c-Met Second-Line Hepatocellular Carcinoma

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02115373
• Collaborator: (none)
• Enrollment: 66
• Location: 1
• Arms: 3
• Actual Duration (Months): 44.9
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

This is a Phase 1b/2, multicenter, single arm trial to assess the efficacy, safety, and pharmacokinetics (PK) of MSC2156119J as monotherapy in subjects with MET+ advanced hepatocellular carcinoma (HCC) with child Pugh Class A liver function who have failed sorafenib treatment.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Tepotinib; Drug: Tepotinib	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Single Arm, Phase Ib/II Study to Evaluate Efficacy, Safety, and PK of MSC2156119J as Monotherapy in Subjects With MET+ Advanced Hepatocellular Carcinoma With Child Pugh Class A Liver Function Who Have Failed Sorafenib Treatment
• Actual Study Start Date: May 18, 2014
• Actual Primary Completion Date: Feb 14, 2018
• Actual Study Completion Date: Feb 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b: Tepotinib 300 mg	Drug: Tepotinib; Participants received a single oral dose of Tepotinib 300 milligram (mg) in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.; Other Names: MSC2156119J
Experimental: Phase 1b: Tepotinib 500 mg	Drug: Tepotinib; Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.; Other Names: MSC2156119J
Experimental: Phase 2: Tepotinib 500 mg	Drug: Tepotinib; Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.; Other Names: MSC2156119J

Outcome Measures

Primary Outcome Measures

1. Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) for Adverse Events (AEs) Version 4.0 [Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)]

   DLT: defined using NCI-CTCAE for AEs 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 for more than 1 day; Grade 4 or Grade 3 thrombocytopenia with nontraumatic bleeding; >=Grade 3 uncontrolled nausea/vomiting and/or diarrhoea despite adequate treatment for more than 3 days; >=Grade 3 any non-hematological AE. (DLT defined specifically for following cases: >=Grade 3 liver AE requiring recovery period of more than 7 days or to Grade 1 or less 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 AEs assessed by investigators to be exclusively related to the participant's underlying disease or medical condition/concomitant treatment are not considered as DLTs.

2. Phase 2: Number of Participants Who Were Progression-free at 12 Weeks (PFS Status) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [At 12 weeks post first-dose in Phase 2]

   PFS status was evaluated by the number of participants who were progression-free at 12 weeks according to RECIST Version 1.1. Participants were considered to be progression-free if the participant had a tumor assessment of Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeter (mm). Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later.

Secondary Outcome Measures

1. Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [Time from first study drug administration to the date of first occurrence of radiological progressive disease (PD), assessed up to 12 months after last participant's first dose (assessed maximum up to 1369 days)]

   TTP was the time (in months) from the date of first study drug administration to the date of radiological confirmation of PD performed according to RECIST Version 1.1. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents the number of participants with progression.

2. Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [From randomization up to first observation of PD or death, assessed maximum up to 1369 days]

   PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PFS was assessed as per RECIST v1.1 as adjudicated by independent endpoint review committee (IERC). PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents number of participants with death or progressive disease.

3. Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC) [From randomization up to first observation of PD or death, assessed maximum up to 1369 days]

   PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PFS was assessed as per mRECIST for HCC as adjudicated by independent endpoint review committee (IERC). PD was defined as an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents number of participants with death or progressive disease.

4. Phase 2: Time-to-symptomatic Progression (TTSP) [From date of randomization up to 1369 days]

   Time-to-symptomatic progression was defined as time (in months) from first study drug administration to the date of deterioration of symptoms assessed by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8) (defined as at least a 4-point increase, i.e., higher score, compared with baseline value), or deterioration to Eastern Cooperative Oncology Group (ECOG) performance score 4, or death. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms). ECOG assess participant's performance status on a scale of 0 to 5, where 0=fully active and 5=dead.

5. Phase 1b and Phase 2: Overall Survival (OS) Time [From date of randomization up to the date of death, assessed maximum up to 1369 days]

   The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. The descriptive data represents number of participants who had an event of death.

6. Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1 [From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days]

   Percentage of participants with best overall tumor assessment of (CR or PR) according to RECIST Version 1.1 was reported. CR defined as disappearance of all target and non-target lesions and 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 the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.

