric Coefficient of Variation 7 |
| MSC2156119J 145 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 8099.6 h*ng/mL | Geometric Coefficient of Variation 18 |
| MSC2156119J 215 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 13938.4 h*ng/mL | Geometric Coefficient of Variation 50.9 |
| MSC2156119J 300 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 18276.5 h*ng/mL | Geometric Coefficient of Variation 12.4 |
| MSC2156119J 400 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 12256.8 h*ng/mL | Geometric Coefficient of Variation 49.1 |
| MSC2156119J 30 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 585.3 h*ng/mL | Geometric Coefficient of Variation 158.4 |
| MSC2156119J 60 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 1241.2 h*ng/mL | Geometric Coefficient of Variation 132.2 |
| MSC2156119J 115 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 1011.1 h*ng/mL | Geometric Coefficient of Variation 110.3 |
| MSC2156119J 115 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 1434.2 h*ng/mL | Geometric Coefficient of Variation 14.3 |
| MSC2156119J 230 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 | 4658.2 h*ng/mL | Geometric Coefficient of Variation 52.4 |
Secondary
Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 hours post-dose on Day 19 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 3031.7 h*ng/mL | Geometric Coefficient of Variation 55.8 |
| MSC2156119J Regimen 2 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 7565.6 h*ng/mL | Geometric Coefficient of Variation 35 |
| MSC2156119J Regimen 3 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 5305.5 h*ng/mL | Geometric Coefficient of Variation 62.6 |
| MSC2156119J 145 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 9051.1 h*ng/mL | — |
| MSC2156119J 215 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 27760.2 h*ng/mL | Geometric Coefficient of Variation 25.1 |
| MSC2156119J 300 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 273.7 h*ng/mL | Geometric Coefficient of Variation 909 |
| MSC2156119J 400 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 2054.1 h*ng/mL | Geometric Coefficient of Variation 33.3 |
| MSC2156119J 30 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 1634.4 h*ng/mL | Geometric Coefficient of Variation 103.5 |
| MSC2156119J 60 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 | 3538.9 h*ng/mL | Geometric Coefficient of Variation 64.9 |
Secondary
Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 | 15597.6 h*ng/mL | Geometric Coefficient of Variation 50 |
| MSC2156119J Regimen 2 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 | 17498.1 h*ng/mL | — |
| MSC2156119J Regimen 3 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 | 20169.3 h*ng/mL | Geometric Coefficient of Variation 33.5 |
| MSC2156119J 145 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 | 21972.2 h*ng/mL | Geometric Coefficient of Variation 42.9 |
| MSC2156119J 215 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 | 27214.4 h*ng/mL | Geometric Coefficient of Variation 59.4 |
| MSC2156119J 300 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 | 39283.7 h*ng/mL | Geometric Coefficient of Variation 28 |
| MSC2156119J 400 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 | 27437.7 h*ng/mL | Geometric Coefficient of Variation 51.7 |
Secondary
Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 848.7 h*ng/mL | Geometric Coefficient of Variation 24.3 |
| MSC2156119J Regimen 2 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 1283.0 h*ng/mL | Geometric Coefficient of Variation 23.9 |
| MSC2156119J Regimen 3 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 1731.3 h*ng/mL | Geometric Coefficient of Variation 14.9 |
| MSC2156119J 145 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 2454.5 h*ng/mL | Geometric Coefficient of Variation 15.4 |
| MSC2156119J 215 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 3090.2 h*ng/mL | Geometric Coefficient of Variation 61.2 |
| MSC2156119J 300 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 5462.8 h*ng/mL | Geometric Coefficient of Variation 49.9 |
| MSC2156119J 400 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 6176.3 h*ng/mL | Geometric Coefficient of Variation 17.8 |
| MSC2156119J 30 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 94.0 h*ng/mL | Geometric Coefficient of Variation 66.2 |
| MSC2156119J 60 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 218.8 h*ng/mL | Geometric Coefficient of Variation 38.5 |
| MSC2156119J 115 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 259.3 h*ng/mL | Geometric Coefficient of Variation 170.5 |
| MSC2156119J 115 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 220.6 h*ng/mL | Geometric Coefficient of Variation 93.4 |
| MSC2156119J 230 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 | 515.3 h*ng/mL | Geometric Coefficient of Variation 74.4 |
Secondary
Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 1771.5 h*ng/mL | Geometric Coefficient of Variation 43.1 |
