Trial Outcomes & Findings for First-in-Human Study of MS201408-0005A as Single Agent and in Combinations (NCT NCT03306420)

NCT ID: NCT03306420

Last Updated: 2020-02-06

Results Overview

DLTs was assessed as per NCI CTCAE v 4.03. DLT defined as any Grade greater than or equal (\>=) 3 nonhematological AE or Immune-related adverse event (irAE) assessed by Investigator or Sponsor during first Cycle (first 28 days) of study treatment. Asymptomatic Grade \>= 3 lipase or amylase elevation not associated with clinical manifestations of pancreatitis. Any TEAE observed in subsequent cycle. Any Grade 4 neutropenia of \>= 5 days duration, Grade \>= 3 febrile neutropenia, Grade 3 hemoglobin decrease despite blood transfusion or erythroid growth factor. Grade 4 hemoglobin decrease assessed as related to study drug. Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Any Grade \>= 3 clinical signs and symptoms related to increased QTc.

• Recruitment status: TERMINATED
• Study phase: PHASE1
• Target enrollment: 15 participants
• Primary outcome timeframe: Cycle 1 (Each Cycle is of 28 days)
• Results posted on: 2020-02-06

Participant Flow

First Participant First Visit: 03-Oct-2017 Last Participant Last Visit: 14-Jan-2019.

Participant milestones

Measure	Part 1A Dose Escalation: M4112 100 mg Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Overall Study STARTED	3	3	3	3	3
Overall Study COMPLETED	3	3	3	3	3
Overall Study NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

First-in-Human Study of MS201408-0005A as Single Agent and in Combinations

Baseline characteristics by cohort

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Total n=15 Participants Total of all reporting groups
Age, Continuous	60.7 Years STANDARD_DEVIATION 14.84 • n=5 Participants	54.7 Years STANDARD_DEVIATION 8.33 • n=7 Participants	43.0 Years STANDARD_DEVIATION 9.54 • n=5 Participants	67.7 Years STANDARD_DEVIATION 7.51 • n=4 Participants	62.3 Years STANDARD_DEVIATION 14.84 • n=21 Participants	57.7 Years STANDARD_DEVIATION 13.04 • n=8 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants	3 Participants n=21 Participants	13 Participants n=8 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=8 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	3 Participants n=8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	3 Participants n=21 Participants	12 Participants n=8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	3 Participants n=8 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants	2 Participants n=21 Participants	12 Participants n=8 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants

PRIMARY outcome

Timeframe: Cycle 1 (Each Cycle is of 28 days)

Population: DLT analysis set included all participants treated in dose escalation cohorts who do not miss greater than (\>) 5 planned total daily doses of M4112 in the first cycle (first 28 days) of the dose escalation part for other than DLT.

DLTs was assessed as per NCI CTCAE v 4.03. DLT defined as any Grade greater than or equal (>=) 3 nonhematological AE or Immune-related adverse event (irAE) assessed by Investigator or Sponsor during first Cycle (first 28 days) of study treatment. Asymptomatic Grade >= 3 lipase or amylase elevation not associated with clinical manifestations of pancreatitis. Any TEAE observed in subsequent cycle. Any Grade 4 neutropenia of >= 5 days duration, Grade >= 3 febrile neutropenia, Grade 3 hemoglobin decrease despite blood transfusion or erythroid growth factor. Grade 4 hemoglobin decrease assessed as related to study drug. Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Any Grade >= 3 clinical signs and symptoms related to increased QTc.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=2 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) as Per National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline up to safety follow-up visit, assessed up to 15.4 months

Population: The safety analysis set included all participants who had received at least 1 dose of the study treatment.

An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment related AE was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Who Experienced a Treatment Related Adverse Events (TRAE) According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 Any TEAE	3 Participants	3 Participants	3 Participants	3 Participants	3 Participants
Part 1A Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Who Experienced a Treatment Related Adverse Events (TRAE) According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 Any Related TEAE	3 Participants	2 Participants	1 Participants	3 Participants	3 Participants

PRIMARY outcome

Timeframe: Baseline up to safety follow-up visit, assessed up to 15.4 months

Population: The safety analysis set included all participants who had received at least 1 dose of the study treatment.

