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

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ClinicalTrials.gov Identifier: NCT04075721
Recruitment Status : Terminated (The study was discontinued given the changed therapeutic landscape, lack of recruitment and totality of the data collected so far.)
First Posted : September 3, 2019
Last Update Posted : May 12, 2021
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

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
Multiple Myeloma Drug: M3258 Drug: Dexamethasone Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 26, 2019
Actual Primary Completion Date : April 1, 2021
Actual Study Completion Date : April 1, 2021


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.




Primary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. 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.

  5. Part B: Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [ Time Frame: up to 556 days ]
  6. Part B: Duration of Response (DOR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [ Time Frame: up to 556 days ]
  7. Part B: Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [ Time Frame: up to 556 days ]
  8. 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) ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. 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) ]
  5. 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) ]
  6. 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) ]
  7. 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) ]
  8. Part A: Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [ Time Frame: up to 556 days ]
  9. Part A: Duration of Response (DOR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [ Time Frame: up to 556 days ]
  10. Part A: Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [ Time Frame: up to 556 days ]
  11. Part B: Progression-Free Survival (PFS) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria [ Time Frame: up to 556 days ]
  12. Part B: Overall Survival Time According to International Myeloma Working Group (IMWG) Criteria [ Time Frame: up to 556 days ]
  13. 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) ]
  14. 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) ]
  15. 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) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04075721


Locations
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United States, Colorado
Colorado Blood Cancer Institute
Denver, Colorado, United States, 80218
United States, District of Columbia
Georgetown University Medical Center- Research Parent
Washington, District of Columbia, United States, 20007
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
France
Centre Hospitalier Regional Universitaire de Lille
Lille, France, 59037
CHU de Nantes
Nantes, France, 44093
CHU de Poitiers
Vauvert, France, 30600
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT04075721    
Other Study ID Numbers: MS201814_0010
2019-000947-28 ( EudraCT Number )
First Posted: September 3, 2019    Key Record Dates
Last Update Posted: May 12, 2021
Last Verified: May 2021
Individual Participant Data (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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
M3258
Dexamethasone
Pharmacokinetics
Relapsed Refractory Multiple Myeloma
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents