Clinical trial NCT05121103
Conditions: Multiple Myeloma, Refractory Diffuse Large B-Cell Lymphoma Diffuse Large B Cell Lymphoma Refractory Multiple Myeloma in Relapse
Sponsor: Epizyme, Inc.
Start date: 2022-05-31; Completion date: 2024-04-30
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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.
Interventions: intervention 1: EZM0414
Intervention descriptions: intervention 1: 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)

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
 
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SET-101 
 
 
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 
 
 
 
Protocol Amendment 3.0: 06 July 2022 
Protocol Amendment 2.0: 10 February 2022 
Protocol Amendment 1.0: 26 July 2021 
Original Protocol: 18 June 2021 
 
 
 
 
 
 
GCP Statement: 
This study is to be performed in full compliance with International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
and all applicable local Good Clinical Practices (GCP) and regulations. All required 
study documentation will be archived as required by regulatory authorities. 
Confidentiality Statement: 
This document is confidential. It contains proprietary information of Epizyme, Inc. (the 
Sponsor). Any viewing or disclosure of such information that is not authorized in writing 
by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 




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INVESTIGATOR’S AGREEMENT 
 
I have read the SET-101 protocol and agree to conduct the study as outlined. I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document History 
Document 
Date 
Amendment 3.0 
06 July 2022 
Amendment 2.0 
10 February 2022 
Amendment 1.0 
26 July 2021 
Original Protocol 
18 June 2021 
Amendment 3.0 
This amendment is being made to: 
•
Added an optional step-down dose level in the dose escalation part of the study
•
Clarify dose modifications for the three lowest dose levels
•
Updates to refine the inclusion and exclusion criteria
•
Clarify disease assessments for subjects with MM
In addition, minor editorial, and document formatting revisions (eg, deletion of repeated 
information in the same sections, addition of abbreviations to tabular footnotes, etc) were made. 
All changes are visible in the tracked version. 
Details of Substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale 
Section 2 (Synopsis) 
Section 7.1 (Overall Study 
Design) 
Section 7.5.2 (Dose Reduction 
and Interruptions) 
Section 7.5.6 (Determination of 
Sample Size and Criteria for 
Early Stopping Due to Futility) 
Section 14.1 (Study Design) 
Section 14.4 (Statistical 
Analysis Groups) 
Section 14.6.1 (DLT Evaluation 
and MTD Determination) 
Added an optional step-down 
dose level cohort in the dose 
escalation part of the study 
To give the study design more 
flexibility to adapt based on 
subject safety. 
Section 2 (Synopsis) 
Section 7.1 (Overall Study 
Design) 
Section 14.1 (Study Design) 
Removed language regarding 
“back-filling” dose levels in the 
dose escalation part of the study 
This amendment added an 
optional step-down dose level. 
Future dose levels may be 
added using protocol 
amendments. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 2 (Synopsis) 
Section 8.1 (Subject Inclusion 
Criteria) 
Removed previous inclusion 
criteria regarding tumor/bone 
marrow biopsies. 
This information is provided in 
Section 12 (Translational 
Research Samples) 
Section 2 (Synopsis) 
Section 8.2 (Subject Exclusion 
Criteria) 
Removed previous exclusion 
criteria regarding Gilbert’s 
syndrome and ASCT eligibility 
This study plans to enroll 
subjects who meet all of the 
inclusion criteria and will not 
exclude subjects based solely 
on Gilbert’s syndrome or 
ASCT eligibility 
Section 2 (Synopsis) 
Section 8.2 (Subject Exclusion 
Criteria) 
Changed the exclusion criterion 
from “clinically significant 
amyloidosis” to “systemic 
amyloidosis” 
To provide a clearer definition 
of the exclusion criterion. 
Section 7.5.2 (Dose Reduction 
and Interruptions) 
Added dose modifications for 
the three lowest dose levels 
To provide more details on 
how to modify EZM0414 in 
the event of a treatment-related 
adverse event 
Section 2 (Synopsis) 
Section 14.9 (Efficacy 
Analyses) 
Update efficacy endpoints to 
remove overall survival as an 
endpoint, define duration of 
response and disease control 
rate as endpoints, and change 
ORR to a primary efficacy 
endpoint. 
Efficacy endpoints were 
updated to better reflect the 
objectives of this trial. 
 
