A Study of the Safety, Tolerability and Effectiveness of EZM0414 Investigative Product in Participants With Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory Diffuse Large B Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
This study will include participants with relapsed/refractory (R/R) Multiple Myeloma (MM). MM is a type of cancer of the blood. This study will also include participants with relapsed/refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL). DLBCL is also a type of cancer of the blood. They are referred to as 'relapsed' when the disease has come back after treatment and 'refractory' when treatment no longer works. The study has 2 main parts, called phase 1 and phase 1b. The main objective of both parts will be to evaluate the safety and tolerability of the study drug, called EZM0414. The main objective of phase 1b will also be to determine the effectiveness of EZM0414. During phase 1 six dose levels will be tested to obtain the most tolerated dose. Participants will receive study drug at the assigned dose level every 28 days. During phase 1b participants will receive study drug at the maximum tolerated dose in 28-day cycles.

Detailed Description
-----------------
The first part of the study will be a Phase 1 dose-escalation designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of EZM0414 in subjects with R/R MM and R/R DLBCL. Six dose levels starting at 100 mg, then 200 mg, 300 mg, 400 mg, 600 mg, and 900 mg as well as an optional step-down dose of 75 mg (if needed) will be tested. The second part of the study is the Phase 1b dose expansion at the MTD designed to evaluate safety and efficacy in subjects with R/R DLBCL and R/R MM with or without select genetic translocation. Dose expansion will enroll subjects in 3 cohorts: Cohort 1 for R/R MM subjects with t(4;14), Cohort 2 for R/R MM subjects without t(4;14), and Cohort 3 for subjects with R/R DLBCL.

Official Title
-----------------
A Phase 1/1b, Open-Label, Multi-Center, Two-Part Study of SETD2 Inhibitor EZM0414 in Subjects With Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Conditions
-----------------
Multiple Myeloma, Refractory, Diffuse Large B-Cell Lymphoma, Diffuse Large B Cell Lymphoma Refractory, Multiple Myeloma in Relapse

Intervention / Treatment
-----------------
* Drug: EZM0414


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Voluntarily provide signed informed consent after review of verbal and written material about the trial and agree to abide with protocol requirements. All study related activities must be carried out after written consent is obtained. Subjects must be ≥18 years of age at the time of signing the ICF (Informed Consent Form). Subjects must have an Eastern Cooperative Oncology Group (ECOG) status of 0 - 2. For MM, subjects must have measurable disease by IMWG (International Myeloma Working Group) 2016 criteria For DLBCL, subjects must have measurable disease by Lugano criteria Females must not be breastfeeding or pregnant at screening Females of childbearing potential must not have had unprotected sexual intercourse while participating in this study Male subjects must either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy, during study treatment and for 30 days after the final dose of study treatment Exclusion Criteria: Subjects with plasma cell leukemia defined as a plasma cell count >2000/mm3. Subjects with Waldenstrom's macroglobulinemia or smoldering MM. Subjects who had prior treatment with SETD2 or NSD2 inhibitor. Subjects with active acute or chronic systemic infection requiring systemic treatment, including COVID-19. Has cardiovascular impairment Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec or history of long QT syndrome. Known left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA). Prior major surgery within 4 weeks of treatment start. Known hypersensitivity to components of the investigational product. Subjects who have received treatment with any unapproved drug product within 4 weeks prior to screening. Current participation in any other interventional clinical study except for follow up. Subjects with a history of or active malignancy other than disease under study Underlying medical/social conditions that in PI opinion will place the subject in significant risk and affect the interpretation of toxicity and adverse events assessments. Inability to take oral medication or known gastrointestinal (GI) disease, GI procedure or medical condition that could interfere with the oral absorption or tolerance of the study drug