7. Phase 1b and Phase 2: Percentage of Participants With Disease Control [From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days]

   Disease control was defined as CR, PR, or SD as the best overall response according to RECIST Version 1.1. Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later. Percentage of Participants With Disease Control were reported.

8. Phase 1b and Phase 2: Percentage of Participants With Biological Response [Baseline up to Cycle 3 (each cycle is 21 days)]

   Percentage of participants with biological response was measured by serum Alpha-Fetoprotein (AFP), defined as a greater than 20% decrease in AFP level by Cycle 3 (each cycle is of 21 days) compared with baseline.

9. Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib [Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)]

10. Phase 1b: Dose Normalized Area Under the Plasma Concentration-Time Curve From Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

    Dose normalized was calculated as 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) divided by the dose.

11. Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib [Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)]

12. Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

    Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.

13. Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

    Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose.

14. Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)]

15. Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

16. Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)]

17. Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)]

18. Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

19. Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

20. Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

21. Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

22. Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 Cycle 1 (each Cycle is 21 days)]

23. Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)]

    The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav ) multiplied by 100

24. Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax)) [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

    Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1.

25. Phase 1b: Accumulation Ratio of AUC (Racc (AUC) [Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)]

    Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed HCC

• Child Pugh Class A liver function score

• For Phase 2 only: MET+ status

• Male or female, 18 years of age or older

• Measurable disease in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (inclusive)

• Availability of a pretreatment tumor biopsy (excluding fine needle aspiration and cytology samples) taken after the subject has discontinued sorafenib and within 28 days before the day of first dosing with MSC2156119J. From the pretreatment biopsy either a formalin-fixed (formalin fixation is mandatory) paraffin-embedded block with tumor tissue (preferred) or at least 15 unstained slides must be sent to the central laboratory prior to enrollment. An associated pathology report must also be sent with the sample

• Previously treated with sorafenib for greater than or equal to 4 weeks and discontinued sorafenib treatment at least 14 days prior to Day 1 due to either intolerance or radiographic progression

• Signed and dated informed consent indicating that the subject (or legally acceptable representative if applicable by local laws) has been informed of all the pertinent aspects of the trial prior to enrollment

• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other trial procedures

• Life expectancy of at least 3 months as judged by the investigator

Exclusion Criteria:

• Prior systemic anticancer treatment for advanced HCC (except for sorafenib as described in the inclusion criteria)

• Prior treatment with any agent targeting the hepatocyte growth factor (HGF)/c-Met pathway

• Local-regional therapy within 4 weeks before Day 1

• Impaired cardiac function

• Other protocol defined exclusion criteria could apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Please contact the Merck KGaA Communication Center located in	Darmstadt		Germany

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

• Study Protocol - Jun 13, 2016
• Statistical Analysis Plan - Mar 15, 2018

More Information

Additional Information:

• : Redacted Clinical study report, redacted clinical study protocol and redacted statistical analysis plan for this study is also available at the HC-PRCI portal (Health Canada-Public release of clinical information)

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT02115373
• Other Study ID Numbers: EMR 200095_005; 2013-002053-30
• First Posted: Apr 16, 2014
• Last Update Posted: Aug 24, 2022
• Last Verified: Aug 1, 2022

• Keywords provided by Merck KGaA, Darmstadt, Germany: Hepatocellular Carcinoma; c-Met inhibitor; Phase 1b; Sorafenib; MSC2156119J
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Tepotinib

Study Results

Participant Flow

Recruitment Details	First participant signed informed consent:18 May 2014, Last participant last visit: 14th Feb 2018
Pre-assignment Detail	In Phase 1b, 24 participants were screened of which, 17 started the treatment. In Phase 2 ,155 participants were screened, of which 49 participants started the treatment.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 milligram (mg) daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Period Title: Overall Study
STARTED	4	13	49
COMPLETED	4	13	49
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg	Total
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Total of all reporting groups
Overall Participants	4	13	49	66
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 25%	3 23.1%	21 42.9%	25 37.9%
>=65 years	3 75%	10 76.9%	28 57.1%	41 62.1%
Sex: Female, Male (Count of Participants)
Female	2 50%	2 15.4%	8 16.3%	12 18.2%
Male	2 50%	11 84.6%	41 83.7%	54 81.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	2 4.1%	2 3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 2%	1 1.5%
White	1 25%	8 61.5%	26 53.1%	35 53%
More than one race	0 0%	1 7.7%	0 0%	1 1.5%
Unknown or Not Reported	3 75%	4 30.8%	20 40.8%	27 40.9%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) for Adverse Events (AEs) Version 4.0
Description	DLT: defined using NCI-CTCAE for AEs 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 for more than 1 day; Grade 4 or Grade 3 thrombocytopenia with nontraumatic bleeding; >=Grade 3 uncontrolled nausea/vomiting and/or diarrhoea despite adequate treatment for more than 3 days; >=Grade 3 any non-hematological AE. (DLT defined specifically for following cases: >=Grade 3 liver AE requiring recovery period of more than 7 days or to Grade 1 or less 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 AEs assessed by investigators to be exclusively related to the participant's underlying disease or medical condition/concomitant treatment are not considered as DLTs.
Time Frame	Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)