| MSC2156119J Regimen 2 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 3657.3 h*ng/mL | Geometric Coefficient of Variation 42 |
| MSC2156119J Regimen 3 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 3794.2 h*ng/mL | Geometric Coefficient of Variation 32.1 |
| MSC2156119J 145 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 4659.6 h*ng/mL | Geometric Coefficient of Variation 44.9 |
| MSC2156119J 215 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 10786.4 h*ng/mL | Geometric Coefficient of Variation 49.4 |
| MSC2156119J 300 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 206.9 h*ng/mL | Geometric Coefficient of Variation 92.6 |
| MSC2156119J 400 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 306.1 h*ng/mL | Geometric Coefficient of Variation 33.9 |
| MSC2156119J 30 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 626.0 h*ng/mL | Geometric Coefficient of Variation 96.5 |
| MSC2156119J 60 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 | 1317.0 h*ng/mL | Geometric Coefficient of Variation 58.3 |
Secondary
Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | 4206.5 h*ng/mL | Geometric Coefficient of Variation 33.5 |
| MSC2156119J Regimen 2 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | NA h*ng/mL | — |
| MSC2156119J Regimen 3 | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | 5917.9 h*ng/mL | Geometric Coefficient of Variation 74.8 |
| MSC2156119J 145 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | 7575.8 h*ng/mL | Geometric Coefficient of Variation 24.6 |
| MSC2156119J 215 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | 11796.4 h*ng/mL | Geometric Coefficient of Variation 48.1 |
| MSC2156119J 300 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | NA h*ng/mL | — |
| MSC2156119J 400 mg: Fed | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | 15542.0 h*ng/mL | Geometric Coefficient of Variation 41.9 |
| MSC2156119J 30 mg: Fasted | Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 | 7637.3 h*ng/mL | Geometric Coefficient of Variation 66.7 |
Secondary
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 1
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 2
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
Secondary
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 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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 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 | 1771.5 h*ng/mL | Geometric Coefficient of Variation 43.1 |
| 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 2 | 3665.3 h*ng/mL | Geometric Coefficient of Variation 41.9 |
| MSC2156119J Regimen 3 | 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 | 3794.2 h*ng/mL | Geometric Coefficient of Variation 32.1 |
| MSC2156119J 145 mg: Fed | 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 | 4659.6 h*ng/mL | Geometric Coefficient of Variation 44.9 |
| MSC2156119J 215 mg: Fed | 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 | 10818.0 h*ng/mL | Geometric Coefficient of Variation 48.9 |
| MSC2156119J 300 mg: Fed | 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 | 206.9 h*ng/mL | Geometric Coefficient of Variation 92.6 |
| MSC2156119J 400 mg: Fed | 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 | 310.5 h*ng/mL | Geometric Coefficient of Variation 27.6 |
| MSC2156119J 30 mg: Fasted | 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 | 745.3 h*ng/mL | Geometric Coefficient of Variation 130.8 |
| MSC2156119J 60 mg: Fasted | 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 | 1323.5 h*ng/mL | Geometric Coefficient of Variation 57.3 |
Secondary
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 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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 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 3 | 4209.3 h*ng/mL | Geometric Coefficient of Variation 33.4 |
| 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 | 3190.8 h*ng/mL | — |
| MSC2156119J Regimen 3 | 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 | 5667.3 h*ng/mL | Geometric Coefficient of Variation 76.1 |
| MSC2156119J 145 mg: Fed | 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 | 4980.9 h*ng/mL | Geometric Coefficient of Variation 86.3 |
| MSC2156119J 215 mg: Fed | 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 | 10355.6 h*ng/mL | Geometric Coefficient of Variation 59.6 |
| MSC2156119J 300 mg: Fed | 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 | 13352.6 h*ng/mL | — |
| MSC2156119J 400 mg: Fed | 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 | 15542.0 h*ng/mL | Geometric Coefficient of Variation 41.9 |
| MSC2156119J 30 mg: Fasted | 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 | 7661.8 h*ng/mL | Geometric Coefficient of Variation 66.7 |
Secondary
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 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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 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 1 | 7532.7 h*ng/mL | Geometric Coefficient of Variation 19.1 |
