Trial Outcomes & Findings for A Japanese Phase 1 Trial of c-Met Inhibitor MSC2156119J in Subjects With Solid Tumors (NCT NCT01832506)

Last Updated: 2020-08-06

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

12 participants

Primary outcome timeframe

Cycle 1 (Day 1 up to 21)

Results posted on

2020-08-06

Participant Flow

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

Participant milestones

Participant milestones
Measure	MSC2156119J 215 mg Subjects were administered with MSC2156119J 215 milligram (mg) orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Overall Study STARTED	3	3	6
Overall Study COMPLETED	3	3	6
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 Participants Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	Total n=12 Participants Total of all reporting groups
Age, Continuous	61.7 years STANDARD_DEVIATION 9.6 • n=5 Participants	62.0 years STANDARD_DEVIATION 5.0 • n=7 Participants	65.7 years STANDARD_DEVIATION 9.8 • n=5 Participants	63.8 years STANDARD_DEVIATION 8.3 • n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	8 Participants n=4 Participants

PRIMARY outcome

Timeframe: Cycle 1 (Day 1 up to 21)

Population: 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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Number of Subjects Experiencing Dose Limiting Toxicity (DLT)	0 subjects	0 subjects	0 subjects

SECONDARY outcome

Timeframe: Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)

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

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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs or TEAEs Leading To Death TEAEs	2 subjects	3 subjects	6 subjects
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs or TEAEs Leading To Death Serious TEAEs	0 subjects	3 subjects	1 subjects
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs or TEAEs Leading To Death TEAEs Leading To Death	0 subjects	0 subjects	1 subjects

SECONDARY outcome

Timeframe: Baseline up to 30 days after last dose of study drug administration (55.1 weeks)

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

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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score of 2 or Higher	0 subjects	0 subjects	0 subjects

SECONDARY outcome

Timeframe: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1

Population: Pharmacokinetic (PK) analysis set included all subjects who had 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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J	244.4 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 29.9	301.3 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 42.6	442.4 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 27.5

SECONDARY outcome

Timeframe: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1

Population: 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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=5 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J	807.5 ng/mL Geometric Coefficient of Variation 11.5	610.1 ng/mL Geometric Coefficient of Variation 84.8	996.8 ng/mL Geometric Coefficient of Variation 17.5

SECONDARY outcome

Timeframe: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1

Population: PK analysis set included all subjects who had 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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Time to Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J	8.000 hours Interval 7.92 to 8.03	8.017 hours Interval 8.0 to 10.02	10.000 hours Interval 3.97 to 23.85

SECONDARY outcome

Timeframe: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1

Population: 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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=5 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Time to Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J	8.000 hours Interval 7.98 to 8.02	9.917 hours Interval 1.95 to 10.23	4.133 hours Interval 3.87 to 9.87

SECONDARY outcome

Timeframe: 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

Timeframe: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1

Population: 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.

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

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=5 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time t (AUC0-t) After Multiple Dose of MSC2156119J	16088.6 h*ng/mL Geometric Coefficient of Variation 12.2	13313.4 h*ng/mL Geometric Coefficient of Variation 82.5	21509.0 h*ng/mL Geometric Coefficient of Variation 16.7

SECONDARY outcome

Timeframe: Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks

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

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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Number of Subjects With Best Overall Response (BOR) CR	0 subjects	0 subjects	0 subjects
Number of Subjects With Best Overall Response (BOR) PR	0 subjects	0 subjects	0 subjects
Number of Subjects With Best Overall Response (BOR) SD	0 subjects	0 subjects	2 subjects
Number of Subjects With Best Overall Response (BOR) PD	3 subjects	3 subjects	3 subjects
Number of Subjects With Best Overall Response (BOR) Not Evaluable	0 subjects	0 subjects	1 subjects

SECONDARY outcome

Timeframe: Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks

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

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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=3 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 Participants Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 Participants Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Number of Subjects With Clinical Benefit	0 subjects	0 subjects	2 subjects

SECONDARY outcome

Timeframe: Day 21 of Cycle 2 and each subsequent cycle up to a maximum of 51.1 weeks

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

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.

