First in Human Dose Escalation and Expansion Study With M3258 in Combination With Dexamethasone

Overview

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

Full Title of Study: “A Phase I Open Label First in Human Dose Escalation and Expansion Study of the Immunoproteasome Inhibitor M3258 in Combination With Dexamethasone in Participants With Relapsed Refractory Multiple Myeloma”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 26, 2021

Interventions

  • Drug: M3258
    • Participants will receive M3258 in a protocol-defined dose escalation scheme in Part A and M3258 at a dose defined and considered to be safe by safety monitoring committee (SMC) in Part B until disease progression.
  • Drug: Dexamethasone
    • Participants will receive 20 milligrams per day of dexamethasone on 2 consecutive days in a weekly regimen along with M3258 in Part A and Part B until disease progression.

Arms, Groups and Cohorts

  • Experimental: Part A (Dose Escalation): M3258
  • Experimental: Part B (Dose Expansion): M3258

Clinical Trial Outcome Measures

Primary Measures

  • Part A: Number of Participants with Dose-Limiting Toxicity (DLTs)
    • Time Frame: Day 1 up to Day 28 of Treatment Cycle 1 (each cycle is of 28 days)
  • Part A: Occurrences of Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs ) in Participants Receiving M3258 in Combination with Dexamethasone
    • Time Frame: 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
    • Time Frame: Day 29 upto 30 days post-last dose (assessed upto maximum 528 days)
  • Part A: 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
    • Time Frame: 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
    • Time Frame: up to 556 days
  • Part B: Duration of Response (DOR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
    • Time Frame: up to 556 days
  • Part B: Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
    • Time Frame: up to 556 days
  • Part B: Occurrences of Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs ) in Participants Receiving M3258 in Combination with Dexamethasone
    • Time Frame: Day 1 upto 30 days post-last dose (assessed upto maximum 556 days)

Secondary Measures

  • Part A:Maximum Observed Plasma Concentration (Cmax) of M3258
    • Time Frame: Day 1 Cycle 1: Pre-dose upto 24 hours post-dose, Day 15 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
    • Time Frame: 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
    • Time Frame: Day 1 Cycle 1: Pre-dose upto 24 hours post-dose, Day 15 Cycle 1: Pre-dose upto 24 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
    • Time Frame: Pre-dose, 2, 6 hours post-dose on Day 1 and Day 15 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: up to 556 days
  • Part A: Duration of Response (DOR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
    • Time Frame: up to 556 days
  • Part A: Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
    • Time Frame: up to 556 days
  • Part B: Progression-Free Survival (PFS) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
    • Time Frame: up to 556 days
  • Part B: Overall Survival Time According to International Myeloma Working Group (IMWG) Criteria
    • Time Frame: up to 556 days
  • Part B: Number of Participants With Treatment-Emergent Serious Adverse Events (TESAEs)
    • Time Frame: Day 1 upto 30 days post-last dose (assessed upto maximum 556 days)
  • Part B: Occurrences of Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs) in Participants Receiving M3258
    • Time Frame: Day 1 upto 30 days post-last dose (assessed upto maximum 556 days)
  • 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
    • Time Frame: 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.

Participating in This Clinical Trial

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
  • Other protocol defined exclusion criteria could apply

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • EMD Serono Research & Development Institute, Inc.
  • Collaborator
    • Merck KGaA, Darmstadt, Germany
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Medical Responsible, Study Director, Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany
  • Overall Contact(s)
    • US Medical Information, 888-275-7376, service@emdgroup.com

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