Outcome Measure Data

Analysis Population Description

DLT analysis set included all participants who completed Cycle 1 and who received 80 percent (%) or more of the planned cumulative dose of Tepotinib (MSC2156119J) in Cycle 1, and participants who experienced a DLT during Cycle 1.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	11
Count of Participants [Participants]	0 0%	0 0%

2. Primary Outcome

Title	Phase 2: Number of Participants Who Were Progression-free at 12 Weeks (PFS Status) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Description	PFS status was evaluated by the number of participants who were progression-free at 12 weeks according to RECIST Version 1.1. Participants were considered to be progression-free if the participant had a tumor assessment of Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeter (mm). Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later.
Time Frame	At 12 weeks post first-dose in Phase 2

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). The outcome measure was planned to be analyzed for Phase 2 only.

Arm/Group Title	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 day treatment cycle until confirmed disease progression.
Measure Participants	49
Count of Participants [Participants]	31 775%

3. Secondary Outcome

Title	Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Description	TTP was the time (in months) from the date of first study drug administration to the date of radiological confirmation of PD performed according to RECIST Version 1.1. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents the number of participants with progression.
Time Frame	Time from first study drug administration to the date of first occurrence of radiological progressive disease (PD), assessed up to 12 months after last participant's first dose (assessed maximum up to 1369 days)

Outcome Measure Data

Analysis Population Description

ITT set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	4	13	49
Count of Participants [Participants]	3 75%	9 69.2%	36 73.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	2.07
	Confidence Interval	(2-Sided) 90%; 1.446 to 7.195
	Parameter Dispersion	Type: Value:
	Estimation Comments	TTP in months was calculated for Phase 1b: Tepotinib 300 mg and Phase 1b: Tepotinib 500 mg combined.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Tepotinib 500 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	3.98
	Confidence Interval	(2-Sided) 90%; 2.858 to 4.238
	Parameter Dispersion	Type: Value:
	Estimation Comments	TTP in months was calculated for Phase 2: Tepotinib 500 mg.

4. Secondary Outcome

Title	Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Description	PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PFS was assessed as per RECIST v1.1 as adjudicated by independent endpoint review committee (IERC). PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents number of participants with death or progressive disease.
Time Frame	From randomization up to first observation of PD or death, assessed maximum up to 1369 days

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	4	13	49
Count of Participants [Participants]	4 100%	12 92.3%	38 77.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 90%; 1.413 to 3.680
	Parameter Dispersion	Type: Value:
	Estimation Comments	PFS time in months was calculated for Phase 1b: Tepotinib 300 mg and Phase 1b: Tepotinib 500 mg combined.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Tepotinib 500 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	3.22
	Confidence Interval	(2-Sided) 90%; 0.03 to 16.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	PFS time in months was calculated for Phase 2: Tepotinib 500 mg.

5. Secondary Outcome

Title	Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC)
Description	PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PFS was assessed as per mRECIST for HCC as adjudicated by independent endpoint review committee (IERC). PD was defined as an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents number of participants with death or progressive disease.
Time Frame	From randomization up to first observation of PD or death, assessed maximum up to 1369 days

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	4	13	49
Count of Participants [Participants]	4 100%	9 69.2%	37 75.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	1.48
	Confidence Interval	(2-Sided) 90%; 1.413 to 3.844
	Parameter Dispersion	Type: Value:
	Estimation Comments	PFS time in months was calculated for Phase 1b: Tepotinib 300 mg and Phase 1b: Tepotinib 500 mg combined.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Tepotinib 500 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	3.35
	Confidence Interval	(2-Sided) 90%; 2.760 to 4.172
	Parameter Dispersion	Type: Value:
	Estimation Comments	PFS time in months was was calculated for Phase 2: Tepotinib 500 mg.