Outcome measures

Outcome measures
Measure	MSC2156119J 215 mg n=12 Participants Subjects were administered with MSC2156119J 215 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg Subjects were administered with MSC2156119J 300 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg Subjects were administered with MSC2156119J 500 mg once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Progression-free Survival (PFS)	1.38 months Interval 1.15 to 1.38	—	—

Adverse Events

MSC2156119J 215 mg

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

MSC2156119J 300 mg

Serious events: 3 serious events

Other events: 3 other events

Deaths: 0 deaths

MSC2156119J 500 mg

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	MSC2156119J 215 mg n=3 participants at risk Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 participants at risk Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 participants at risk Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
Respiratory, thoracic and mediastinal disorders DYSPNOEA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
General disorders MALAISE	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Metabolism and nutrition disorders DECREASED APPETITE	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Nervous system disorders ALTERED STATE OF CONSCIOUSNESS	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)

Other adverse events

Additional Information

Merck KGaA Communication Center

Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	MSC2156119J 215 mg n=3 participants at risk Subjects were administered with MSC2156119J 215 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 300 mg n=3 participants at risk Subjects were administered with MSC2156119J 300 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.	MSC2156119J 500 mg n=6 participants at risk Subjects were administered with MSC2156119J 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity.
General disorders FATIGUE	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	66.7% 2/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
General disorders OEDEMA PERIPHERAL	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	66.7% 4/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
General disorders MALAISE	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
General disorders PYREXIA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
General disorders VESSEL PUNCTURE SITE ERYTHEMA	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Gastrointestinal disorders CONSTIPATION	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	66.7% 2/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	50.0% 3/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Gastrointestinal disorders NAUSEA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	66.7% 2/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	50.0% 3/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Gastrointestinal disorders VOMITING	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	50.0% 3/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Gastrointestinal disorders ABDOMINAL DISCOMFORT	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Gastrointestinal disorders ASCITES	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Gastrointestinal disorders DENTAL CARIES	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Gastrointestinal disorders PROCTALGIA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Gastrointestinal disorders STOMATITIS	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Metabolism and nutrition disorders DECREASED APPETITE	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	50.0% 3/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Metabolism and nutrition disorders HYPOALBUMINAEMIA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	66.7% 4/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Metabolism and nutrition disorders HYPONATRAEMIA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Investigations AMYLASE INCREASED	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 2/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Investigations LIPASE INCREASED	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 2/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Investigations BLOOD CREATININE INCREASED	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Investigations C-REACTIVE PROTEIN INCREASED	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) CANCER PAIN	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) TUMOUR ASSOCIATED FEVER	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Nervous system disorders DYSGEUSIA	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Nervous system disorders DIZZINESS	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Nervous system disorders HYPOAESTHESIA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Nervous system disorders NEUROPATHY PERIPHERAL	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Psychiatric disorders INSOMNIA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 2/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Psychiatric disorders ANXIETY	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Psychiatric disorders DEPRESSION	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Respiratory, thoracic and mediastinal disorders DYSPNOEA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Skin and subcutaneous tissue disorders DERMATITIS ACNEIFORM	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Skin and subcutaneous tissue disorders DRUG ERUPTION	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Skin and subcutaneous tissue disorders URTICARIA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Blood and lymphatic system disorders IRON DEFICIENCY ANAEMIA	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Eye disorders EYE MOVEMENT DISORDER	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Infections and infestations NASOPHARYNGITIS	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Infections and infestations SUBCUTANEOUS ABSCESS	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Injury, poisoning and procedural complications WOUND COMPLICATION	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Musculoskeletal and connective tissue disorders BACK PAIN	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	16.7% 1/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Renal and urinary disorders URINARY TRACT OBSTRUCTION	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Vascular disorders DEEP VEIN THROMBOSIS	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Vascular disorders THROMBOPHLEBITIS	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)
Vascular disorders VARICOSE VEIN	0.00% 0/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	33.3% 1/3 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)	0.00% 0/6 • Baseline Up to 30 days after last dose of study drug administration (55.1 weeks)