The laboratory measurements included hematology, biochemistry and hormonal tests. Number of participants with any clinically significant abnormalities in laboratory measurements were reported. Clinical significance was determined by the investigator.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline up to safety follow-up visit, assessed up to 15.4 months

Population: The safety analysis set included all participants who had received at least 1 dose of the study treatment.

Vital signs assessment included blood pressure, pulse rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Vital Signs	2 Participants	0 Participants	1 Participants	1 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline up to safety follow-up visit, assessed up to 15.4 months

Population: The safety analysis set included all participants who had received at least 1 dose of the study treatment.

ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, 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. Number of participants with on-treatment shift in ECOG PS Score from 0 to 1 were reported.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Number of Participants With On-Treatment Shift in Eastern Cooperative Oncology Performance Status (ECOG PS) Score From 0 to 1	1 Participants	0 Participants	1 Participants	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline up to safety follow-up visit, assessed up to 15.4 months

Population: The safety analysis set included all participants who had received at least 1 dose of the study treatment.

A complete physical examination (including, general appearance, skin, pulmonary, cardiovascular, gastrointestinal, external genitourinary only as medically relevant, lymphatic, neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, and cognitive status) was performed. Number of participants with clinical significant change from baseline in physical examination abnormalities were reported. Clinical significance was determined by the investigator.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Abnormalities	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)

Population: Pharmacokinetic (PK) analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "number analyzed" signifies those participants who were evaluable for this outcome measure at given time points.

Area under the drug concentration-time curve from 0 to 8 h post dosing for M4112. AUC0-8 was calculated according to the mixed log-linear trapezoidal rule.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post Dose AUC(0-8h) of M4112 Cycle 1 Day 1	3550 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 14.4	8740 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 13.6	27700 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 21.4	50400 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 7.7	14600 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 85.1
Part 1A Dose Escalation: Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post Dose AUC(0-8h) of M4112 Cycle 1 Day 15	4790 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 25.4	7580 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 11.5	31500 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 28.8	59500 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 12.7	NA nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 93200 ng\*h/mL.

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)

Population: PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "number analyzed" signifies those participants who were evaluable for this outcome measure at given time points.

Pharmacokinetic PK parameter Cmax was obtained directly from the plasma concentration versus time curve.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of M4112 Cycle 1 Day 1	806 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 9.9	2110 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 13.6	7670 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 39.6	11700 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 24.6	2770 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 83.6
Part 1A Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of M4112 Cycle 1 Day 15	975 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 34.9	1720 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 20.5	6560 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 27.4	12100 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 2.2	NA nanogram per milliliter (ng/mL) Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 21100 ng/mL.

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)

Population: PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "number analyzed" signifies those participants who were evaluable for this outcome measure at given time points.

Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Time to Reach Maximum Plasma Concentration (Tmax) of M4112 Cycle 1 Day 1	1.08 Hours Interval 1.08 to 2.12	2.10 Hours Interval 2.07 to 3.08	1.08 Hours Interval 1.07 to 1.08	1.00 Hours Interval 0.97 to 1.07	2.08 Hours Interval 2.07 to 4.12
Part 1A Dose Escalation: Time to Reach Maximum Plasma Concentration (Tmax) of M4112 Cycle 1 Day 15	3.08 Hours Interval 2.12 to 4.13	2.10 Hours Interval 1.0 to 6.08	1.08 Hours Interval 0.5 to 3.0	1.03 Hours Interval 0.93 to 2.17	NA Hours Interval 2.0 to 2.0 Median was not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 2.00 hours.

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)

Population: PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "number analyzed" signifies those participants who were evaluable for this outcome measure at given time points.

Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (AUC0-8/Dose) of M4112 Cycle 1 Day 1	35.5 ng*h/mL/mg Geometric Coefficient of Variation 14.4	43.7 ng*h/mL/mg Geometric Coefficient of Variation 13.6	69.1 ng*h/mL/mg Geometric Coefficient of Variation 21.4	84.0 ng*h/mL/mg Geometric Coefficient of Variation 7.7	18.2 ng*h/mL/mg Geometric Coefficient of Variation 85.1
Part 1A Dose Escalation: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (AUC0-8/Dose) of M4112 Cycle 1 Day 15	47.9 ng*h/mL/mg Geometric Coefficient of Variation 25.4	37.9 ng*h/mL/mg Geometric Coefficient of Variation 11.5	78.8 ng*h/mL/mg Geometric Coefficient of Variation 28.8	99.2 ng*h/mL/mg Geometric Coefficient of Variation 12.7	NA ng*h/mL/mg Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 116 ng\*h/mL/mg.