6. Secondary Outcome

Title	Phase 2: Time-to-symptomatic Progression (TTSP)
Description	Time-to-symptomatic progression was defined as time (in months) from first study drug administration to the date of deterioration of symptoms assessed by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8) (defined as at least a 4-point increase, i.e., higher score, compared with baseline value), or deterioration to Eastern Cooperative Oncology Group (ECOG) performance score 4, or death. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms). ECOG assess participant's performance status on a scale of 0 to 5, where 0=fully active and 5=dead.
Time Frame	From date of randomization up to 1369 days

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, Overall number of participants analyzed signified those participants who had symptomatic progression. As per planned analysis, data for this outcome was analyzed for Phase 2 only.

Arm/Group Title	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	41
Median (Full Range) [months]	4.86

7. Secondary Outcome

Title	Phase 1b and Phase 2: Overall Survival (OS) Time
Description	The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. The descriptive data represents number of participants who had an event of death.
Time Frame	From date of randomization up to the date of death, assessed maximum up to 1369 days

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	4	13	49
Count of Participants [Participants]	3 75%	11 84.6%	40 81.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	7.20
	Confidence Interval	(2-Sided) 90%; 3.680 to 10.119
	Parameter Dispersion	Type: Value:
	Estimation Comments	Overall Survival time in months was calculated for Phase 1b: Tepotinib 300 mg and Phase 1b: Tepotinib 500 mg combined.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Tepotinib 500 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	5.55
	Confidence Interval	(2-Sided) 90%; 5.092 to 8.181
	Parameter Dispersion	Type: Value:
	Estimation Comments	Overall Survival time in months was calculated for Phase 2: Tepotinib 500 mg.

8. Secondary Outcome

Title	Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1
Description	Percentage of participants with best overall tumor assessment of (CR or PR) according to RECIST Version 1.1 was reported. CR defined as disappearance of all target and non-target lesions and 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 the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.
Time Frame	From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	4	13	49
Number (90% Confidence Interval) [percentage of Participants]	50.0 1250%	0.0 0%	8.2 16.7%

9. Secondary Outcome

Title	Phase 1b and Phase 2: Percentage of Participants With Disease Control
Description	Disease control was defined as CR, PR, or SD as the best overall response according to RECIST Version 1.1. Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later. Percentage of Participants With Disease Control were reported.
Time Frame	From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	4	13	49
Number (90% Confidence Interval) [percentage of participants]	50.0 1250%	30.8 236.9%	57.1 116.5%

10. Secondary Outcome

Title	Phase 1b and Phase 2: Percentage of Participants With Biological Response
Description	Percentage of participants with biological response was measured by serum Alpha-Fetoprotein (AFP), defined as a greater than 20% decrease in AFP level by Cycle 3 (each cycle is of 21 days) compared with baseline.
Time Frame	Baseline up to Cycle 3 (each cycle is 21 days)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, "Overall number of participants analyzed" signified the participants with baseline and post baseline AFP assessments.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg	Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 day treatment cycle until confirmed disease progression.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 day treatment cycle until confirmed disease progression.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 day treatment cycle until confirmed disease progression.
Measure Participants	3	11	45
Number (90% Confidence Interval) [percentage of participants]	66.7 1667.5%	45.5 350%	31.1 63.5%

11. Secondary Outcome

Title	Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib
Time Frame	Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	4440 (6.7)	5060 (38.9)
Cycle 1 Day 15	15200 (18.2)	12900 (50.4)

12. Secondary Outcome

Title	Phase 1b: Dose Normalized Area Under the Plasma Concentration-Time Curve From Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib
Description	Dose normalized was calculated as 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) divided by the dose.
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	14.8 (6.7)	10.1 (38.9)
Cycle 1 Day 15	50.7 (18.2)	25.8 (50.4)

13. Secondary Outcome

Title	Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib
Time Frame	Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	NA (NA)	NA (NA)
Cycle 1 Day 15	NA (NA)	NA (NA)

14. Secondary Outcome

Title	Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib
Description	Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	261 (8.4)	278 (39.3)
Cycle 1 Day 15	734 (19.6)	677 (44.6)

