History of Changes for Study: NCT04075721

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

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Study Record Versions

Version	Submitted Date	Changes
1	August 29, 2019	None (earliest Version on record)
2	January 28, 2020	Recruitment Status, Contacts/Locations, Study Status, Oversight and Study Identification
3	March 17, 2020	Study Status
4	April 21, 2020	Study Status and Contacts/Locations
5	June 8, 2020	Study Status, References and Contacts/Locations
6	August 7, 2020	Outcome Measures, Arms and Interventions, Study Status, Study Identification, Eligibility, Study Design and Study Description
7	September 2, 2020	Study Status
8	November 3, 2020	Study Status and Contacts/Locations
9	May 10, 2021	Recruitment Status, Study Status, Contacts/Locations and Study Design

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	MS201814_0010
Brief Title:	First in Human Dose Escalation and Expansion Study With M3258 in Combination With Dexamethasone
Official Title:	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
Secondary IDs:

Study Status


Record Verification:	August 2019
Overall Status:	Not yet recruiting
Study Start:	September 18, 2019
Primary Completion:	March 26, 2021 [Anticipated]
Study Completion:	March 26, 2021 [Anticipated]

First Submitted:	August 29, 2019
First Submitted that Met QC Criteria:	August 29, 2019
First Posted:	September 3, 2019 [Actual]

Last Update Submitted that Met QC Criteria:	August 29, 2019
Last Update Posted:	September 3, 2019 [Actual]

Sponsor/Collaborators


Sponsor:	EMD Serono Research & Development Institute, Inc.
Responsible Party:	Sponsor
Collaborators:	Merck KGaA, Darmstadt, Germany

Oversight


U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Data Monitoring:	No

Study Description


Brief Summary:	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).
Detailed Description:

Conditions


Conditions:	Multiple Myeloma
Keywords:	M3258 Dexamethasone Pharmacokinetics Relapsed Refractory Multiple Myeloma

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 1
Interventional Study Model:	Parallel Assignment
Number of Arms:	2
Masking:	None (Open Label)
Allocation:	Non-Randomized
Enrollment:	60 [Anticipated]

Arms and Interventions

Arms

Assigned Interventions

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 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.

Experimental: Part B (Dose Expansion): M3258

Drug: M3258

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.

Outcome Measures


Primary Outcome Measures:
1.	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) ]
2.	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) ]
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: 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: 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 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 15 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 15 Cycle 1: Pre-dose upto 24 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 15 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: 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) ]
14.	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) ]
15.	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.

Eligibility


Minimum Age:	18 Years
Maximum Age:
Sex:	All
Gender Based:
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 Other protocol defined exclusion criteria could apply

Contacts/Locations


Central Contact Person:	US Medical Information Telephone: 888-275-7376 Email: service@emdgroup.com
Central Contact Backup:	Communication Center Telephone: +49 6151 72 5200 Email: service@emdgroup.com
Study Officials:	Medical Responsible Study Director Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Locations:	United States, Massachusetts
	Please Contact U.S. Medical Information Rockland, Massachusetts, United States, 02370
	Germany
	Please Contact the Communication Center Darmstadt, Germany, 64293

IPDSharing

Plan to Share IPD:

No
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

References


Links:
Available IPD/Information: