Multiple MyelomaPhase 1NCT04075721
First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone
A Phase 1 study testing M3258 and M3258 20 mg in people with Multiple Myeloma, run by EMD Serono Research & Development Institute, Inc. at 7 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multiple Myeloma
- What is being tested?
- M3258 and M3258 20 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 7 sitesin 2 countries
- Study dates
- 26 Sep 2019to 1 Apr 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
7 sites in 2 countries.
7 sites in 2 countries
United States4 sites
Colorado Blood Cancer Institute
Denver, Colorado, 80218
Hackensack University Medical Center
Hackensack, New Jersey, 07601
Sarah Cannon Research Institute
Nashville, Tennessee, 37203
Georgetown University Medical Center- Research Parent
Washington D.C., District of Columbia, 20007
France3 sites
Centre Hospitalier Regional Universitaire de Lille
Lille, 59037
CHU de Nantes
Nantes, 44093
CHU de Poitiers
Vauvert, 30600
About this study
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
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
- Being tested
- M3258, M3258 20 mg
- Keywords
- M3258, Dexamethasone, Pharmacokinetics, Relapsed Refractory Multiple Myeloma
- Medical subject headings
- Multiple Myeloma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
M3258Drug
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 20 mgDrug
Participants received M3258 at a dose of 20 mg orally, twice per week on Day 1 and Day 4 until disease progression.
| Study group | Role | What they receive |
|---|---|---|
| M3258 10 mg QD | Experimental | Not described Receives: Drug: M3258 |
| M3258 10 mg Twice per Week | Experimental | Not described Receives: Drug: M3258 |
| M3258 20 mg Twice per Week | Experimental | Not described Receives: Drug: M3258 20 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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
The number of participants with treatment-emergent changes from baseline in increased Body Temperature (degree Celsius [°C]) were reported by using criteria: Baseline temperature (temp.) less than (<) 37°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and greater than or equal to (>=)3°C; Baseline temp. 37 - <38°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and >=3°C; Baseline temp. 38 - <39°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and >=3°C; Baseline temp. 39-<40°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and >=3°C; Baseline temp. >=40°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and >=3°C.
Measured: 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
The number of participants with treatment-emergent changes from baseline (BS) in Increase (Ic.)/Decrease (Dc.) Systolic Blood Pressure (SBP) and diastolic blood pressure (DBP) (millimeter of mercury [mmHg]) were reported by using criteria: Ic./Dc. BS SBP/DBP <140/<90 mmHg, on maximal treatment (TR) change =<20 mmHg, >20 - =<40 mmHg and >40 mmHg; Ic./Dc. BS SBP/DBP >=140/>=90 mmHg, on maximal TR change =<20 mmHg, >20 - =<40 mmHg and >40 mmHg.
Measured: 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
The number of participants with treatment-emergent changes from baseline in Increase (Ic.)/Decrease (Dc.) maximal Respiration Rate (RR) were reported by using criteria: Ic./Dc. BS RR <20 breaths per minute (breaths/min), on TR change (ch) =<5 breaths/min, >5 - =<10 breaths/min and >10 breaths/min. Ic./Dc. BS RR >=20 breaths/min, on TR ch =<5 breaths/min, >5 - =<10 breaths/min and >10 breaths/min.
Measured: 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
Cmax was obtained directly from the concentration versus time curve. Single dose PK data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (>) 2 in which a measurement of greater than (>) lower limit of quantification (LLOQ) represents a valid measurement.
Measured: 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
Cmax was obtained directly from the concentration versus time curve.
Measured: 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)
Part A: Single Dose: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC0-t) of M3258
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. Single dose PK data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (>) 2 in which a measurement of greater than (>) lower limit of quantification (LLOQ) represents a valid measurement.
Measured: 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: Single Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258
Area under the plasma concentration versus time curve from time zero to 24 hours post dosing for M3258. Single dose PK data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (>) 2 in which a measurement of greater than (>) lower limit of quantification (LLOQ) represents a valid measurement.