15. Secondary Outcome

Title	Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib
Description	Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose.
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	0.871 (8.4)	0.556 (39.3)
Cycle 1 Day 15	2.45 (19.6)	1.35 (44.6)

16. Secondary Outcome

Title	Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	9
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)]	526 (28.0)	435 (57.9)

17. Secondary Outcome

Title	Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 day treatment cycle until confirmed disease progression.
Measure Participants	3	12
Cycle 1 Day 1	10.0	8.0
Cycle 1 Day 15	8.0	6.1

18. Secondary Outcome

Title	Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	9
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)]	635 (18.2)	542 (50.7)

19. Secondary Outcome

Title	Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	9
Geometric Mean (Geometric Coefficient of Variation) [Liter per hour (L/h)]	17.7 (18.2)	34.9 (50.4)

20. Secondary Outcome

Title	Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	NA (NA)	NA (NA)
Cycle 1 Day 15	NA (NA)	NA (NA)

21. Secondary Outcome

Title	Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	NA (NA)	NA (NA)
Cycle 1 Day 15	NA (NA)	NA (NA)

22. Secondary Outcome

Title	Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	NA (NA)	NA (NA)
Cycle 1 Day 15	NA (NA)	NA (NA)

23. Secondary Outcome

Title	Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Cycle 1 Day 1	NA	NA
Cycle 1 Day 15	NA	NA

24. Secondary Outcome

Title	Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	12
Median (Full Range) [hours]	0.53	0.50

25. Secondary Outcome

Title	Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib
Description	The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav ) multiplied by 100
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	9
Geometric Mean (Geometric Coefficient of Variation) [percentage fluctuation]	31.5 (30.5)	35.9 (44.1)

26. Secondary Outcome

Title	Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax))
Description	Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1.
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	10
Geometric Mean (Geometric Coefficient of Variation) [ratio]	2.81 (24.1)	2.32 (23.0)

27. Secondary Outcome

Title	Phase 1b: Accumulation Ratio of AUC (Racc (AUC)
Description	Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1.
Time Frame	Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome Measure Data

Analysis Population Description

PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Arm/Group Title	Phase 1b: Tepotinib 300 mg	Phase 1b: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Measure Participants	3	9
Geometric Mean (Geometric Coefficient of Variation) [ratio]	3.43 (22.6)	2.51 (22.0)

