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

NCT04075721 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: MS201814_00102019-000947-28
• Study Type: interventional
• Target: 10
• Locations: 2 countries
• Sites: 7

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).

Conditions

Multiple Myeloma

Keywords

M3258; Dexamethasone; Pharmacokinetics; Relapsed Refractory Multiple Myeloma

Outcome Measures

Primary Outcomes (6)

• 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

  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.

  Day 1 up to Day 28

• Part A: Number of Participants With Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs)

  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.

  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 Adverse Event (TEAEs) Outside of Dose-Limiting Toxicity (DLT) Period That Safety Monitoring Committee Deems Relevant for Determination of the Maximum Tolerated Dose

  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.

  Day 29 up to 20.1 weeks

• Part A: Change From Baseline in 12-lead Electrocardiogram (ECG) Findings: QT Interval - Fridericia's Correction Formula

  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.

  Cycle 1 Day 1 pre-dose (Baseline), pre-dose on Cycle 2 Day 1 (each Cycle is of 28 days)

• Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score

  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).

  Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)

• 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

  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.

  Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)

Secondary Outcomes (16)

• 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: 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: 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: 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)

Study Arms (3)

M3258 10 mg QD

EXPERIMENTAL

Drug: M3258

M3258 10 mg Twice per Week

EXPERIMENTAL

Drug: M3258

M3258 20 mg Twice per Week

EXPERIMENTAL

Drug: M3258 20 mg

Interventions

M3258 DRUG

Participants received M3258 at a dose of 10 milligrams (mg) orally, once daily (QD) or twice per week on Day 1 and Day 4 until disease progression.

M3258 10 mg QD; M3258 10 mg Twice per Week

M3258 20 mg DRUG

Participants received M3258 at a dose of 20 mg orally, twice per week on Day 1 and Day 4 until disease progression.

M3258 20 mg Twice per Week

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• EMD Serono Research & Development Institute, Inc.: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (7)

Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

Location

Georgetown University Medical Center- Research Parent

Washington D.C., District of Columbia, 20007, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Centre Hospitalier Regional Universitaire de Lille

Lille, 59037, France

Location

CHU de Nantes

Nantes, 44093, France

Location

CHU de Poitiers

Vauvert, 30600, France

Location

Related Publications (2)

• 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 (beta5i) 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.

  PMID: 34045234 RESULT

• Lignet F, Esdar C, Walter-Bausch G, Friese-Hamim M, Stinchi S, Drouin E, El Bawab S, Becker AD, Gimmi C, Sanderson MP, Rohdich F. Translational PK/PD Modeling of Tumor Growth Inhibition and Target Inhibition to Support Dose Range Selection of the LMP7 Inhibitor M3258 in Relapsed/Refractory Multiple Myeloma. J Pharmacol Exp Ther. 2023 Jan;384(1):163-172. doi: 10.1124/jpet.122.001355. Epub 2022 Oct 23.

  PMID: 36273822 DERIVED

Related Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources

MeSH Terms

Conditions

Multiple Myeloma

Interventions

M3258

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Limitations and Caveats

Part B was not conducted as the study was early discontinued due to lack of participant's recruitment into Part A before Part A reached its primary objective.

Results Point of Contact

• Title: Communication Center
• Organization: Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 29, 2019
• First Posted: September 3, 2019
• Study Start: September 26, 2019
• Primary Completion: April 1, 2021
• Study Completion: April 1, 2021
• Last Updated: March 24, 2023
• Results First Posted: March 24, 2023

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3); US (4)