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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: M3258
* Drug: M3258 20 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants having Eastern Co-operative Oncology Group (ECOG) Performance Status less than or equals to (<=) 1 Adequate hematological, hepatic and renal function as defined in the protocol Participant must have measurable disease of Multiple Myeloma (MM) and received greater than (>) 3 prior lines of therapy for MM including a Proteasome Inhibitors (PI), an Immunomodulatory Imide Drug (IMiD) and an anti-CD38 mAb or who are refractory to at least PI agent (carfilzomib or bortezomib) and IMiD according to the International Myeloma Working Group (IMWG) criteria Participant must have documented evidence progressive disease as defined by the IMWG criteria either on or after their last regimen Other protocol defined inclusion criteria could apply Exclusion Criteria: Any condition, including any uncontrolled disease state that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation. An active second malignancy or evidence of disease of cancer (other than MM) before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator, with concurrence with the Sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years). Cerebrovascular accident/stroke (< 6 months prior enrollment) or neurologic instability per clinical evaluation due to tumor involvement of the Central Nervous System Diagnosis of fever within 1 week prior to study intervention administration Part B: Participants planning to undergo a stem cell transplant should not be enrolled to reduce disease burden prior to transplant. Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: M3258 10 mg QD<br> | Drug: M3258<br>* 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.<br>|
| Experimental: M3258 10 mg Twice per Week<br> | Drug: M3258<br>* 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.<br>|
| Experimental: M3258 20 mg Twice per Week<br> | Drug: M3258 20 mg<br>* Participants received M3258 at a dose of 20 mg orally, twice per week on Day 1 and Day 4 until disease progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Day 1 up to Day 28 | 
| Part A: Number of Participants With Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs) | 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. | Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks) | 
| 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 | 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. | Day 29 up to 20.1 weeks | 
| Part A: Change From Baseline in 12-lead Electrocardiogram (ECG) Findings: QT Interval - Fridericia's Correction Formula | 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. | Cycle 1 Day 1 pre-dose (Baseline), pre-dose on Cycle 2 Day 1 (each Cycle is of 28 days) | 
| Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | 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). | Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks) | 
| 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 | 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. | Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Body Temperature Increase | 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. | Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks) | 
| 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 | 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. | Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks) | 
| Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Respiration Rate Increase/Decrease | 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. | Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks) | 
| Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3258 | 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. | Cycle 1 Day 1: Pre-dose 1, 2, 3, 4, 5, 6, 8 and 24 hours post-dose (each Cycle is of 28 days) | 
| Part A: Mutilple Dose: Maximum Observed Plasma Concentration (Cmax) of M3258 | Cmax was obtained directly from the concentration versus time curve. | Cycle 1 Day 8 or Cycle 1 Day 15: Pre-dose 1, 2, 3, 4, 5, 6, and 8 hours post-dose (each Cycle is of 28 days) | 
| Part A: Single Dose: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC0-t) of M3258 | 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. | Cycle 1 Day 1: Pre-dose 1, 2, 3, 4, 5, 6, 8 and 24 hours post-dose (each Cycle is of 28 days) | 
| Part A: Single Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258 | 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. | Cycle 1 Day 1: Pre-dose 1, 2, 3, 4, 5, 6, 8 and 24 hours post-dose (each Cycle is of 28 days) | 
| Part A: Multiple Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258 | Area under the plasma concentration versus time curve from time zero to 24 hours post dosing for M3258. | Cycle 1 Day 8 or Cycle 1 Day 15: Pre-dose 1, 2, 3, 4, 5, 6, and 8 hours post-dose (each Cycle is of 28 days) | 
| Part A: Single Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 1 | 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. | Baseline (Pre-dose), 2, 6 and 24 hours post-dose on Cycle 1 Day 1 (each Cycle is of 28 days) | 
| Part A: Multiple Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 8 (or Day 15) | Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement. | Cycle 1 Day 1 pre-dose (Baseline), Pre-dose, 2 and 6 hours post-dose on Cycle 1 Day 8 (or Day 15) (each Cycle is of 28 days) | 
| Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis | 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. | Baseline, 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 (Week 20.1) (each Cycle is of 28 days) | 
| Part A: Change From Baseline in Urine M-protein Level Using Electrophoresis | 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. | Baseline, 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 (Week 20.1) (each Cycle is of 28 days) | 
| Part A: Change From Baseline in Free Light Chain Ratio | 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. | Baseline, 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 (Week 20.1) (each Cycle is of 28 days) | 
| Part A: Number of Participants With Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria | 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. | Time from first dose of study treatment up to 18.2 months | 
| Duration of Response (DoR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria | 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 from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 18.2 months | 
| Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria | 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. | Time from the first dose of study treatment up to documentation of first response, assessed up to 18.2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M3258, Dexamethasone, Pharmacokinetics, Relapsed Refractory Multiple Myeloma