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

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01832506
• Collaborator: (none)
• Enrollment: 12
• Locations: 2
• Arm: 1
• Actual Duration (Months): 18
• Patients Per Site: 6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors	Drug: MSC2156119J	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Japanese Multicenter, Open Label, Phase I Trial of c-Met Inhibitor MSC2156119J Given Orally as Monotherapy to Subjects With Solid Tumors
• Actual Study Start Date: Apr 30, 2013
• Actual Primary Completion Date: Mar 31, 2014
• Actual Study Completion Date: Oct 31, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MSC2156119J	Drug: MSC2156119J; Subjects will be administered with MSC2156119J 215 mg, 300 mg and 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.

Outcome Measures

Primary Outcome Measures

1. Number of Subjects Experiencing Dose Limiting Toxicity (DLT) [Cycle 1 (Day 1 up to 21)]

   DLT: defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0, as any of following toxicities: Grade 4 neutropenia for more than 7 days; greater than or equal to (>=) Grade 3 febrile neutropenia; Grade 4 or Grade 3 thrombocytopenia with bleeding; >=Grade 3 nausea despite adequate treatment; >=Grade 3 any non-hematological AE (DLT defined specifically for following cases: >=Grade 3 liver adverse event [AE] requiring recovery period of more than 7 days or to Grade 1 without liver metastases or Grade 2 with liver metastases ; >=Grade 3 lipase and/or amylase elevation with confirmation of pancreatitis. An isolated lipase and/or amylase elevation of >=Grade 3 without clinical/radiological evidence of pancreatitis was not classified as DLT); and >=Grade 2 any AE not otherwise defined as DLT that, due to prolonged recovery to Grade 1 (or less) or baseline status, led to delay of treatment with IMP for more than 21 days.

Secondary Outcome Measures

1. Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs or TEAEs Leading To Death [Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)]

   An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs.

2. Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score of 2 or Higher [Baseline up to 30 days after last dose of study drug administration (55.1 weeks)]

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

3. Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1]

4. Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1]

5. Time to Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1]

6. Time to Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1]

7. Apparent Terminal Half-life (t1/2) of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1]

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

8. Area Under the Concentration Time Curve From Time Zero to Extrapolated Infinite Time (AUC[Inf]) of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1]

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

9. Apparent Body Clearance (CL/f) of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1]

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

10. Apparent Volume of Distribution Associated To The Terminal Phase (Vz/f) of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1]

    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed and is calculated by Dose/(AUC(inf)*λz).

11. Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time t (AUC0-t) After Single Dose of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1]

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

12. Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time t (AUC0-t) After Multiple Dose of MSC2156119J [pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1]

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

13. Number of Subjects With Best Overall Response (BOR) [Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 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.

14. Number of Subjects With Clinical Benefit [Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks]

    Clinical Benefit was defined as CR or PR at any time point or SD at week 12 or later, based on tumor assessment as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: defined as at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter while on study. PD: defined as at least a 20% increase in sum of longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions.

15. Progression-free Survival (PFS) [Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks]

    PFS was defined as the time in months from the first administration of trial treatment until first observation of progressive disease (PD), or death due to any cause when death occurs within 12 weeks of the last tumor assessment or first administration of trial treatment (whichever is later). Any subject with neither assessment of tumor progression, nor death within 12 weeks after last tumor assessment date was censored on the date of last tumor assessment. PFS was planned to be presented for "MSC2156119J Combined" reporting arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A subject with a histologically or cytologically confirmed diagnosis of malignant solid tumor which is refractory to standard therapy or to which no effective standard therapy is applicable

• An archived tumor tissue is available or biopsy of tumor tissues can be newly performed

• A Japanese male or female, age greater than or equal to (>=) 20 years

• A subject who has read the Subject Information Sheet and understood the details of this clinical trial, and is willing and able to give his/her informed consent.

