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

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.

Time frame: 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.

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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.

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

Time frame: 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.

Time frame: 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 pre-dose observed plasma concentration (Cpre/dose) of M4112 was reported.

Time frame: 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.

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.

Time frame: 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.

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

Time frame: 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.

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.

Time frame: 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.

Maximum pre-dose observed plasma concentration was reported.

Time frame: 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.

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.

Time frame: 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.

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.

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

Time frame: 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.

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.

Time frame: 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.

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

Time frame: 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.