Details of Non-substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale 
Section 2 (Synopsis) 
Administrative updates 
Updates based on the current 
study timeline and plan. 
Section 2 (Synopsis) 
Changed the format of 
objectives and endpoints from a 
list to a table 
For clarity and to align with 
Section 6 
Section 2 (Synopsis)  
Section 6 (Trial Objectives and 
Purpose) 
Clarify overall survival is not an 
endpoint in this study 
This study is not designed to 
capture overall survival. This 
was previously included as an 
endpoint as an oversight. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 2 (Synopsis) 
Section 7.1 (Overall Study 
Design) 
Clarification on when safety, 
tolerability, PK and PD data, as 
available, will be reviewed. 
Previous amendment was not 
clear that, in addition to the 
Safety Review Committee 
review needed before starting 
new dose levels, safety, 
tolerability, PK and PD data, as 
available, will be reviewed 
after 4 dose levels, after the 
600 mg dose level, after the 
900 mg dose level, and at the 
MTD dose level. 
Section 2 (Synopsis) 
Additional edits can be found in 
the redline. 
Edits to align the synopsis and 
body text. 
Section 7.1 (Overall Study 
Design) 
Moved location of study 
schema 
To present information on the 
study design in the same order 
used in the synopsis 
Table 8 (Schedule of 
Assessments for Dose 
Escalation and Dose 
Expansion) 
Section 13.1.3 (Vital Signs) 
Section 13.1.7 
(Electrocardiogram (ECG)) 
Clarify timing of vital signs and 
ECGs 
To provide more details on the 
single assessments compared to 
the serial assessments of vital 
signs and ECGs. 
Section 5.2.6.1 (Multiple 
Myeloma) 
Table 8 (Schedule of 
Assessments for Dose 
Escalation and Dose 
Expansion) 
Clarified disease assessments 
for subjects with MM 
To provide more details on 
when and how disease 
assessments will be conducted. 
 




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marrow aspirates, tumor/bone marrow 
biopsies, and blood samples.  
• 
To assess pharmacokinetics (PK) of EZM0414 
when administered as monotherapy in subjects 
with R/R MM and R/R DLBCL. 
• 
Pharmacokinetic parameters including but 
not limited to: AUC0–t: area under the plasma 
concentration-time curve from time 0 to the 
time of the last quantifiable concentration; 
Cmax: observed maximum plasma 
concentration; Tmax: observed time at Cmax; 
λz: terminal phase elimination rate constant; 
t1/2: terminal elimination half-life. 
Part 2: Phase 1b Dose Expansion Phase 
Primary Safety 
• 
To determine the safety and tolerability of 
EZM0414 in subjects with R/R MM and R/R 
DLBCL. 
• 
Adverse event assessment according to 
CTCAE 5.0, assessment of changes in 
physical examination, vital signs (blood 
pressure, heart rate, respiration rate, and 
body temperature), 12-lead ECG, clinical 
laboratory tests (hematology including 
coagulation profile, serum chemistries, and 
urinalysis), ECOG performance status, and 
concomitant medication monitoring. 
• 
To establish the recommended Phase 2 dose 
(RP2D). 
• 
Adverse events, clinical laboratory tests, and 
pharmacokinetic profile. 
Primary Efficacy 
• To determine the efficacy of EZM0414 as 
demonstrated by the effect on ORR in 
subjects with R/R MM and R/R DLBCL. 
• ORR defined as the proportion of 
responders as assessed by Investigator 
per IMWG 2016 guidelines for MM 
(sCR, CR, VGPR, and PR) or Lugano 
2014 guidelines for DLBCL (CR+PR). 
Secondary 
• 
To determine the efficacy of EZM0414 as 
demonstrated by the effect on ORR, PFS, and 
DOR in subjects with R/R MM and R/R 
DLBCL.  
• 
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. 
• 
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 


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escalation part and are rolled over to the dose 
expansion part). 
• 
DOR defined as the time from initial 
response to documented progression or 
death, whichever comes first, as assessed by 
Investigator per IMWG 2016 guidelines for 
MM or Lugano 2014 guidelines for DLBCL. 
Exploratory 
• 
To determine H3K36me3 in tumor tissue 
biopsy and blood samples. 
• 
To determine exploratory biomarkers such as 
histones and histone methylation, somatic 
mutations, DNA methylation and other DNA 
alterations such as t(4;14) and others, protein 
levels, RNA expression, and immune cells in 
bone marrow aspirates, tumor/bone marrow 
biopsies, and blood samples.  
• 
To determine the pharmacokinetic profile of 
EZM0414. 
• 
H3K36me3 in tumor/bone marrow biopsy 
and blood collected at baseline and during 
treatment.  
• 
Biomarkers such as histones and histone 
methylation, somatic mutations, DNA 
methylation and other DNA alterations such 
as t(4;14) and others, protein levels, RNA 
expression, immune cells in bone marrow 
aspirates, tumor biopsies, and blood samples. 
• 
Pharmacokinetic parameters including but 
not limited to: AUC0–t: area under the plasma 
concentration-time curve from time 0 to the 
time of the last quantifiable concentration; 
Cmax: observed maximum plasma 
concentration; Tmax: observed time at Cmax; 
λz: terminal phase elimination rate constant; 
t1/2: terminal elimination half-life, Cmax/D: 
maximum observed concentration 
normalized to the dose; and AUC/D: AUC 
normalized to the dose. 
Study Design: 
This is a first-in-human (FIH), 2-part, multi-center, open-label Phase 1/1b safety, tolerability, PK, and 
efficacy study of oral SETD2 inhibitor, EZM0414, in subjects with R/R MM and R/R DLBCL. The 
first part of the study will be a Phase 1 dose-escalation designed to evaluate the safety, tolerability, 
and 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 level 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. 


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Figure 1:
Study Schema
Note: if needed, the Part 1: Phase 1 Dose Escalation may include an optional step-down dose level of 75 mg. 
Abbreviations: DLBCL = diffuse large B cell lymphoma; DLT = dose limiting toxicities; MM = multiple 
myeloma; MTD = maximum tolerated dose; R/R = relapsed/refractory. 
Methodology: 
Part 1: Phase 1 Safety Dose Escalation
Part 1 is a safety dose escalation to determine the MTD for dose expansion in Part 2 of the study. 
Bayesian Optimal Interval (BOIN) design will be used to evaluate the safety and tolerability 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 level of 75 mg (if 
needed) will be tested in this dose escalation part of the study. Safety, tolerability, PK, and PD data
will be reviewed, as available, initially after 4 planned dose levels (100 mg, 200 mg, 300 mg, and 400 
mg) are evaluable, then again when the 600 mg dose level is evaluable, then again when the 900 mg 
dose level is evaluable, and lastly when the MTD is determined. Subjects will be enrolled and treated 
in groups of at least 3 subjects, and up to 36 subjects (at least 3 subjects each with t(4;14) MM, non-
t(4;14) MM and DLBCL) will be enrolled in order to evaluate at least 9 subjects for MTD. Successive 
subjects within a given dose level will follow a staggered dose pattern with at least 48 hours between 
subjects. Additional daily dose levels and/or dosing schedules (including BID regimen) may be 
studied based on clinical safety, tolerability, and PK data obtained during this study. 
All subjects will be treated with the study drug in cycles of 28 days and the DLTs that occur within 
the first cycle will be used to determine MTD. Progression to the next dose level will be based upon 
the dose escalation/de-escalation/elimination rules (See Section 14.1) and Safety Review Committee
(SRC) review of the safety and PK data (if available) of the current dose group.  
A screening visit will occur within 28 days of signing an informed consent form (ICF). In Cycle 1 
(except Day 2 and Day 3), EZM0414 will be administered orally once daily (QD) without food (no 
food two hours prior and one hour after EZM0414 dose, water is permitted without restrictions) in 
continuous 28-day cycles. Subjects will continue to receive treatment at the assigned dose level until 
disease progression, occurrence of unacceptable toxicity, withdrawal of consent, or need for treatment 
prohibited on this study. No intra-patient dose escalation will be permitted. Dose limiting toxicities 
(as defined in Table 3) will be assessed during the first treatment cycle and dose modifications for 
EZM0414 are discussed in Table 4.