Measured: 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: Multiple Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258
Area under the plasma concentration versus time curve from time zero to 24 hours post dosing for M3258.
Measured: 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)
Part A: Single Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 1
Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement. Single dose Pd data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (>) 2 in which a measurement of greater than (>) lower limit of quantification (LLOQ) represents a valid measurement.
Measured: Baseline (Pre-dose), 2, 6 and 24 hours post-dose on Cycle 1 Day 1 (each Cycle is of 28 days)
Part A: Multiple Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 8 (or Day 15)
Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement.
Measured: Cycle 1 Day 1 pre-dose (Baseline), Pre-dose, 2 and 6 hours post-dose on Cycle 1 Day 8 (or Day 15) (each Cycle is of 28 days)
Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis
Change from baseline in serum monoclonal (M)-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention.
Measured: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)
Part A: Change From Baseline in Urine M-protein Level Using Electrophoresis
Change from baseline in urine M-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention.
Measured: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)
Part A: Change From Baseline in Free Light Chain Ratio
Change from baseline in free light chain ratio was reported at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention.
Measured: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)
Part A: Number of Participants With Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
OR is defined as a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IMWG Criteria: sCR: CR (negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow); normal free light chain (FLC) ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis/>= 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours; PR: >= 50% reduction of serum M-Protein and reduction in urinary M-protein by >= 90%/to < 200 mg/24 hours. In addition to the above, if present at baseline a >= 50% reduction in the size of soft tissue plasmacytomas is also required.
Measured: Time from first dose of study treatment up to 18.2 months
Duration of Response (DoR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
DOR was defined participants with confirmed response, as time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to date of first documentation of progression disease (PD)/death due to any cause, whichever occurred first. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. PR: >= 50% reduction of serum M-Protein and reduction in urinary M-protein by >= 90%/to < 200 mg/24 hours. In addition to the above, if present at baseline a >= 50% reduction in the size of soft tissue plasmacytomas is also required. PD: >= 25% increase from lowest response value in serum. Development of new or increased size of existing bone lesions or soft tissue plasmacytomas. Hypercalcemia attributed to the plasma cell proliferative disorder.
Measured: Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 18.2 months
Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
Time to response was defined as the time from the first dose of M3258 to the documentation of first response (Complete Response [CR] or Partial Response [PR]). CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. PR: >= 50% reduction of serum M-Protein and reduction in urinary M-protein by >= 90% or to < 200 mg/24 hours. In addition to the above, if present at baseline a >= 50% reduction in the size of soft tissue plasmacytomas is also required.
Measured: Time from the first dose of study treatment up to documentation of first response, assessed up to 18.2 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Sep 2019
- Study start26 Sep 2019
- Primary completion1 Apr 2021
- Study completion1 Apr 2021
Why it stopped: The study was early discontinued due to lack of participant enrollment.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Multiple MyelomaStudies of the same condition, open and under way.
- More trials run by EMD Serono Research & Development Institute, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Responsible party
- Sponsor
- Investigators
- Medical Responsible, Study director, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04075721
- Sponsor's protocol ID
- MS201814_0010
- Other IDs
- 2019-000947-28, 2019
- Status last verified
- Jun 2022
- First submitted
- 29 Aug 2019
- Last updated
- 24 Mar 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports 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 http://bit.ly/IPD21
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 (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.
PubMed 34045234Lignet 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.
PubMed 36273822
Study at a glance
From the registry record, last updated by the sponsor on 24 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04075721
- Acronym / sponsor ID
- MS201814_0010
- Conditions
- Multiple Myeloma
- Keywords
- M3258, Dexamethasone, Pharmacokinetics, Relapsed Refractory Multiple Myeloma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was early discontinued due to lack of participant enrollment.
