Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Dexamethasone acetate

Participants received M3258 at a dose of 10 milligrams (mg) orally, once daily (QD) or twice per week on Day 1 and Day 4 until disease progression.

M3258

Participants received M3258 at a dose of 20 mg orally, twice per week on Day 1 and Day 4 until disease progression.

M3258 20 mg

Medical Responsible

The purpose of this study was to determine the safety, tolerability, pharmacokinetics, pharmacodynamics and early efficacy signs of M3258 as a single agent and co-administered with dexamethasone in participants with Relapsed Refractory Multiple Myeloma (RRMM).

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

A Phase I Open Label First in Human Dose Escalation of the Immunoproteasome Inhibitor M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone in Participants With Relapsed Refractory Multiple Myeloma

We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website http://bit.ly/IPD21

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.

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.

Merck KGaA, Darmstadt, Germany

EMD Serono Research & Development Institute, Inc.

Safety analysis set included all participants who were administered any dose of the study medication.

Participants received M3258 at a dose of 10 milligrams (mg) orally, once daily (QD) until disease progression.

M3258 10 mg QD

Participants received M3258 at a dose of 10 mg orally, twice per week on Day 1 and Day 4 until disease progression.

M3258 10 mg Twice Per Week

M3258 20 mg Twice Per Week

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Part B was not conducted as the study was early discontinued due to lack of participant's recruitment into Part A before Part A reached its primary objective.

Communication Center

DLT analysis set: all participants who received at least 1 dose of study intervention and meet at least 1 of criteria specified in statistical analysis plan.

Part A: Number of Participants With Dose-Limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0

Participants with TEAEs

Participants with TRAEs

Part A: Number of Participants With Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs)

Part A: Number of Participants With Treatment-Emergent Adverse Event (TEAEs) Outside of Dose-Limiting Toxicity (DLT) Period That Safety Monitoring Committee Deems Relevant for Determination of the Maximum Tolerated Dose

Safety analysis set included all participants who were administered any dose of the study medication. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Part A: Change From Baseline in 12-lead Electrocardiogram (ECG) Findings: QT Interval - Fridericia's Correction Formula

Baseline score 0, worst post-baseline score 0

Baseline score 0, worst post-baseline score 1

Baseline score 0, worst post-baseline score 2

Baseline score 0, worst post-baseline score 3

Baseline score 0, worst post-baseline score 4

Baseline score 0, worst post-baseline score 5

Baseline score 1, worst post-baseline score 0

Baseline score 1, worst post-baseline score 1

Baseline score 1, worst post-baseline score 2

Baseline score 1, worst post-baseline score 3

Baseline score 1, worst post-baseline score 4

Baseline score 1, worst post-baseline score 5

Baseline score 2, worst post-baseline score 0

Baseline score 2, worst post-baseline score 1

Baseline score 2, worst post-baseline score 2

Baseline score 2, worst post-baseline score 3

Baseline score 2, worst post-baseline score 4

Baseline score 2, worst post-baseline score 5

Baseline score 3, worst post-baseline score 0

Baseline score 3, worst post-baseline score 1

Baseline score 3, worst post-baseline score 2

Baseline score 3, worst post-baseline score 3

Baseline score 3, worst post-baseline score 4

Baseline score 3, worst post-baseline score 5

Baseline score 4, worst post-baseline score 0

Baseline score 4, worst post-baseline score 1

Baseline score 4, worst post-baseline score 2

Baseline score 4, worst post-baseline score 3

Baseline score 4, worst post-baseline score 4

Baseline score 4, worst post-baseline score 5

Baseline score 5, worst post-baseline score 0

Baseline score 5, worst post-baseline score 1

Baseline score 5, worst post-baseline score 2

Baseline score 5, worst post-baseline score 3

Baseline score 5, worst post-baseline score 4

Baseline score 5, worst post-baseline score 5

Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score

Hematology

Chemistry

Coagulation

Number of Participants With Shift From Baseline Grade Less Than (<) 3 in Clinical Laboratory Parameters to Grade Greater Than or Equal to (>=) 3 on Treatment