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Safety assessments will be performed throughout the study and at each study visit. Vital signs 
including blood pressure, respiration rate, heart rate, and body temperature will be collected according 
to schedule of assessments (Table 8 and Table 9). 
A single 12-lead ECG will be collected at screening and triplicate ECGs 1-minute apart will be 
collected at all other time points mentioned in Table 8 and Table 9. Subjects should be seated resting 
for 10 min prior to collection of all study ECGs. 
Blood samples will be collected from all subjects for PK analyses at time points mentioned in 
Table 9. 
At time points where vital signs, ECG and PK blood samples are required, the following order of 
collection is recommended (1) vital signs, (2) ECG (3) Blood sample for PK analyses and biomarker 
analyses. 
Translational samples for research  
Bone marrow aspirates and a bone marrow biopsy will be collected at screening or Cycle 1 Day 1 
(pre-dose) in subjects with MM. For subjects with MM, a bone marrow biopsy and bone marrow 
aspirations will be performed on-treatment (Cycle 3 Day 1). In subjects with MM a bone marrow 
biopsy and bone marrow aspirates will be performed at VGPR. A non-mandatory bone marrow 
biopsy and bone marrow aspirates can be performed at progression in MM subjects. If a standard of 
care (SOC) bone marrow will be performed, a bone marrow aspiration will be requested for research 
in MM subjects. In subjects with DLBCL, archival tissue sample not older than 6 months will be 
collected. In DLBCL subjects with not enough archival tissue available, an optional fresh biopsy is 
recommended at screening or Cycle 1 Day 1 (pre-dose). An on-treatment biopsy (Cycle 3 Day 1) will 
be optional for subjects with DLBCL. An optional tumor biopsy will be taken in subjects with 
DLBCL at PR. A non-mandatory tumor biopsy at progression can be taken for subjects with DLBCL. 
Biopsies in patients with DLBCL will be optional and a separate ICF will be provided. Blood samples 
for exploratory analyses in MM and DLBCL subjects will be collected pre-dose at Cycle 1 Day 1, 
Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1 and after that every other cycle until Cycle 26 and 
then every 4 Cycles after Cycle 26, at progression, and at any response event. In blood samples and 
tumor tissue/tumor cells DNA alterations such as mutations, copy number variation (CNV), and other 
DNA alterations will be assessed, RNA expression will be investigated in tumor tissue/tumor cells 
and/or blood samples as well as protein expression and methylation status. Different assays such as 
next-generation sequencing (NGS), fluorescent-in situ hybridization (FISH), immunohistochemistry, 
and others will be performed to investigate translational research samples. 
Assessment of Safety 
In the Phase 1 safety portion, a SRC will monitor safety data on an ongoing basis. All dose escalation 
decisions will be made by the SRC and Sponsor upon review of all available data. Determination of 
the MTD will be informed by all available data, including the overall tolerability of EZM0414. 
Assessment of response  
Assessment of response to treatment will be performed according to IMWG 2016 (Kumar, 2016; 
Appendix 1) consensus criteria in MM subjects and Lugano Classification (Cheson, 2014; 
Appendix 2) in DLBCL subjects. 
In MM: IMWG 2016 consensus criteria that includes serum M-protein, 24-hour urine M-protein, 
serum free light chain kappa, lambda, and their ratio, bone marrow aspiration (CR) and bone marrow 
biopsy (sCR). Hence, subjects with MM would need to undergo a bone marrow biopsy or bone 
marrow aspiration for IMWG response assessment (Kumar, 2016; Appendix 1). 
In DLBCL: International Working Group consensus response evaluation criteria in lymphoma, 
Lugano Classification (Cheson, 2014; Appendix 2). Hence subjects with a previously positive or 
unknown bone marrow biopsy at baseline would undergo a bone marrow biopsy in suspected CR. 
 


