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

• ClinicalTrials.gov Identifier: NCT04075721
• Recruitment Status: Terminated
• First Posted: September 3, 2019
• Last Update Posted: May 12, 2021
• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Tracking Information

• First Submitted Date: August 29, 2019
• First Posted Date: September 3, 2019
• Last Update Posted Date: May 12, 2021
• Actual Study Start Date: September 26, 2019
• Actual Primary Completion Date: April 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 7, 2020)

• Part A and Part B: 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 and Part B: Occurrences of Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs ) [ 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 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 [ 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: Occurrence of Study Treatment-Emergent SAEs Including Deaths [ Time Frame: Day 1 upto 30 days post-last dose (assessed upto maximum 556 days) ]

Original Primary Outcome Measures (submitted: August 29, 2019)

• 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) ]

Current Secondary Outcome Measures (submitted: August 7, 2020)

• Part A:Maximum Observed Plasma Concentration (Cmax) of M3258 [ Time Frame: 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 [ 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 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 [ Time Frame: 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 [ 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: Maximum Observed Plasma Concentration (Cmax) of M3258 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) ]

Original Secondary Outcome Measures (submitted: August 29, 2019)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone
• Official Title: 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
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• 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.

Study Arms

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

  • Drug: M3258
  • Drug: Dexamethasone

• Publications *: Sanderson MP, Friese-Hamim M, Walter-Bausch G, Busch M, Gaus S, Musil D, Rohdich F, Zanelli U, Downey-Kopyscinski SL, Mitsiades CS, Schadt O, Klein M, Esdar C. M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models. Mol Cancer Ther. 2021 Aug;20(8):1378-1387. doi: 10.1158/1535-7163.MCT-21-0005. Epub 2021 May 27.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 10, 2021): 10
• Original Estimated Enrollment (submitted: August 29, 2019): 60
• Actual Study Completion Date: April 1, 2021
• Actual Primary Completion Date: April 1, 2021 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT04075721
• Other Study ID Numbers: MS201814_0010; 2019-000947-28 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients 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 https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

• Current Responsible Party: EMD Serono ( EMD Serono Research & Development Institute, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: EMD Serono Research & Development Institute, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible; Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

• PRS Account: EMD Serono
• Verification Date: May 2021