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label EZM0414<br>Participants will receive EZM0414 in continuous 28-day cycles. EZM0414 will be administered orally once daily (QD) without food. Participants who receive EZM0414 at Maximum tolerated dose (MTD) and do not have Dose limiting toxicities (DLT) in the dose escalation part of the study will be rolled over to a cohort of this dose expansion part. Cohort 1 for R/R MM Participants. Cohort 2 for R/R MM Participants. Cohort 3 for Participants with R/R DLBCL. | Drug: EZM0414<br>* Immediate-release film-coated tablets: Six dose levels starting at 100 mg, and then 200 mg, 300 mg, 400 mg, 600 mg, and 900 mg as well as an optional step-down dose level of 75 mg (if needed)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Adverse Events (AEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Through study completion, an average of 3 years | 
| Percentage of participants with clinically significant changes in physical examination | Percentage of participants with clinically significant changes in physical examination findings will be reported. The clinical significance will be evaluated by the Investigator based on the CTCAE, version 5.0. | Through study completion, an average of 3 years | 
| Percentage of participants with clinically significant changes in vital signs | Percentage of participants with clinically significant changes in vital signs will be reported. The clinical significance will be evaluated by the investigator based on the CTCAE, version 5.0. | Through study completion, an average of 3 years | 
| Percentage of participants with clinically significant changes in 12-lead ECG readings | Percentage of participants with clinically significant changes in ECG readings will be reported. The clinical significance will be will be evaluated by the investigator based on the CTCAE, version 5.0. | Through study completion, an average of 3 years | 
| Percentage of participants with clinically significant changes in laboratory parameters (hematology including coagulation profile, serum chemistries, and urinalysis) | Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, hematology and coagulation) will be reported. The clinical significance will be evaluated by the Investigator based on the CTCAE, version 5.0. | Through study completion, an average of 3 years | 
| Performance status evaluated by ECOG | ECOG is a 6-point performance status scale used to assess performance using participant as a key indicator (e.g., 0 = fully active, 2 = up and about more than 50% of walking hours, 5 = dead) Performance status will be assessed per usual clinical practice and will be recorded in the medical record. | Through study completion, an average of 3 years | 
| Concomitant medication monitoring | Defined as any medication or vaccine, including over-the-counter or prescription medicines, vitamins, and/or herbal supplements that the participant is receiving at the time of enrollment or received during the study. | Through study completion, an average of 3 years | 
| Part 1 Phase 1: Dose limiting toxicities (DLT) | Events will be assessed as DLTs according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) | Through study completion, an average of 3 years | 
| Part 2 Phase 1b: Establishing Maximum Tolerated Dose (MTD) and a recommended Phase 2 Dose (RP2D) | Recommended Phase 2 will be established by analyzing AE, clinical laboratory tests and pharmacokinetics Profile. | Through study completion, an average of 3 years | 
| Part 2 Phase 1b: Objective Response Rate (ORR) | Defined as the proportion of responders as assessed by Investigator per International Myeloma Working Group (IMWG) 2016 guidelines for MM (Stringent complete response (sCR), Complete Response (CR), Very good partial response (VGPR), and Partial Response (PR)) or Lugano 2014 guidelines for Diffuse large B cell lymphoma (DLBCL) (CR+PR). | Through study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2 Phase 1b: Progression-free survival (PFS) | Defined as the time from start of treatment until the first documented PD, as assessed by Investigator per IMWG 2016 guidelines for MM or Lugano 2014 guidelines for DLBCL or death due to any cause, whichever occurs first. | Through study completion, an average of 3 years | 
| Part 2 Phase 1b: Disease Control Rate (DCR) | Defined as the proportion of subjects who have achieved confirmed CR, sCR, PR, VGPR, minimal response or stable disease (SD) per IMWG 2016 Guidelines for MM or CR, PR, or SD per Lugano 2014 Guidelines for DLBCL since administration of EZM0414 in dose expansion part (including the cycle 1 observations of the subjects who receive EZM0414 at MTD in the dose escalation part and are rolled over to the dose expansion part). | Through study completion, an average of 3 years | 
| Part 2 Phase 1b: Duration of response (DOR) | Defined as the time from initial CR or PR to documented progression or death, whichever comes first, as assessed by Investigator per IMWG 2016 guidelines for MM or Lugano 2014 guidelines for DLBCL | Through study completion, an average of 3 years |