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)

Population: PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "number analyzed" signifies those participants who were evaluable for this outcome measure at given time points.

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

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4112 Cycle 1 Day 1	8.06 ng/mL/mg Geometric Coefficient of Variation 9.9	10.5 ng/mL/mg Geometric Coefficient of Variation 13.6	19.2 ng/mL/mg Geometric Coefficient of Variation 39.6	19.6 ng/mL/mg Geometric Coefficient of Variation 24.6	3.47 ng/mL/mg Geometric Coefficient of Variation 83.6
Part 1A Dose Escalation: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4112 Cycle 1 Day 15	9.75 ng/mL/mg Geometric Coefficient of Variation 34.9	8.58 ng/mL/mg Geometric Coefficient of Variation 20.5	16.4 ng/mL/mg Geometric Coefficient of Variation 27.4	20.2 ng/mL/mg Geometric Coefficient of Variation 2.2	NA ng/mL/mg Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 26.4 ng/mL/mg.

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)

Population: PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Accumulation ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 hours After Administration (Racc[AUC0-8h]) of M4112 was reported. Racc(AUC0-8h) calculated as AUC0-8h, on Cycle 1 Day 15 divided by AUC0-8h on Cycle 1 Day 1.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=1 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (Racc[AUC0-8h]) of M4112	1.35 Ratio Geometric Coefficient of Variation 11.4	0.868 Ratio Geometric Coefficient of Variation 15.3	1.14 Ratio Geometric Coefficient of Variation 50.1	1.18 Ratio Geometric Coefficient of Variation 9.4	NA Ratio Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 4.67.

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)

Population: PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Accumulation ratio for Cmax was calculated as Cmax, Cycle 1 Day 15 divided by Cmax, Cycle 1 Day 1.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=1 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part IA Dose Escalation: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4112	1.21 Ratio Geometric Coefficient of Variation 24.8	0.815 Ratio Geometric Coefficient of Variation 7.0	0.856 Ratio Geometric Coefficient of Variation 66.8	1.03 Ratio Geometric Coefficient of Variation 23.0	NA Ratio Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants Individual value was 5.26.

SECONDARY outcome

Timeframe: Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)

Population: PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "number analyzed" signifies those participants who were evaluable for this outcome measure at given time points.

Maximum pre-dose observed plasma concentration was reported.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Pre-dose Observed Plasma Concentration (Cpre) of M4112 Cycle 1 Day 8	156 ng/mL Geometric Coefficient of Variation 58.2	96.5 ng/mL Geometric Coefficient of Variation 85.0	1240 ng/mL Geometric Coefficient of Variation 51.6	4410 ng/mL Geometric Coefficient of Variation 54.5	5200 ng/mL Geometric Coefficient of Variation 105.4
Part 1A Dose Escalation: Pre-dose Observed Plasma Concentration (Cpre) of M4112 Cycle 1 Day 15	221 ng/mL Geometric Coefficient of Variation 20.5	199 ng/mL Geometric Coefficient of Variation 53.9	1630 ng/mL Geometric Coefficient of Variation 45.7	3380 ng/mL Geometric Coefficient of Variation 42.4	NA ng/mL Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 9810 ng/mL.
Part 1A Dose Escalation: Pre-dose Observed Plasma Concentration (Cpre) of M4112 Cycle 2 Day 1	128 ng/mL Geometric Coefficient of Variation 67.7	NA ng/mL Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual values were 83.3 and 85.2 ng/mL.	957 ng/mL Geometric Coefficient of Variation 72.1	NA ng/mL Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual values were 1910 and 2560 ng/mL.	NA ng/mL Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 8560 ng/mL.

SECONDARY outcome

Timeframe: Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)

Population: PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here "number analyzed" signifies those participants who were evaluable for this outcome measure at given time points.