Adverse Events

Time Frame	From date of randomization up to 1369 days
Arm/Group Title	Phase 1b: Tepotinib 300 mg		Phase 1b: Tepotinib 500 mg		Phase 2: Tepotinib 500 mg
Arm/Group Description	Participants received a single oral dose of Tepotinib 300 milligram (mg) daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.		Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.		Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
All Cause Mortality
	Phase 1b: Tepotinib 300 mg		Phase 1b: Tepotinib 500 mg		Phase 2: Tepotinib 500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		11/13 (84.6%)		40/49 (81.6%)
Serious Adverse Events
	Phase 1b: Tepotinib 300 mg		Phase 1b: Tepotinib 500 mg		Phase 2: Tepotinib 500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/4 (50%)		5/13 (38.5%)		21/49 (42.9%)
Gastrointestinal disorders
Abdominal pain	1/4 (25%)		0/13 (0%)		0/49 (0%)
Ascites	0/4 (0%)		2/13 (15.4%)		3/49 (6.1%)
Gastrointestinal haemorrhage	0/4 (0%)		0/13 (0%)		1/49 (2%)
General disorders
Disease progression	1/4 (25%)		1/13 (7.7%)		7/49 (14.3%)
Localised oedema	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Oedema peripheral	0/4 (0%)		2/13 (15.4%)		1/49 (2%)
Discomfort	0/4 (0%)		0/13 (0%)		1/49 (2%)
General physical health deterioration	0/4 (0%)		0/13 (0%)		1/49 (2%)
Pyrexia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Vascular stent stenosis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hepatobiliary disorders
Cholangitis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hepatic failure	0/4 (0%)		0/13 (0%)		1/49 (2%)
Jaundice	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hepatorenal syndrome	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Infections and infestations
Device related infection	0/4 (0%)		0/13 (0%)		1/49 (2%)
Peritonitis bacterial	0/4 (0%)		0/13 (0%)		1/49 (2%)
Sepsis	0/4 (0%)		1/13 (7.7%)		1/49 (2%)
Peritonitis	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Post procedural infection	1/4 (25%)		0/13 (0%)		0/49 (0%)
Investigations
Blood bilirubin increased	1/4 (25%)		0/13 (0%)		0/49 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hypercreatininaemia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hyponatraemia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Decreased appetite	1/4 (25%)		0/13 (0%)		0/49 (0%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/4 (0%)		0/13 (0%)		1/49 (2%)
Tumour pain	0/4 (0%)		0/13 (0%)		1/49 (2%)
Nervous system disorders
Coma	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Hepatic encephalopathy	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Cerebral thrombosis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hypoglycaemic coma	0/4 (0%)		0/13 (0%)		1/49 (2%)
Renal and urinary disorders
Acute kidney injury	1/4 (25%)		1/13 (7.7%)		3/49 (6.1%)
Chronic kidney disease	0/4 (0%)		0/13 (0%)		1/49 (2%)
Reproductive system and breast disorders
Prostatitis	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	0/4 (0%)		0/13 (0%)		1/49 (2%)
Other (Not Including Serious) Adverse Events
	Phase 1b: Tepotinib 300 mg		Phase 1b: Tepotinib 500 mg		Phase 2: Tepotinib 500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		12/13 (92.3%)		48/49 (98%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)		0/13 (0%)		7/49 (14.3%)
Coagulopathy	0/4 (0%)		0/13 (0%)		1/49 (2%)
Lymph node pain	0/4 (0%)		0/13 (0%)		1/49 (2%)
Thrombocytopenia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Cardiac disorders
Atrial fibrillation	0/4 (0%)		0/13 (0%)		1/49 (2%)
Ear and labyrinth disorders
Vertigo	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Eye disorders
Eyelid oedema	1/4 (25%)		0/13 (0%)		0/49 (0%)
Lacrimation increased	0/4 (0%)		2/13 (15.4%)		1/49 (2%)
Gastrointestinal disorders
Abdominal distension	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Abdominal pain	2/4 (50%)		2/13 (15.4%)		8/49 (16.3%)
Abdominal pain upper	0/4 (0%)		1/13 (7.7%)		4/49 (8.2%)
Ascites	0/4 (0%)		2/13 (15.4%)		15/49 (30.6%)
Constipation	2/4 (50%)		0/13 (0%)		9/49 (18.4%)
Diarrhoea	0/4 (0%)		2/13 (15.4%)		16/49 (32.7%)
Dry mouth	1/4 (25%)		0/13 (0%)		1/49 (2%)