• A female of child-bearing potential must have a negative blood pregnancy test result at her screening period. A female subject of child-bearing potential must be willing to avoid pregnancy by using an adequate method of contraception Life expectancy is at least 3 months

• Other inclusion criteria apply

Exclusion Criteria:

• Known Human immunodeficiency virus (HIV) positivity, active hepatitis C, or active hepatitis B

• Presence of liver fibrosis or liver cirrhosis that has been histologically diagnosed

• Signs or symptoms that suggest transmissible spongiform encephalopathy

• Received major surgery within 6 weeks before Day 1 in Cycle 1

• Known drug abuse or alcohol abuse

• Known hypersensitivity to any of the trial treatment ingredients

• Hematological test abnormalities

• Renal impairment as defined in the protocol

• Liver dysfunction as defined in the protocol

• History or presence of central nervous system metastasis

• History or presence of disease or condition that may hamper compliance or absorption of the investigational medicinal product (IMP) due to difficulty in swallowing or absorption

• Poor performance status of Eastern Cooperative Oncology Group Performance status (ECOG PS) >= 2

• Received any anti-cancer therapy days Received extensive prior radiotherapy that irradiates more than 30 percent of bone marrow

• Received any radiotherapy within 4 weeks before Day 1 in Cycle 1

• Pregnancy and lactation period

• History of receiving treatment with any c-Met signaling pathway inhibitor

• Participation in another interventional clinical trial within the past 30 days from Day 1 in Cycle 1

• Other significant disease that in the Investigator's opinion would exclude the subject from the trial

• Legal incapacity or limited legal capacity

• Other exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research site	Kashiwa		Japan
2	Research site	Shizuoka		Japan

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck Serono Co., Ltd., Japan

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Trial Awareness and Transparency website

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01832506
• Other Study ID Numbers: EMR 200095-003
• First Posted: Apr 16, 2013
• Last Update Posted: Aug 6, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Merck KGaA, Darmstadt, Germany: Solid Tumors; MSC2156119J; c-Met inhibitor; Japanese; Phase 1
• Additional relevant MeSH terms: Neoplasms

Study Results

Participant Flow

Recruitment Details	First/last subject (informed consent): 15 April 2013/20 September 2013. Last subject completed: 22 October 2014.

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 milligram (mg) orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	3	3	6
COMPLETED	3	3	6
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg	Total
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	3	3	6	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.7 (9.6)	62.0 (5.0)	65.7 (9.8)	63.8 (8.3)
Sex: Female, Male (Count of Participants)
Female	1 33.3%	1 33.3%	2 33.3%	4 33.3%
Male	2 66.7%	2 66.7%	4 66.7%	8 66.7%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects Experiencing Dose Limiting Toxicity (DLT)
Description	DLT: defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0, as any of following toxicities: Grade 4 neutropenia for more than 7 days; greater than or equal to (>=) Grade 3 febrile neutropenia; Grade 4 or Grade 3 thrombocytopenia with bleeding; >=Grade 3 nausea despite adequate treatment; >=Grade 3 any non-hematological AE (DLT defined specifically for following cases: >=Grade 3 liver adverse event [AE] requiring recovery period of more than 7 days or to Grade 1 without liver metastases or Grade 2 with liver metastases ; >=Grade 3 lipase and/or amylase elevation with confirmation of pancreatitis. An isolated lipase and/or amylase elevation of >=Grade 3 without clinical/radiological evidence of pancreatitis was not classified as DLT); and >=Grade 2 any AE not otherwise defined as DLT that, due to prolonged recovery to Grade 1 (or less) or baseline status, led to delay of treatment with IMP for more than 21 days.
Time Frame	Cycle 1 (Day 1 up to 21)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	6
Number [subjects]	0	0	0

2. Secondary Outcome

Title	Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs or TEAEs Leading To Death
Description	An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs.
Time Frame	Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	6
TEAEs	2	3	6
Serious TEAEs	0	3	1
TEAEs Leading To Death	0	0	1