Dose normalized pre-dose observed plasma concentration (Cpre/dose) of M4112 was reported.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Dose Normalized Pre-dose Observed Plasma Concentration (Cpre/Dose) of M4112 Cycle 1 Day 8	1.56 ng/mL/mg Geometric Coefficient of Variation 58.2	0.482 ng/mL/mg Geometric Coefficient of Variation 85.0	3.11 ng/mL/mg Geometric Coefficient of Variation 51.6	7.35 ng/mL/mg Geometric Coefficient of Variation 54.5	6.50 ng/mL/mg Geometric Coefficient of Variation 105.4
Part 1A Dose Escalation: Dose Normalized Pre-dose Observed Plasma Concentration (Cpre/Dose) of M4112 Cycle 1 Day 15	2.21 ng/mL/mg Geometric Coefficient of Variation 20.5	0.997 ng/mL/mg Geometric Coefficient of Variation 53.9	4.08 ng/mL/mg Geometric Coefficient of Variation 45.7	5.63 ng/mL/mg Geometric Coefficient of Variation 42.4	NA ng/mL/mg Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 12.3 ng/mL/mg.
Part 1A Dose Escalation: Dose Normalized Pre-dose Observed Plasma Concentration (Cpre/Dose) of M4112 Cycle 2 Day 1	1.28 ng/mL/mg Geometric Coefficient of Variation 67.7	NA ng/mL/mg Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual values were 0.417 and 0.426 ng/mL/mg.	2.39 ng/mL/mg Geometric Coefficient of Variation 72.1	NA ng/mL/mg Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual values were 3.18 and 4.27 ng/mL/mg.	NA ng/mL/mg Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 10.7 ng/mL/mg.

SECONDARY outcome

Timeframe: Baseline up to safety follow-up visit, assessed up to 15.4 months

Population: Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.

Time-matched, replicate ECGs and PK samples collected in the dose-escalation phase and planned to analyze QTC response using slope analysis of exposure/response.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From first dose of study drug administration until PD, assessed up to 15.4 months

Population: The safety analysis set included all participants who had received at least 1 dose of the study treatment. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

BOR was determined according to Response Evaluation Criteria in Solid Tumors version1.1(RECIST 1.1).Best response obtained among all tumor assessment visits after the date of first study drug administration until documented disease progression. BOR rate is defined as the number of participants with BOR was either confirmed complete response (CR) partial response (PR), stable disease (SD) and progressive disease (PD) relative to the number of participants belonging to the study of interest. CR:Disappearance of all target lesions; PR:At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; PD:At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; SD:Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=2 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR) Complete Response	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR) Partial Response	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR) Stable Disease	2 Participants	3 Participants	3 Participants	1 Participants	0 Participants
Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR) Progressive Disease	1 Participants	0 Participants	0 Participants	2 Participants	2 Participants

SECONDARY outcome

Timeframe: From first dose of study drug administration until PD, assessed up to 15.4 months

Population: Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.

Duration of response defined as time from first documentation of objective response complete response (CR) or partial response (PR) whichever is first recorded) to date of first documentation of objective progression of disease or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of longest diameter (SLD) of all lesions.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From first dose of study drug administration until PD, assessed up to 15.4 months

Population: The safety analysis set included all participants who had received at least 1 dose of the study treatment.

Disease control was defined as percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. 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. Percentage of participants with disease control were reported.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Disease Control Rate	66.7 Percentage of Participants Interval 9.4 to 99.2	100 Percentage of Participants Interval 29.2 to 100.0	100 Percentage of Participants Interval 29.2 to 100.0	33.3 Percentage of Participants Interval 0.8 to 90.6	0.0 Percentage of Participants Interval 0.0 to 70.8

SECONDARY outcome

Timeframe: From first dose of study drug administration until PD, assessed up to 15.4 months

Population: Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.

Tumor response was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) as judged by RECIST version 1.1. CR was defined for target lesions (TLs) as the disappearance of all lesions, and for non-target lesions (NTLs) as the disappearance of all non-target non-measurable lesions and/or normalization of serum levels of tumor markers. PR was defined for TLs as at least a 30 percent (%) decrease from baseline (BL) in the sum of longest diameter (SLD) of TLs.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From first dose of study drug administration until PD, assessed up to 15.4 months

Population: The safety analysis set included all participants who had received at least 1 dose of the study treatment.