Dyspepsia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Dysphagia	1/4 (25%)		0/13 (0%)		1/49 (2%)
Gastric varices	0/4 (0%)		0/13 (0%)		1/49 (2%)
Gastrooesophageal reflux disease	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Haematemesis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Inguinal hernia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Nausea	1/4 (25%)		2/13 (15.4%)		11/49 (22.4%)
Odynophagia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Varices oesophageal	0/4 (0%)		0/13 (0%)		1/49 (2%)
Vomiting	2/4 (50%)		0/13 (0%)		7/49 (14.3%)
Eructation	1/4 (25%)		0/13 (0%)		0/49 (0%)
Toothache	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
General disorders
Asthenia	0/4 (0%)		2/13 (15.4%)		15/49 (30.6%)
Chest pain	0/4 (0%)		0/13 (0%)		1/49 (2%)
Chills	0/4 (0%)		0/13 (0%)		1/49 (2%)
Disease progression	0/4 (0%)		0/13 (0%)		1/49 (2%)
Fatigue	1/4 (25%)		2/13 (15.4%)		10/49 (20.4%)
Generalised oedema	0/4 (0%)		0/13 (0%)		1/49 (2%)
Localised oedema	0/4 (0%)		1/13 (7.7%)		2/49 (4.1%)
Oedema	0/4 (0%)		0/13 (0%)		3/49 (6.1%)
Oedema peripheral	3/4 (75%)		10/13 (76.9%)		32/49 (65.3%)
Pyrexia	1/4 (25%)		1/13 (7.7%)		4/49 (8.2%)
Pain	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Hepatobiliary disorders
Hepatic vein thrombosis	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Hepatic failure	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hepatic pain	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hepatocellular injury	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Hepatomegaly	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hyperbilirubinaemia	0/4 (0%)		0/13 (0%)		4/49 (8.2%)
Hypertransaminasaemia	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Jaundice	0/4 (0%)		0/13 (0%)		1/49 (2%)
Infections and infestations
Hepatitis B	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Nasopharyngitis	1/4 (25%)		0/13 (0%)		1/49 (2%)
Peritonitis	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Angular cheilitis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Bronchitis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Clostridium difficile colitis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Conjunctivitis	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Gastroenteritis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Genital herpes	0/4 (0%)		0/13 (0%)		1/49 (2%)
Herpes zoster	0/4 (0%)		0/13 (0%)		1/49 (2%)
Infection	0/4 (0%)		0/13 (0%)		1/49 (2%)
Influenza	0/4 (0%)		0/13 (0%)		1/49 (2%)
Lung infection	0/4 (0%)		0/13 (0%)		1/49 (2%)
Paronychia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Pneumonia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Rash pustular	0/4 (0%)		0/13 (0%)		1/49 (2%)
Septic shock	0/4 (0%)		0/13 (0%)		1/49 (2%)
Upper respiratory tract infection	0/4 (0%)		0/13 (0%)		1/49 (2%)
Urinary tract infection	0/4 (0%)		0/13 (0%)		3/49 (6.1%)
Injury, poisoning and procedural complications
Fall	0/4 (0%)		1/13 (7.7%)		1/49 (2%)
Overdose	0/4 (0%)		0/13 (0%)		1/49 (2%)
Wound	0/4 (0%)		0/13 (0%)		1/49 (2%)
Lumbar vertebral fracture	1/4 (25%)		0/13 (0%)		0/49 (0%)
Rib fracture	1/4 (25%)		0/13 (0%)		0/49 (0%)
Investigations
Alanine aminotransferase increased	2/4 (50%)		4/13 (30.8%)		3/49 (6.1%)
Aspartate aminotransferase increased	1/4 (25%)		1/13 (7.7%)		6/49 (12.2%)
Blood alkaline phosphatase increased	2/4 (50%)		2/13 (15.4%)		5/49 (10.2%)
Blood bilirubin increased	0/4 (0%)		1/13 (7.7%)		5/49 (10.2%)
Blood creatinine increased	1/4 (25%)		2/13 (15.4%)		7/49 (14.3%)
Blood thyroid stimulating hormone increased	0/4 (0%)		0/13 (0%)		1/49 (2%)
Blood urea increased	0/4 (0%)		2/13 (15.4%)		3/49 (6.1%)
International normalised ratio increased	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Lipase increased	1/4 (25%)		1/13 (7.7%)		5/49 (10.2%)
Prothrombin time prolonged	0/4 (0%)		0/13 (0%)		1/49 (2%)
Transaminases increased	0/4 (0%)		0/13 (0%)		1/49 (2%)
Urobilinogen urine increased	0/4 (0%)		0/13 (0%)		1/49 (2%)
Weight decreased	1/4 (25%)		1/13 (7.7%)		2/49 (4.1%)
Weight increased	0/4 (0%)		0/13 (0%)		1/49 (2%)
Amylase increased	1/4 (25%)		0/13 (0%)		0/49 (0%)
