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
Overview
- Phase
- Phase 1
- Intervention
- M3258
- Conditions
- Multiple Myeloma
- Sponsor
- EMD Serono Research & Development Institute, Inc.
- Enrollment
- 10
- Locations
- 7
- Primary Endpoint
- 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
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
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).
Investigators
Eligibility Criteria
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
Arms & Interventions
M3258 10 mg QD
Intervention: M3258
M3258 10 mg Twice per Week
Intervention: M3258
M3258 20 mg Twice per Week
Intervention: M3258 20 mg
Outcomes
Primary Outcomes
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
Time Frame: Day 29 up to 20.1 weeks
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.
Part A: Number of Participants With Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs)
Time Frame: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)
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.
Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
Time Frame: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)
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).
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
Time Frame: Day 1 up to Day 28
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.
Part A: Change From Baseline in 12-lead Electrocardiogram (ECG) Findings: QT Interval - Fridericia's Correction Formula
Time Frame: Cycle 1 Day 1 pre-dose (Baseline), pre-dose on Cycle 2 Day 1 (each Cycle is of 28 days)
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.
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
Time Frame: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)
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.
Secondary Outcomes
- 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(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(Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks))
- Part A: Mutilple Dose: Maximum Observed Plasma Concentration (Cmax) of 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: Maximum Observed Plasma Concentration (Cmax) of M3258(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: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis(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(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: Multiple Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 8 (or Day 15)(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: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Body Temperature Increase(Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks))
- Part A: Single Dose: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC0-t) of M3258(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(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(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(Baseline (Pre-dose), 2, 6 and 24 hours post-dose on Cycle 1 Day 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(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(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 from the first dose of study treatment up to documentation of first response, assessed up to 18.2 months)
- Part A: Change From Baseline in Free Light Chain Ratio(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))