3. Secondary Outcome

Title	Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score of 2 or Higher
Description	ECOG PS score is widely used by doctors and researchers to assess how a subjects' disease is progressing, and is used to assess how the disease affects the daily living abilities of the subject, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 4, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
Time Frame	Baseline up to 30 days after last dose of study drug administration (55.1 weeks)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	6
Number [subjects]	0	0	0

4. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	6
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)]	244.4 (29.9)	301.3 (42.6)	442.4 (27.5)

5. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	5
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	807.5 (11.5)	610.1 (84.8)	996.8 (17.5)

6. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	6
Median (Full Range) [hours]	8.000	8.017	10.000

7. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	5
Median (Full Range) [hours]	8.000	9.917	4.133

8. Secondary Outcome

Title	Apparent Terminal Half-life (t1/2) of MSC2156119J
Description	Terminal half-life is the time measured for the plasma concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base 2 (Ln2) divided by elimination rate constant (λz), where 'λz' is calculated by a linear regression of the log-linear concentration-time curve.
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	0	0	0

9. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time Zero to Extrapolated Infinite Time (AUC[Inf]) of MSC2156119J
Description	AUC(inf) was calculated by combining AUC0-t and AUCextra. AUCextra represented an extrapolated value obtained by Clast/λz, where Clast was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and λz is the terminal elimination rate constant.
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	0	0	0

10. Secondary Outcome

Title	Apparent Body Clearance (CL/f) of MSC2156119J
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. CL/F = Dose/AUC(inf), where AUC(inf) =AUC0-t + AUCextra. AUCextra represented an extrapolated value obtained by Clast/λz, where Clast was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and λz is the terminal elimination rate constant.
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	0	0	0

11. Secondary Outcome

Title	Apparent Volume of Distribution Associated To The Terminal Phase (Vz/f) of MSC2156119J
Description	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed and is calculated by Dose/(AUC(inf)*λz).
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1 and Day 14 Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	0	0	0

12. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time t (AUC0-t) After Single Dose of MSC2156119J
Description	Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLQ) AUC0-t was calculated according to the mixed log-linear trapezoidal rule
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	6
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	4060.8 (30.7)	5412.7 (45.0)	8235.0 (30.9)

13. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time t (AUC0-t) After Multiple Dose of MSC2156119J
Description	Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the LLQ. AUC0-t was calculated according to the mixed log-linear trapezoidal rule
Time Frame	pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 200 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	5
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	16088.6 (12.2)	13313.4 (82.5)	21509.0 (16.7)

14. Secondary Outcome

Title	Number of Subjects With Best Overall Response (BOR)
Description	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	Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	6
CR	0	0	0
PR	0	0	0
SD	0	0	2
PD	3	3	3
Not Evaluable	0	0	1

15. Secondary Outcome

Title	Number of Subjects With Clinical Benefit
Description	Clinical Benefit was defined as CR or PR at any time point or SD at week 12 or later, based on tumor assessment as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: defined as at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter while on study. PD: defined as at least a 20% increase in sum of longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions.
Time Frame	Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J 215 mg	MSC2156119J 300 mg	MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	3	3	6
Number [subjects]	0	0	2

16. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as the time in months from the first administration of trial treatment until first observation of progressive disease (PD), or death due to any cause when death occurs within 12 weeks of the last tumor assessment or first administration of trial treatment (whichever is later). Any subject with neither assessment of tumor progression, nor death within 12 weeks after last tumor assessment date was censored on the date of last tumor assessment. PFS was planned to be presented for "MSC2156119J Combined" reporting arm.
Time Frame	Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MSC2156119J Combined
Arm/Group Description	All subjects who were administered with MSC2156119J 215 mg, 300mg or 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Measure Participants	12
Median (90% Confidence Interval) [months]	1.38