Baseline temp. <37°C, on treatment change <1°C

Baseline temp.<37°C, on treatment change 1 - <2°C

Baseline temp. <37°C, on treatment change 2 - <3°C

Baseline temp. <37°C, on treatment change >=3°C

Baseline temp. 37 - <38°C, on treatment change <1°C

Baseline temp. 37 - <38°C, on treatment change 1 - <2°C

Baseline temp. 37 - <38°C, on treatment change 2 - <3°C

Baseline temp. 37 - <38°C, on treatment change >=3°C

Baseline temp. 38 - <39°C, on treatment change <1°C

Baseline temp. 38 - <39°C, on treatment change 1 - <2°C

Baseline temp. 38 - <39°C, on treatment change 2 - <3°C

Baseline temp. 38 - <39°C, on treatment change >=3°C

Baseline temp. 39 - <40°C, on treatment change <1°C

Baseline temp. 39 - <40°C, on treatment change 1 - <2°C

Baseline temp. 39 - <40°C, on treatment change 2 - <3°C

Baseline temp. 39 - <40°C, on treatment change >=3°C

Baseline temp. >=40°C, on treatment change <1°C

Baseline temp. >=40°C, on treatment change 1 - <2°C

Baseline temp. >=40°C, on treatment change 2 - <3°C

Baseline temp. >=40°C, on treatment change >=3°C

Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Body Temperature Increase

Ic. BS SBP <140 mmHg, on TR change =<20 mmHg

Ic. BS SBP <140 mmHg, on TR change >20 - =<40 mmHg

Ic. BS SBP <140 mmHg, on TR change >40 mmHg

Ic. BS SBP >=140 mmHg, on TR change =<20 mmHg

Ic. BS SBP >=140 mmHg, on TR change >20 - =<40 mmHg

Ic. BS SBP >=140 mmHg, on TR change >40 mmHg

Dc. BS SBP <140 mmHg, on TR change =<20 mmHg

Dc. BS SBP <140 mmHg, on TR change >20 - =<40 mmHg

Dc. BS SBP <140 mmHg, on TR change >40 mmHg

Dc. BS SBP >=140 mmHg, on TR change =<20 mmHg

Dc. BS SBP >=140 mmHg, on TR change >20 - =<40 mmHg

Dc. BS SBP >=140 mmHg, on TR change >40 mmHg

Ic. BS DBP <90 mmHg, on TR change =<20 mmHg

Ic. BS DBP <90 mmHg, on TR change >20 - =<40 mmHg

Ic. BS DBP <90 mmHg, on TR change >40 mmHg

Ic. BS DBP >=90 mmHg, on TR change =<20 mmHg

Ic. BS DBP >=90 mmHg, on TR change >20 - =<40 mmHg

Ic. BS DBP >=90 mmHg, on TR change >40 mmHg

Dc. BS DBP <90 mmHg, on TR change =<20 mmHg

Dc. BS DBP <90 mmHg, on TR change >20 - =<40 mmHg

Dc. BS DBP <90 mmHg, on TR change >40 mmHg

Dc. BS DBP >=90 mmHg, on TR change =<20 mmHg

Dc. BS DBP >=90 mmHg,on TR change >20 - =<40 mmHg

Dc. BS DBP >=90 mmHg, on TR change >40 mmHg

Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Systolic Blood Pressure Increase/Decrease and Maximal Diastolic Blood Pressure Increase/Decrease

Ic. BS RR <20 breaths/min, on TR ch =<5 breaths/min

Ic.BS RR<20 breaths/min, on TR Ch >5 - = <10 breaths/min

Ic. BS RR <20 breaths/min, on TR ch >10 breaths/min

Ic. BS RR >=20 breaths/min, on TR ch =<5 breaths/min

IC.BS RR >=20 breaths/min, on TR ch >5 - =<10 breaths/min

Ic. BS RR >=20 breaths/min, on TR ch >10 breaths/min

Dc. BS RR <20 breaths/min, on TR ch =<5 breaths/min

Dc. BS RR <20 breaths/min, on TR Ch >5 - =<10 breaths/min

Dc. BS RR <20 breaths/min, on TR ch >10 breaths/min

Dc. BS RR >=20 breaths/min, on TR ch =<5 breaths/min

Dc.BS RR >=20 breaths/min, on TR ch >5 - =<10 breaths/min

Dc. BS RR >=20 breaths/min, on TR ch >10 breaths/min

Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Respiration Rate Increase/Decrease

Participants received M3258 at a dose of 10 mg orally, QD or twice per week until disease progression.

M3258 10 mg QD or Twice Per Week

Pharmacokinetic (PK) analysis set included all participants, who received at least one dose of study intervention, have no clinically important protocol deviations or important events affecting PK, and provide at least one measurable post-dose concentration. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3258

Participants received M3258 at a dose of 10 mg orally, twice per week until disease progression.

Part A: Mutilple Dose: Maximum Observed Plasma Concentration (Cmax) of M3258

PK analysis set included all participants, who received at least one dose of study intervention, have no clinically important protocol deviations or important events affecting PK, and provide at least one measurable post-dose concentration. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Part A: Single Dose: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC0-t) of M3258

The most participants who had evaluable PK, samples at 24 hour (Day 2) were collected. Therefore, the AUC0-t and AUC0-24 would not differ and AUC0-24 at single dose was not reported. It was also planned to carry the trough value at steady state for QD dosing forward and impute it as trough value at 24 hours. Due to the change from the QD to twice per week dosing this did not apply anymore and AUC0-24 at steady state was not calculated.

Part A: Single Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258

Part A: Multiple Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258

Cycle 1 Day 1: 2 hours post-dose

Cycle 1 Day 1: 6 hours post-dose

Cycle 1 Day 1: 24 hours post-dose

The Pharmacodynamic (Pd) population included all participants who received at least one dose of study intervention, had no clinically important protocol deviations or important events affecting Pd, and provide at least one measurable Pd endpoint post-dose. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signifies those participants who were evaluable for specified timepoints.

Part A: Single Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 1

Cycle 1 Day 8 (or Day 15): Pre-dose

Cycle 1 Day 8 (or Day 15): 2 hours post-dose

Cycle 1 Day 8 (or Day 15): 6 hours post-dose

The Pd population included all participants who received at least one dose of study intervention, had no clinically important protocol deviations or important events affecting Pd, and provide at least one measurable Pd endpoint post-dose. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signifies those participants who were evaluable for specified timepoints.

Part A: Multiple Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 8 (or Day 15)

Cycle 2 Day 1

Cycle 3 Day 1

Safety analysis set included all participants who were administered any dose of the trial medication. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signifies those participants who were evaluable for specified timepoints.

Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis

Spots Global Cancer Trial Database for First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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