Gamma-glutamyltransferase increased	1/4 (25%)		1/13 (7.7%)		0/49 (0%)
Glomerular filtration rate decreased	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Haemoglobin decreased	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/4 (0%)		1/13 (7.7%)		8/49 (16.3%)
Cell death	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hypercreatininaemia	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Hyperglycaemia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hyperkalaemia	0/4 (0%)		1/13 (7.7%)		5/49 (10.2%)
Hyperlipasaemia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hypoalbuminaemia	0/4 (0%)		1/13 (7.7%)		13/49 (26.5%)
Hypocalcaemia	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Hypokalaemia	0/4 (0%)		0/13 (0%)		3/49 (6.1%)
Hypomagnesaemia	0/4 (0%)		1/13 (7.7%)		3/49 (6.1%)
Hyponatraemia	0/4 (0%)		0/13 (0%)		3/49 (6.1%)
Malnutrition	0/4 (0%)		0/13 (0%)		1/49 (2%)
Type 1 diabetes mellitus	0/4 (0%)		0/13 (0%)		1/49 (2%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Back pain	1/4 (25%)		0/13 (0%)		5/49 (10.2%)
Bone pain	0/4 (0%)		1/13 (7.7%)		4/49 (8.2%)
Muscle spasms	0/4 (0%)		0/13 (0%)		1/49 (2%)
Musculoskeletal chest pain	1/4 (25%)		0/13 (0%)		1/49 (2%)
Musculoskeletal pain	0/4 (0%)		0/13 (0%)		1/49 (2%)
Pain in extremity	1/4 (25%)		1/13 (7.7%)		1/49 (2%)
Pain in jaw	0/4 (0%)		0/13 (0%)		1/49 (2%)
Flank pain	1/4 (25%)		0/13 (0%)		0/49 (0%)
Osteoporosis	1/4 (25%)		0/13 (0%)		0/49 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/4 (0%)		0/13 (0%)		1/49 (2%)
Metastases to bone	0/4 (0%)		0/13 (0%)		1/49 (2%)
Tumour pain	0/4 (0%)		0/13 (0%)		1/49 (2%)
Nervous system disorders
Dizziness	0/4 (0%)		0/13 (0%)		1/49 (2%)
Dysgeusia	1/4 (25%)		0/13 (0%)		2/49 (4.1%)
Headache	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Hepatic encephalopathy	0/4 (0%)		0/13 (0%)		1/49 (2%)
Sciatica	0/4 (0%)		0/13 (0%)		1/49 (2%)
Migraine with aura	1/4 (25%)		0/13 (0%)		0/49 (0%)
Psychiatric disorders
Anxiety	0/4 (0%)		2/13 (15.4%)		2/49 (4.1%)
Depressed mood	0/4 (0%)		0/13 (0%)		1/49 (2%)
Depression	0/4 (0%)		0/13 (0%)		1/49 (2%)
Insomnia	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Renal and urinary disorders
Acute kidney injury	1/4 (25%)		1/13 (7.7%)		3/49 (6.1%)
Dysuria	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Renal impairment	1/4 (25%)		2/13 (15.4%)		0/49 (0%)
Glomerulonephritis membranoproliferative	0/4 (0%)		0/13 (0%)		1/49 (2%)
Ketonuria	0/4 (0%)		0/13 (0%)		1/49 (2%)
Pollakiuria	0/4 (0%)		0/13 (0%)		1/49 (2%)
Renal failure	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Reproductive system and breast disorders
Scrotal oedema	0/4 (0%)		0/13 (0%)		1/49 (2%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/4 (25%)		0/13 (0%)		0/49 (0%)
Acute respiratory failure	0/4 (0%)		0/13 (0%)		1/49 (2%)
Cough	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Dyspnoea	0/4 (0%)		0/13 (0%)		1/49 (2%)
Dyspnoea exertional	0/4 (0%)		0/13 (0%)		1/49 (2%)
Pleural effusion	0/4 (0%)		0/13 (0%)		6/49 (12.2%)
Skin and subcutaneous tissue disorders
Alopecia	0/4 (0%)		0/13 (0%)		1/49 (2%)
Dry skin	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hyperkeratosis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Nail disorder	0/4 (0%)		0/13 (0%)		1/49 (2%)
Night sweats	0/4 (0%)		0/13 (0%)		1/49 (2%)
Palmar-plantar erythrodysaesthesia syndrome	0/4 (0%)		0/13 (0%)		1/49 (2%)
Pruritus	0/4 (0%)		0/13 (0%)		5/49 (10.2%)
Rash	0/4 (0%)		1/13 (7.7%)		4/49 (8.2%)
Rash maculo-papular	0/4 (0%)		0/13 (0%)		1/49 (2%)
Skin lesion	0/4 (0%)		0/13 (0%)		1/49 (2%)
Papule	1/4 (25%)		0/13 (0%)		0/49 (0%)
Vascular disorders
Lymphoedema	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Peripheral venous disease	1/4 (25%)		0/13 (0%)		0/49 (0%)
Venous thrombosis	0/4 (0%)		1/13 (7.7%)		0/49 (0%)
Deep vein thrombosis	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hot flush	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hypertension	0/4 (0%)		0/13 (0%)		1/49 (2%)
Hypotension	0/4 (0%)		0/13 (0%)		2/49 (4.1%)
Hypovolaemic shock	0/4 (0%)		0/13 (0%)		1/49 (2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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