Adverse Events

Time Frame	Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Arm/Group Title	MSC2156119J 215 mg		MSC2156119J 300 mg		MSC2156119J 500 mg
Arm/Group Description	Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.		Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.		Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
All Cause Mortality
	MSC2156119J 215 mg		MSC2156119J 300 mg		MSC2156119J 500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MSC2156119J 215 mg		MSC2156119J 300 mg		MSC2156119J 500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		3/3 (100%)		1/6 (16.7%)
General disorders
MALAISE	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
Metabolism and nutrition disorders
DECREASED APPETITE	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
Nervous system disorders
ALTERED STATE OF CONSCIOUSNESS	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	0/3 (0%)		1/3 (33.3%)		1/6 (16.7%)
Other (Not Including Serious) Adverse Events
	MSC2156119J 215 mg		MSC2156119J 300 mg		MSC2156119J 500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		3/3 (100%)		6/6 (100%)
Blood and lymphatic system disorders
IRON DEFICIENCY ANAEMIA	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
Eye disorders
EYE MOVEMENT DISORDER	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
Gastrointestinal disorders
CONSTIPATION	1/3 (33.3%)		2/3 (66.7%)		3/6 (50%)
NAUSEA	0/3 (0%)		2/3 (66.7%)		3/6 (50%)
VOMITING	0/3 (0%)		1/3 (33.3%)		3/6 (50%)
ABDOMINAL DISCOMFORT	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
ASCITES	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
DENTAL CARIES	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
PROCTALGIA	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
STOMATITIS	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
General disorders
FATIGUE	1/3 (33.3%)		2/3 (66.7%)		1/6 (16.7%)
OEDEMA PERIPHERAL	0/3 (0%)		0/3 (0%)		4/6 (66.7%)
MALAISE	0/3 (0%)		1/3 (33.3%)		1/6 (16.7%)
PYREXIA	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
VESSEL PUNCTURE SITE ERYTHEMA	1/3 (33.3%)		0/3 (0%)		0/6 (0%)
Infections and infestations
NASOPHARYNGITIS	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
SUBCUTANEOUS ABSCESS	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
Injury, poisoning and procedural complications
WOUND COMPLICATION	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
Investigations
AMYLASE INCREASED	0/3 (0%)		0/3 (0%)		2/6 (33.3%)
LIPASE INCREASED	0/3 (0%)		0/3 (0%)		2/6 (33.3%)
BLOOD CREATININE INCREASED	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
C-REACTIVE PROTEIN INCREASED	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
Metabolism and nutrition disorders
DECREASED APPETITE	1/3 (33.3%)		1/3 (33.3%)		3/6 (50%)
HYPOALBUMINAEMIA	0/3 (0%)		0/3 (0%)		4/6 (66.7%)
HYPONATRAEMIA	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
Musculoskeletal and connective tissue disorders
BACK PAIN	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CANCER PAIN	1/3 (33.3%)		0/3 (0%)		1/6 (16.7%)
TUMOUR ASSOCIATED FEVER	0/3 (0%)		1/3 (33.3%)		1/6 (16.7%)
Nervous system disorders
DYSGEUSIA	1/3 (33.3%)		1/3 (33.3%)		1/6 (16.7%)
DIZZINESS	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
HYPOAESTHESIA	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
NEUROPATHY PERIPHERAL	1/3 (33.3%)		0/3 (0%)		0/6 (0%)
Psychiatric disorders
INSOMNIA	0/3 (0%)		0/3 (0%)		2/6 (33.3%)
ANXIETY	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
DEPRESSION	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
Renal and urinary disorders
URINARY TRACT OBSTRUCTION	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	0/3 (0%)		1/3 (33.3%)		1/6 (16.7%)
Skin and subcutaneous tissue disorders
DERMATITIS ACNEIFORM	0/3 (0%)		0/3 (0%)		1/6 (16.7%)
DRUG ERUPTION	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
URTICARIA	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
Vascular disorders
DEEP VEIN THROMBOSIS	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
THROMBOPHLEBITIS	0/3 (0%)		1/3 (33.3%)		0/6 (0%)
VARICOSE VEIN	0/3 (0%)		1/3 (33.3%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.