Trial Outcomes & Findings for First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone (NCT NCT04075721)

First participant signed informed consent: 26 September 2019, Last participant last visit: 01 April 2021.

This study was planned to be conducted in 2 parts; Part A: Dose escalation part and Part B: Dose expansion part. However, because of early discontinuation, only Part A was conducted; due to lack of participant enrollment before Part A reached its primary objective and before Part B was started.

First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone

DLT: any of adverse events (AEs), assessed by Investigator and/Sponsor at any dose, regimen, and judged not to be related to underlying disease/any previous/concomitant medication/concurrent condition during first cycle of study treatment. DLT was confirmed by Safety Monitoring Committee. DLTs: Grade (Gr) greater than/equal to (\>=) 3 nonhematologic AE with exception of: Single laboratory values out of abnormal range; Gr3 diarrhea persisting less than or equal to \[\<=\] 72 hour (hr); Nausea and vomiting \<= 72 hr; Transient Gr3 fatigue, local reactions, flu-like symptoms \<= 72 hr; Gr3 nonrecurrent skin toxicity; Asymptomatic Gr \>= 3 lipase/amylase elevation. Any Gr \>= 4 hematologic AE: Gr \>= 3 febrile neutropenia with Absolute Neutrophil Count (ANC) \<1000 per cube millimeter and temperature of \>38.3 Celsius (°C); Gr \>= 3 thrombocytopenia; Gr4 thrombocytopenia lasting \>7 days.

Adverse Event (AE): any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. TEAEs: events that started from first dose of study intervention to 30 days after end of study intervention, or the cutoff date, whichever occurred first. TEAEs included both serious TEAEs (Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect) and non-serious TEAEs. TRAEs are defined as those AEs which are reasonably related to the study intervention.

Adverse Event (AE): any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. TEAEs: events that started from first dose of study intervention to 30 days after end of study intervention, or the cutoff date, whichever occurred first. TEAEs included both serious TEAEs (Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect) and non-serious TEAEs. TRAEs are defined as those AEs which are reasonably related to the study intervention.

12-lead ECG were recorded after the participants have rested for at least 15 minutes in supine position. Change from baseline in 12-Lead ECG findings that is QT interval - Fridericia's correction formula at pre-dose on Cycle 2 Day 1 were reported.

ECOG performance status measured to assess participant's performance status on a scale of 0 to 5, where 0 = Fully active, able to carry on all pre-disease activities without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities; 3 = Capable of only limited self-care, confined to bed/chair for more than 50 percent of waking hours; 4 = Completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5 = dead. ECOG performance status was reported in terms of number of participants with shifts in score from baseline value vs worst post-baseline value (that is \[i.e.\] highest score).

Laboratory parameters included hematology, chemistry, and coagulation. Number of participants with shifts from baseline (Grade \<3) to \>= Grade 3 were reported as per NCI-CTCAE, v5.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.

The number of participants with treatment-emergent changes from baseline in increased Body Temperature (degree Celsius \[°C\]) were reported by using criteria: Baseline temperature (temp.) less than (\<) 37°C, on treatment change \<1°C, 1 - \<2°C, 2 - \<3°C and greater than or equal to (\>=)3°C; Baseline temp. 37 - \<38°C, on treatment change \<1°C, 1 - \<2°C, 2 - \<3°C and \>=3°C; Baseline temp. 38 - \<39°C, on treatment change \<1°C, 1 - \<2°C, 2 - \<3°C and \>=3°C; Baseline temp. 39-\<40°C, on treatment change \<1°C, 1 - \<2°C, 2 - \<3°C and \>=3°C; Baseline temp. \>=40°C, on treatment change \<1°C, 1 - \<2°C, 2 - \<3°C and \>=3°C.

The number of participants with treatment-emergent changes from baseline (BS) in Increase (Ic.)/Decrease (Dc.) Systolic Blood Pressure (SBP) and diastolic blood pressure (DBP) (millimeter of mercury \[mmHg\]) were reported by using criteria: Ic./Dc. BS SBP/DBP \<140/\<90 mmHg, on maximal treatment (TR) change =\<20 mmHg, \>20 - =\<40 mmHg and \>40 mmHg; Ic./Dc. BS SBP/DBP \>=140/\>=90 mmHg, on maximal TR change =\<20 mmHg, \>20 - =\<40 mmHg and \>40 mmHg.

The number of participants with treatment-emergent changes from baseline in Increase (Ic.)/Decrease (Dc.) maximal Respiration Rate (RR) were reported by using criteria: Ic./Dc. BS RR \<20 breaths per minute (breaths/min), on TR change (ch) =\<5 breaths/min, \>5 - =\<10 breaths/min and \>10 breaths/min. Ic./Dc. BS RR \>=20 breaths/min, on TR ch =\<5 breaths/min, \>5 - =\<10 breaths/min and \>10 breaths/min.

Cmax was obtained directly from the concentration versus time curve. Single dose PK data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (\>) 2 in which a measurement of greater than (\>) lower limit of quantification (LLOQ) represents a valid measurement.

Cmax was obtained directly from the concentration versus time curve.

Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. Single dose PK data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (\>) 2 in which a measurement of greater than (\>) lower limit of quantification (LLOQ) represents a valid measurement.

Area under the plasma concentration versus time curve from time zero to 24 hours post dosing for M3258. Single dose PK data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (\>) 2 in which a measurement of greater than (\>) lower limit of quantification (LLOQ) represents a valid measurement.

Area under the plasma concentration versus time curve from time zero to 24 hours post dosing for M3258.

Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement. Single dose Pd data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (\>) 2 in which a measurement of greater than (\>) lower limit of quantification (LLOQ) represents a valid measurement.

Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement.

Change from baseline in serum monoclonal (M)-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention.

Change from baseline in urine M-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention.

Change from baseline in free light chain ratio was reported at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention.

OR is defined as a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IMWG Criteria: sCR: CR (negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow); normal free light chain (FLC) ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis/\>= 90% reduction in serum M-protein and urine M-protein level \< 100 mg/24 hours; PR: \>= 50% reduction of serum M-Protein and reduction in urinary M-protein by \>= 90%/to \< 200 mg/24 hours. In addition to the above, if present at baseline a \>= 50% reduction in the size of soft tissue plasmacytomas is also required.

DOR was defined participants with confirmed response, as time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to date of first documentation of progression disease (PD)/death due to any cause, whichever occurred first. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. PR: \>= 50% reduction of serum M-Protein and reduction in urinary M-protein by \>= 90%/to \< 200 mg/24 hours. In addition to the above, if present at baseline a \>= 50% reduction in the size of soft tissue plasmacytomas is also required. PD: \>= 25% increase from lowest response value in serum. Development of new or increased size of existing bone lesions or soft tissue plasmacytomas. Hypercalcemia attributed to the plasma cell proliferative disorder.

Time to response was defined as the time from the first dose of M3258 to the documentation of first response (Complete Response \[CR\] or Partial Response \[PR\]). CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. PR: \>= 50% reduction of serum M-Protein and reduction in urinary M-protein by \>= 90% or to \< 200 mg/24 hours. In addition to the above, if present at baseline a \>= 50% reduction in the size of soft tissue plasmacytomas is also required.