First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone
Study Details
Study Description
Brief Summary
The purpose of this study is 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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part A (Dose Escalation): M3258
|
Drug: M3258
Participants will receive M3258 in a protocol-defined dose escalation scheme in Part A and M3258 at a dose and regimen defined and considered to be safe by safety monitoring committee (SMC) in Part B until disease progression.
|
| Experimental: Part B (Dose Expansion): M3258
|
Drug: M3258
Participants will receive M3258 in a protocol-defined dose escalation scheme in Part A and M3258 at a dose and regimen defined and considered to be safe by safety monitoring committee (SMC) in Part B until disease progression.
Drug: Dexamethasone
Participants will receive dexamethasone at a cumulative dose of 40 milligrams per week along with M3258 in Part B until disease progression.
|
Outcome Measures
Primary Outcome Measures
- Part A and Part B: Number of Participants with Dose-Limiting Toxicity (DLTs) [Day 1 up to Day 28 of Treatment Cycle 1 (each cycle is of 28 days)]
- Part A and Part B: Occurrences of Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs ) [Day 1 upto 30 days post-last dose (assessed upto maximum 556 days)]
- Part A:Number of Participants with Treatment-Emergent Adverse Event (TEAEs) Outside of Dose-Limiting Toxicity (DLTs) Period [Day 29 upto 30 days post-last dose (assessed upto maximum 528 days)]
- Part A and Part B: Number of Participants With Treatment Emergent Changes From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status, Vital Signs, Laboratory Parameters and 12-lead Electrocardiogram (ECG) Findings [Day 1 upto 30 days post-last dose (assessed upto maximum 556 days)]
Number of participants with treatment emergent changes from baseline in ECOG performance status, vital signs, laboratory parameters and 12-lead ECG findings will be reported.
- Part B: Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [up to 556 days]
- Part B: Duration of Response (DOR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [up to 556 days]
- Part B: Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [up to 556 days]
- Part B: Occurrence of Study Treatment-Emergent SAEs Including Deaths [Day 1 upto 30 days post-last dose (assessed upto maximum 556 days)]
Secondary Outcome Measures
- Part A:Maximum Observed Plasma Concentration (Cmax) of M3258 [Day 1 Cycle 1: Pre-dose upto 24 hours post-dose, Day 8 Cycle 1: Pre-dose upto 8 hours post-dose (each Cycle is of 28 days)]
- Part A: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC 0-t) of M3258 [Pre-dose upto 24 hours post-dose on Day 1 of Cycle 1 (each cycle is of 28 days)]
- Part A: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258 [Day 1 Cycle 1: Pre-dose upto 24 hours post-dose, Day 8 Cycle 1: Pre-dose upto 8 hours post-dose (each Cycle is of 28 days)]
- Part A: Change in Large Multifunctional Protease 7 (LMP7) Activity as Assessed by LMP7 Activity Assay [Pre-dose, 2, 6 hours post-dose on Day 1 and Day 8 of Cycle 1; Pre-dose on Day 2 of Cycle 1 (each cycle is of 28 days)]
- Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis [Baseline (Cycle 1 Day 1), Day 1 of each 28-day treatment Cycle until end of study (assessed upto maximum 556 days)]
- Part A: Change From Baseline in Urine M-protein Level Using Electrophoresis [Baseline (Cycle 1 Day 1), Day 1 of each 28-day treatment Cycle until end of study (assessed upto maximum 556 days)]
- Part A: Change From Baseline in Free Light Chain Protein Level Using Electrophoresis [Baseline (Cycle 1 Day 1), Day 1 of each 28-day treatment Cycle until end of study (assessed upto maximum 556 days)]
- Part A: Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [up to 556 days]
- Part A: Duration of Response (DOR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [up to 556 days]
- Part A: Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [up to 556 days]
- Part B: Progression-Free Survival (PFS) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [up to 556 days]
- Part B: Overall Survival Time According to International Myeloma Working Group (IMWG) Criteria [up to 556 days]
- Part B: Maximum Observed Plasma Concentration (Cmax) of M3258 [Day 1 Cycle 1: Pre-dose, 1, 2, 3, 4, 5, and 6 and 24 hours Post-dose; Day 8 Cycle 1: pre-dose, 2, 4, and 6 hours post-dose (each cycle is of 28 days)]
- Part B: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC 0-t) of M3258 [Day 1 Cycle 1: Pre-dose, 1, 2, 3, 4, 5, and 6 and 24 hours Post-dose (each cycle is of 28 days)]
- Part B: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258 [Day 1 Cycle 1: Pre-dose, 1, 2, 3, 4, 5, and 6 and 24 hours Post-dose; Day 8 Cycle 1: pre-dose, 2, 4, and 6 hours post-dose (each cycle is of 28 days)]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Participants having Eastern Co-operative Oncology Group (ECOG) Performance Status less than or equals to (<=) 1
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Adequate hematological, hepatic and renal function as defined in the protocol
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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
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Participant must have documented evidence progressive disease as defined by the IMWG criteria either on or after their last regimen
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Other protocol defined inclusion criteria could apply
Exclusion Criteria:
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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.
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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).
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Cerebrovascular accident/stroke (< 6 months prior enrollment) or neurologic instability per clinical evaluation due to tumor involvement of the Central Nervous System
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Diagnosis of fever within 1 week prior to study intervention administration
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Part B: Participants planning to undergo a stem cell transplant should not be enrolled to reduce disease burden prior to transplant.
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Other protocol defined exclusion criteria could apply
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Colorado Blood Cancer Institute | Denver | Colorado | United States | 80218 |
| 2 | Georgetown University Medical Center- Research Parent | Washington | District of Columbia | United States | 20007 |
| 3 | Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
| 4 | Sarah Cannon Research Institute | Nashville | Tennessee | United States | 37203 |
| 5 | Centre Hospitalier Regional Universitaire de Lille | Lille | France | 59037 | |
| 6 | CHU de Nantes | Nantes | France | 44093 | |
| 7 | CHU de Poitiers | Vauvert | France | 30600 |
Sponsors and Collaborators
- EMD Serono Research & Development Institute, Inc.
- Merck KGaA, Darmstadt, Germany
Investigators
- Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- MS201814_0010
- 2019-000947-28