NCT04075721 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1
Status at capture: TERMINATED
Registry last update: 2023-03-24

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).

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Body Temperature Increase

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outcome · POSTED

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

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outcome · POSTED

Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Respiration Rate Increase/Decrease

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outcome · POSTED

Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3258

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outcome · POSTED

Part A: Mutilple Dose: Maximum Observed Plasma Concentration (Cmax) of M3258

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outcome · POSTED

Part A: Single Dose: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC0-t) of M3258

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outcome · POSTED

Part A: Single Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258

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outcome · POSTED

Part A: Multiple Dose: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3258

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outcome · POSTED

Part A: Single Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 1

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outcome · POSTED

Part A: Multiple Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 8 (or Day 15)

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outcome · POSTED

Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis

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outcome · POSTED

Part A: Change From Baseline in Urine M-protein Level Using Electrophoresis

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outcome · POSTED

Part A: Change From Baseline in Free Light Chain Ratio

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outcome · POSTED

Part A: Number of Participants With Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria

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outcome · POSTED

Duration of Response (DoR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria

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outcome · POSTED

Time to Response as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

intervention Names
Drug: M3258
label
M3258 10 mg QD
type
EXPERIMENTAL
intervention Names
Drug: M3258
label
M3258 10 mg Twice per Week
type
EXPERIMENTAL
intervention Names
Drug: M3258 20 mg
label
M3258 20 mg Twice per Week
type
EXPERIMENTAL

interventions

arm Group Labels
M3258 10 mg QD
M3258 10 mg Twice per Week
description
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.
name
M3258
type
DRUG
arm Group Labels
M3258 20 mg Twice per Week
description
Participants received M3258 at a dose of 20 mg orally, twice per week on Day 1 and Day 4 until disease progression.
name
M3258 20 mg
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 10
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
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
description
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.
measure
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)
description
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.
measure
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
description
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.
measure
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)
description
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).
measure
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)
description
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.
measure
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)

secondary Outcomes

description
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.
measure
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)
description
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.
measure
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)
description
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.
measure
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)
description
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.
measure
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)
description
Cmax was obtained directly from the concentration versus time curve.
measure
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)
description
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.
measure
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)
description
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.
measure
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)
description
Area under the plasma concentration versus time curve from time zero to 24 hours post dosing for M3258.
measure
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)
description
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.
measure
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)
description
Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement.
measure
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)
description
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.
measure
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)
description
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.
measure
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)

Full study description

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).

Source references

references

citation
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
type
RESULT
citation
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
type
DERIVED