| 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 1 | 14113.2 h*ng/mL | Geometric Coefficient of Variation 32.1 |
| 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 | 18334.0 h*ng/mL | Geometric Coefficient of Variation 19.4 |
| MSC2156119J 145 mg: Fed | 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 | 18409.6 h*ng/mL | Geometric Coefficient of Variation 14.3 |
| MSC2156119J 215 mg: Fed | 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 | 56102.4 h*ng/mL | Geometric Coefficient of Variation 73.7 |
| MSC2156119J 300 mg: Fed | 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 | 82253.4 h*ng/mL | Geometric Coefficient of Variation 10.1 |
| MSC2156119J 400 mg: Fed | 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 | 44598.2 h*ng/mL | Geometric Coefficient of Variation 80.7 |
| MSC2156119J 30 mg: Fasted | 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 | 2008.0 h*ng/mL | Geometric Coefficient of Variation 344 |
| MSC2156119J 60 mg: Fasted | 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 | 4483.4 h*ng/mL | Geometric Coefficient of Variation 284.9 |
| MSC2156119J 115 mg: Fasted | 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 | 3555.4 h*ng/mL | Geometric Coefficient of Variation 116.3 |
| MSC2156119J 115 mg: Fed | 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 | 4234.1 h*ng/mL | Geometric Coefficient of Variation 40.3 |
| MSC2156119J 230 mg: Fasted | 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 | 13872.2 h*ng/mL | Geometric Coefficient of Variation 62.3 |
Secondary
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 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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 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 | 4079.6 h*ng/mL | Geometric Coefficient of Variation 71.1 |
| 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 2 | 5079.7 h*ng/mL | Geometric Coefficient of Variation 116 |
| 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 2 | 4962.0 h*ng/mL | Geometric Coefficient of Variation 33.3 |
| MSC2156119J 145 mg: Fed | 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 | 7963.8 h*ng/mL | Geometric Coefficient of Variation 34 |
| MSC2156119J 215 mg: Fed | 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 | 36701.1 h*ng/mL | Geometric Coefficient of Variation 26.1 |
| MSC2156119J 300 mg: Fed | 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 | 375.2 h*ng/mL | Geometric Coefficient of Variation 278.2 |
| MSC2156119J 400 mg: Fed | 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 | 2056.6 h*ng/mL | Geometric Coefficient of Variation 31.4 |
| MSC2156119J 30 mg: Fasted | 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 | 2562.0 h*ng/mL | Geometric Coefficient of Variation 78.9 |
| MSC2156119J 60 mg: Fasted | 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 | 2899.0 h*ng/mL | Geometric Coefficient of Variation 132.4 |
Secondary
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
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 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 3 | 15694.9 h*ng/mL | Geometric Coefficient of Variation 50.8 |
| 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 | 17498.1 h*ng/mL | — |
| 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 3 | 20210.4 h*ng/mL | Geometric Coefficient of Variation 33.5 |
| MSC2156119J 145 mg: Fed | 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 | 17107.8 h*ng/mL | Geometric Coefficient of Variation 3.2 |
| MSC2156119J 215 mg: Fed | 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 | 27716.9 h*ng/mL | Geometric Coefficient of Variation 58.6 |
| MSC2156119J 300 mg: Fed | 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 | 39730.6 h*ng/mL | Geometric Coefficient of Variation 29.5 |
| MSC2156119J 400 mg: Fed | 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 | 18915.7 h*ng/mL | Geometric Coefficient of Variation 87.5 |
Secondary
Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2
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
Time frame: Baseline, Day 1 Cycle 2
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MSC2156119J Regimen 1 | Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Cytoplasm H-Score (n=16, 17, 30) | 1.05 fold change | Standard Deviation 0.577 |
| MSC2156119J Regimen 1 | Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Membrane H-Score (n= 0, 4, 5) | NA fold change | — |
| MSC2156119J Regimen 2 | Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Cytoplasm H-Score (n=16, 17, 30) | 1.09 fold change | Standard Deviation 0.57 |
| MSC2156119J Regimen 2 | Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Membrane H-Score (n= 0, 4, 5) | 1.29 fold change | Standard Deviation 0.934 |
| MSC2156119J Regimen 3 | Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Cytoplasm H-Score (n=16, 17, 30) | 1.12 fold change | Standard Deviation 0.551 |
| MSC2156119J Regimen 3 | Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 | Membrane H-Score (n= 0, 4, 5) | 1.23 fold change | Standard Deviation 0.541 |
Secondary
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.