- Enrolment
- 10 participants (actual)
- Lead sponsor
- EMD Serono Research & Development Institute, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Study start
- 26 Sep 2019 (actual)
- Primary completion
- 1 Apr 2021 (actual)
- Study completion
- 1 Apr 2021 (actual)
- First posted
- 3 Sep 2019 (actual)
- Results
- Posted 24 Mar 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| M3258Participants 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. | Drug | M3258 10 mg QD, M3258 10 mg Twice per Week |
| M3258 20 mgParticipants received M3258 at a dose of 20 mg orally, twice per week on Day 1 and Day 4 until disease progression. | Drug | M3258 20 mg Twice per Week |
Primary outcome
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
Time frame: Day 1 up to Day 28
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.
Part A: Number of Participants With Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs)
Time frame: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)
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.
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
Time frame: Day 29 up to 20.1 weeks
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.
Part A: Change From Baseline in 12-lead Electrocardiogram (ECG) Findings: QT Interval - Fridericia's Correction Formula
Time frame: Cycle 1 Day 1 pre-dose (Baseline), pre-dose on Cycle 2 Day 1 (each Cycle is of 28 days)
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.
Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
Time frame: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)
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).
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
Time frame: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)
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.
16 secondary outcomes
Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Body Temperature Increase
Time frame: 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 frame: 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 frame: 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
Time frame: 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
Time frame: 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)
Part A: Single Dose: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC0-t) of M3258
Time frame: 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: Single Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258
Time frame: 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: Multiple Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258
Time frame: 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)
Part A: Single Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 1
Time frame: Baseline (Pre-dose), 2, 6 and 24 hours post-dose on Cycle 1 Day 1 (each Cycle is of 28 days)
Part A: Multiple Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 8 (or Day 15)
Time frame: Cycle 1 Day 1 pre-dose (Baseline), Pre-dose, 2 and 6 hours post-dose on Cycle 1 Day 8 (or Day 15) (each Cycle is of 28 days)
Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis
Time frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)
Part A: Change From Baseline in Urine M-protein Level Using Electrophoresis
Time frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)
Part A: Change From Baseline in Free Light Chain Ratio
Time frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)
Part A: Number of Participants With Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
Time frame: Time from first dose of study treatment up to 18.2 months
Duration of Response (DoR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
Time frame: Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 18.2 months
Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria
Time frame: Time from the first dose of study treatment up to documentation of first response, assessed up to 18.2 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Mar 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 34045234Sanderson 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.
- Derived from this study: PubMed 36273822Lignet 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.
- Trial Awareness and Transparency websiteLink provided by the sponsor.
- US Medical Information website, Medical ResourcesLink provided by the sponsor.
- Individual participant dataSharing planned: No. We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports 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 http://bit.ly/IPD21
Related trials for Multiple Myeloma
Not yet recruitingPhase 2
Study of YKST02 in Adults With Relapsed or Refractory Multiple Myeloma
Relapsed or Refractory Multiple Myeloma (RRMM)
RecruitingPhase 2
Engaging T-cells to Eliminate MRD in Newly Diagnosed Myeloma Optimizing Response With Talquetmab and Teclistamab (ROTATE)
Multiple Myeloma
Active, not recruitingPhase 3
A Phase III Study of Eque-cel in Subjects With Len-refractory RRMM (FUMANBA-03)
Multiple Myeloma
Active, not recruitingPhase 1/2
A Window of Opportunity Trial to Learn if Linvoseltamab is Safe and Well Tolerated, and How Well it Works in Adult Participants With Recently Diagnosed Multiple Myeloma Who Have Not Already Received Treatment
Multiple Myeloma
Active, not recruitingPhase 2
Testing AZD5363 as a Potential Targeted Treatment in Cancers With AKT Genetic Changes (MATCH-Subprotocol Y)
Advanced Lymphoma, Advanced Malignant Solid Neoplasm
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Responsible study director
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
7 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing M3258 and M3258 20 mg in people with Multiple Myeloma, run by EMD Serono Research & Development Institute, Inc. at 7 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 24 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United States, France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: Day 1 up to Day 28). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04075721, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2023.