Progression free survival time defined as time from start date to the date of the first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.

Outcome measures

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 Participants Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 Participants Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 Participants Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 Participants Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 Participants Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Part 1A Dose Escalation: Progression Free Survival Time (PFS)	3.7 Months Interval 1.9 to 8.1	5.5 Months Interval 3.9 to 5.5	NA Months Interval 2.1 to 10.2 The Median was not reached due to higher number (\>50%) of censored participants.	1.8 Months Interval 1.1 to 3.7	1.2 Months Interval 0.0 to 1.2

Adverse Events

Part 1A Dose Escalation: M4112 100 mg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Part 1A Dose Escalation: M4112 200 mg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Part 1A Dose Escalation: M4112 400 mg

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Part 1A Dose Escalation: M4112 600 mg

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Part 1A Dose Escalation: M4112 800 mg

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 participants at risk Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 participants at risk Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 participants at risk Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 participants at risk Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 participants at risk Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Gastrointestinal disorders Ascites	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
General disorders Disease progression	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Skin and subcutaneous tissue disorders Dermatitis allergic	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months

Other adverse events

Measure	Part 1A Dose Escalation: M4112 100 mg n=3 participants at risk Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 200 mg n=3 participants at risk Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 400 mg n=3 participants at risk Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 600 mg n=3 participants at risk Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).	Part 1A Dose Escalation: M4112 800 mg n=3 participants at risk Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
Investigations Lymphocyte count decreased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Platelet count decreased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Red blood cell count decreased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Weight decreased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Weight increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Metabolism and nutrition disorders Decreased appetite	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Metabolism and nutrition disorders Hyperphosphataemia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Blood and lymphatic system disorders Anaemia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Blood and lymphatic system disorders Anaemia of malignant disease	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Cardiac disorders Palpitations	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Endocrine disorders Hypothyroidism	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Eye disorders Vision blurred	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Abdominal distension	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Constipation	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	66.7% 2/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Dry mouth	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Dyspepsia	66.7% 2/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Dysphagia	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Gastritis	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Ileus	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Nausea	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Gastrointestinal disorders Vomiting	66.7% 2/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
General disorders Fatigue	66.7% 2/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
General disorders Oedema	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
General disorders Oedema peripheral	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
General disorders Pyrexia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Infections and infestations Influenza	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Alanine aminotransferase increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Amylase increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Aspartate aminotransferase increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	66.7% 2/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Blood alkaline phosphatase increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Blood bilirubin increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Blood creatine phosphokinase increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Blood creatinine increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Blood urea increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Electrocardiogram QT prolonged	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Gamma-glutamyltransferase increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Investigations Lipase increased	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	66.7% 2/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Musculoskeletal and connective tissue disorders Bone pain	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Nervous system disorders Dysaesthesia	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Nervous system disorders Peripheral sensory neuropathy	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Psychiatric disorders Insomnia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Renal and urinary disorders Azotaemia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Renal and urinary disorders Urinary tract obstruction	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Renal and urinary disorders Urinary tract pain	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Reproductive system and breast disorders Pelvic pain	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Respiratory, thoracic and mediastinal disorders Cough	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Respiratory, thoracic and mediastinal disorders Dry throat	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Respiratory, thoracic and mediastinal disorders Dyspnoea	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Respiratory, thoracic and mediastinal disorders Pharyngeal haemorrhage	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Skin and subcutaneous tissue disorders Rash erythematous	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Skin and subcutaneous tissue disorders Rash generalised	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Skin and subcutaneous tissue disorders Rash maculo-papular	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Vascular disorders Hot flush	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Vascular disorders Hypertension	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months
Vascular disorders Hypotension	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	0.00% 0/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months	33.3% 1/3 • Baseline up to safety follow-up visit, assessed up to 15.4 months

Additional Information

Communication Center

Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: service@emdgroup.com

Results disclosure agreements

• Principal investigator is a sponsor employee A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.
• Publication restrictions are in place

Restriction type: OTHER