Time frame: Baseline up to 153.3 weeks
Population: Safety set included all subjects who had received at least 1 dose of MSC2156119J treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MSC2156119J Regimen 1 | Number of Subjects With Best Overall Response (BOR) | PD | 25 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Best Overall Response (BOR) | SD | 12 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Best Overall Response (BOR) | CR | 0 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Best Overall Response (BOR) | PR | 0 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Best Overall Response (BOR) | Not evaluable | 5 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Best Overall Response (BOR) | SD | 10 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Best Overall Response (BOR) | CR | 0 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Best Overall Response (BOR) | PR | 0 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Best Overall Response (BOR) | PD | 27 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Best Overall Response (BOR) | Not evaluable | 8 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Best Overall Response (BOR) | Not evaluable | 10 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Best Overall Response (BOR) | PD | 38 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Best Overall Response (BOR) | CR | 0 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Best Overall Response (BOR) | SD | 12 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Best Overall Response (BOR) | PR | 2 subjects |
Secondary
Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS)
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.
Time frame: Day 1 Cycle 2
Population: Safety set included all subjects who had received at least 1 dose of MSC2156119J treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MSC2156119J Regimen 1 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 3 | 2 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 2 | 4 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 0 | 3 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 1 | 9 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score Missing | 24 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 2 | 10 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 0 | 5 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 1 | 7 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 3 | 2 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score Missing | 21 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score Missing | 27 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 3 | 8 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 0 | 1 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 2 | 14 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) | MMS Score 1 | 12 subjects |
Secondary
Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death
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.
Time frame: Baseline up to 158.01 weeks
Population: Safety set included all subjects who had received at least 1 dose of MSC2156119J treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MSC2156119J Regimen 1 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs | 41 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Serious TEAEs | 14 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading to Discontinuation | 3 subjects |
| MSC2156119J Regimen 1 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading To Death | 0 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading To Death | 0 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs | 45 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading to Discontinuation | 4 subjects |
| MSC2156119J Regimen 2 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Serious TEAEs | 17 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading To Death | 1 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Serious TEAEs | 22 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading to Discontinuation | 13 subjects |
| MSC2156119J Regimen 3 | Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs | 59 subjects |
Secondary
Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 112.6 ng/mL | Geometric Coefficient of Variation 26.1 |
| MSC2156119J Regimen 2 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 204.6 ng/mL | Geometric Coefficient of Variation 24.2 |
| MSC2156119J Regimen 3 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 262.8 ng/mL | Geometric Coefficient of Variation 10.2 |
| MSC2156119J 145 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 379.3 ng/mL | Geometric Coefficient of Variation 19.8 |
| MSC2156119J 215 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 697.2 ng/mL | Geometric Coefficient of Variation 49.8 |
| MSC2156119J 300 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 810.9 ng/mL | Geometric Coefficient of Variation 12.3 |
| MSC2156119J 400 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 562.5 ng/mL | Geometric Coefficient of Variation 45 |
| MSC2156119J 30 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 28.54 ng/mL | Geometric Coefficient of Variation 181.7 |
| MSC2156119J 60 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 59.76 ng/mL | Geometric Coefficient of Variation 110 |
| MSC2156119J 115 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 48.33 ng/mL | Geometric Coefficient of Variation 102.8 |
| MSC2156119J 115 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 155.6 ng/mL | Geometric Coefficient of Variation 249.6 |
| MSC2156119J 230 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 | 210.1 ng/mL | Geometric Coefficient of Variation 54.8 |
Secondary
Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 88.55 ng/mL | Geometric Coefficient of Variation 53 |
| MSC2156119J Regimen 2 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 181.4 ng/mL | Geometric Coefficient of Variation 34.4 |
| MSC2156119J Regimen 3 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 178.4 ng/mL | Geometric Coefficient of Variation 67.6 |
| MSC2156119J 145 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 300.5 ng/mL | Geometric Coefficient of Variation 8.9 |
| MSC2156119J 215 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 722.4 ng/mL | Geometric Coefficient of Variation 32.2 |
| MSC2156119J 300 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 8.458 ng/mL | Geometric Coefficient of Variation 339.9 |
| MSC2156119J 400 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 54.30 ng/mL | Geometric Coefficient of Variation 48.5 |
| MSC2156119J 30 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 52.30 ng/mL | Geometric Coefficient of Variation 140.7 |
| MSC2156119J 60 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 | 70.04 ng/mL | Geometric Coefficient of Variation 68.5 |
Secondary
Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 | 741.6 ng/mL | Geometric Coefficient of Variation 45.7 |
| MSC2156119J Regimen 2 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 | 795.0 ng/mL | — |
| MSC2156119J Regimen 3 | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 | 943.1 ng/mL | Geometric Coefficient of Variation 34.6 |
| MSC2156119J 145 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 | 1006 ng/mL | Geometric Coefficient of Variation 39.4 |
| MSC2156119J 215 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 | 1219 ng/mL | Geometric Coefficient of Variation 59.2 |
| MSC2156119J 300 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 | 1805 ng/mL | Geometric Coefficient of Variation 31.2 |
| MSC2156119J 400 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 | 1291 ng/mL | Geometric Coefficient of Variation 48.1 |
Secondary
Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 56.62 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 20.4 |
| MSC2156119J Regimen 2 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 70.65 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 19.3 |
| MSC2156119J Regimen 3 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 107.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 29.6 |
| MSC2156119J 145 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 147.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 24 |
| MSC2156119J 215 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 193.8 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 55.3 |
| MSC2156119J 300 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 306.4 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 42.2 |
| MSC2156119J 400 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 348.1 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 18.6 |
| MSC2156119J 30 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 3.445 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 104.5 |
| MSC2156119J 60 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 12.64 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 44.5 |
| MSC2156119J 115 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 13.72 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 142 |
| MSC2156119J 115 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 13.38 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 74.1 |
| MSC2156119J 230 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 | 29.03 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 94.1 |
Secondary
Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 55.55 ng/mL | Geometric Coefficient of Variation 53.6 |
| MSC2156119J Regimen 2 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 115.5 ng/mL | Geometric Coefficient of Variation 59.3 |
| MSC2156119J Regimen 3 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 134.8 ng/mL | Geometric Coefficient of Variation 22.3 |
| MSC2156119J 145 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 142.4 ng/mL | Geometric Coefficient of Variation 58.9 |
| MSC2156119J 215 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 333.7 ng/mL | Geometric Coefficient of Variation 78.5 |
| MSC2156119J 300 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 5.926 ng/mL | Geometric Coefficient of Variation 102.3 |
| MSC2156119J 400 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 10.79 ng/mL | Geometric Coefficient of Variation 67.1 |
| MSC2156119J 30 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 22.24 ng/mL | Geometric Coefficient of Variation 141 |
| MSC2156119J 60 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 | 37.42 ng/mL | Geometric Coefficient of Variation 64.4 |
Secondary
Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | 246.5 ng/mL | Geometric Coefficient of Variation 32.7 |
| MSC2156119J Regimen 2 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | 552.0 ng/mL | — |
| MSC2156119J Regimen 3 | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | 329.9 ng/mL | Geometric Coefficient of Variation 72.4 |
| MSC2156119J 145 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | 433.5 ng/mL | Geometric Coefficient of Variation 27.6 |
| MSC2156119J 215 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | 666.1 ng/mL | Geometric Coefficient of Variation 46 |
| MSC2156119J 300 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | 761.0 ng/mL | — |
| MSC2156119J 400 mg: Fed | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | 863.4 ng/mL | Geometric Coefficient of Variation 37.4 |
| MSC2156119J 30 mg: Fasted | Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 | 460.9 ng/mL | Geometric Coefficient of Variation 58.7 |
Secondary
Progression-free Survival (PFS)
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.
Time frame: Baseline up to 153.3 weeks
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSC2156119J Regimen 1 | Progression-free Survival (PFS) | 1.4 months |
| MSC2156119J Regimen 2 | Progression-free Survival (PFS) | 1.3 months |
| MSC2156119J Regimen 3 | Progression-free Survival (PFS) | 1.4 months |
Secondary
Relative Percentage Change In Sum of Longest Diameter (SOLD) of Target Lesions to Post-Baseline Nadir
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.
Time frame: Baseline, On Treatment (up to 153.3 weeks)
Population: Safety set included all subjects who had received at least 1 dose of MSC2156119J treatment. Here Number of Participants Analyzed signifies those subjects who presented a measurable tumor at baseline and at least one post-baseline tumor assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MSC2156119J Regimen 1 | Relative Percentage Change In Sum of Longest Diameter (SOLD) of Target Lesions to Post-Baseline Nadir | 25.67 percent change | Standard Deviation 28.738 |
| MSC2156119J Regimen 2 | Relative Percentage Change In Sum of Longest Diameter (SOLD) of Target Lesions to Post-Baseline Nadir | 16.19 percent change | Standard Deviation 22.055 |
| MSC2156119J Regimen 3 | Relative Percentage Change In Sum of Longest Diameter (SOLD) of Target Lesions to Post-Baseline Nadir | 18.87 percent change | Standard Deviation 39.464 |
Secondary
Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSC2156119J Regimen 1 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 2.125 hours |
| MSC2156119J Regimen 2 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J Regimen 3 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J 145 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 4.000 hours |
| MSC2156119J 215 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J 300 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J 400 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 0.250 hours |
| MSC2156119J 30 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 4.000 hours |
| MSC2156119J 60 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 4.000 hours |
| MSC2156119J 115 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 6.000 hours |
| MSC2156119J 115 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 0.00 hours |
| MSC2156119J 230 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 | 4.000 hours |
Secondary
Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
Population: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSC2156119J Regimen 1 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 10.000 hours |
| MSC2156119J Regimen 2 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 10.000 hours |
| MSC2156119J Regimen 3 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 8.000 hours |
| MSC2156119J 145 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 10.000 hours |
| MSC2156119J 215 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 8.000 hours |
| MSC2156119J 300 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 8.000 hours |
| MSC2156119J 400 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 8.067 hours |
| MSC2156119J 30 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 17.083 hours |
| MSC2156119J 60 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 | 10.000 hours |
Secondary
Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3
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.
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSC2156119J Regimen 1 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 | 10.000 hours |
| MSC2156119J Regimen 2 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 | 10.000 hours |
| MSC2156119J Regimen 3 | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 | 8.000 hours |
| MSC2156119J 145 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 | 3.183 hours |
| MSC2156119J 215 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 | 8.833 hours |
| MSC2156119J 300 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 | 9.075 hours |
| MSC2156119J 400 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 | 8.000 hours |
Secondary
Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSC2156119J Regimen 1 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J Regimen 2 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 10.000 hours |
| MSC2156119J Regimen 3 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 10.000 hours |
| MSC2156119J 145 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J 215 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J 300 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 10.000 hours |
| MSC2156119J 400 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J 30 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 4.000 hours |
| MSC2156119J 60 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 8.000 hours |
| MSC2156119J 115 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 10.000 hours |
| MSC2156119J 115 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 24.000 hours |
| MSC2156119J 230 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 | 8.000 hours |
Secondary
Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48, 49.32 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSC2156119J Regimen 1 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 9.000 hours |
| MSC2156119J Regimen 2 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 8.000 hours |
| MSC2156119J Regimen 3 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 9.000 hours |
| MSC2156119J 145 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 8.000 hours |
| MSC2156119J 215 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 24.000 hours |
| MSC2156119J 300 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 10.000 hours |
| MSC2156119J 400 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 17.042 hours |
| MSC2156119J 30 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 33.083 hours |
| MSC2156119J 60 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 | 24.000 hours |
Secondary
Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3
Time frame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSC2156119J Regimen 1 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 8.000 hours |
| MSC2156119J Regimen 2 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 8.000 hours |
| MSC2156119J Regimen 3 | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 10.000 hours |
| MSC2156119J 145 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 10.000 hours |
| MSC2156119J 215 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 10.000 hours |
| MSC2156119J 300 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 10.000 hours |
| MSC2156119J 400 mg: Fed | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 24.000 hours |
| MSC2156119J 30 mg: Fasted | Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 | 8.025 hours |