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Part 2: Phase 1b Safety and Efficacy Dose Expansion 
In the dose expansion phase, Bayesian optimal phase 2 (BOP2) design will be used to evaluate safety 
and efficacy in subjects with or without select genetic translocation in R/R MM and R/R DLBCL.  
In dose expansion part, 3 cohorts of subjects will be enrolled (20 subjects/cohort) and treated:  
• 
Cohort 1: R/R MM with t(4;14)  
• 
Cohort 2: R/R MM without t(4;14) 
• 
Cohort 3: R/R DLBCL 
During the treatment period, subjects will receive EZM0414 in continuous 28-day cycles. EZM0414 
will be administered orally once daily (QD) without food (nothing to eat two hours prior and one hour 
after EZM0414 dose, water is permitted as needed). The subjects who receive EZM0414 at MTD and 
do not have DLT in the dose escalation part of the study will be rolled over to a cohort of this dose 
expansion part, depending on their condition (R/R MM or R/R DLBCL) and the select genetic 
translocation for R/R MM. All subjects will continue to receive treatment at the MTD in Phase 1b 
part until disease progression, occurrence of unacceptable toxicity, withdrawal of consent or need for 
treatment prohibited on this study. Subjects with R/R MM regardless of t(4;14) status will be enrolled 
first. Dose modifications for EZM0414 are discussed in Table 4. 
Safety assessments will be performed throughout the study and at each study visit. Vital signs 
including blood pressure, heart rate, respiration rate, and body temperature will be collected according 
to schedule of assessments (Table 8 and Table 10). 
A single 12-lead ECG will be collected at screening and triplicate ECGs, 1-minute apart will be 
collected at time points mentioned in Table 8 and Table 10. 
Blood samples will be collected from all subjects for PK analyses at the time points mentioned in 
Table 10. 
At time points where vital signs, ECG and PK blood samples are required, the following order of 
collection is recommended 1) vital signs, 2) ECG and 3) blood sample for PK analyses and biomarker 
analyses. 
Assessment of response 
Assessment of response to treatment will be performed according to IMWG 2016 consensus criteria 
(Kumar, 2016; Appendix 1) in MM subjects and Lugano Classification (Cheson, 2014; Appendix 2) 
in DLBCL subjects. To assess response according to IMWG 2016, subjects with MM will undergo 
bone marrow aspirates or biopsies to assess CR or stringent CR respectively. To assess complete 
response according to Lugano Classification, subjects with DLBCL might undergo a bone marrow 
biopsy. In MM subjects, treatment response will include serum M-protein, 24-hour urine M-protein, 
serum free light chain kappa, lambda, and their ratio. In DLBCL, imaging will be used to assess 
response. 
Translational samples for research  
Bone marrow aspirates and a bone marrow biopsy will be collected from all MM subjects at baseline 
(at screening or Cycle 1 Day 1 pre-dose), on-treatment (Cycle 3 Day 1) and at VGPR. A non-
mandatory bone marrow biopsy and bone marrow aspirates will be taken for subjects with MM at 
disease progression. If a SOC bone marrow will be performed, a bone marrow aspiration will be 
requested for research in subjects with MM. In subjects with DLBCL, archival tissue sample not older 
than 6 months will be collected and if not available, an optional fresh biopsy will be performed at 
screening or Cycle 1 Day 1 (pre-dose). An optional on-treatment biopsy (Cycle 3 Day 1) and at PR 
will be performed in DLBCL subjects. Non-mandatory tumor biopsies in subjects with DLBCL at 
disease progression. All biopsies for subjects with DLBCL will be optional and a separate ICF will be 
provided. Blood samples will be collected predose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, 
Cycle 3 Day 1, after that at every other cycle until Cycle 26 and then every 4 cycles after Cycle 26, at 


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progression, and at any response event. The translational research samples will be investigated for 
clones harboring t(4;14) translocation, somatic mutations such as SETD2 or multiple myeloma SET 
domain (MMSET), expression of H3K36me2, and H3K36me3. Other markers and analysis might be 
performed as well.  
Biomarker results including PD data will be correlated with PK data or outcome to investigate 
possible differences between subjects who respond to treatment versus those who do not respond.  
Sample Size Justification: 
Part 1: Phase 1 Safety Dose Escalation 
Bayesian optimal interval design (Liu, 2015; Yuan, 2016; Zhou, 2017) will be used to evaluate the 
safety and tolerability of EZM0414 in subjects with R/R MM and R/R DLBCL. Six dose levels (j=6, 
ie, starting at 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, and 900 mg) as well as an optional step-
down dose level of 75 mg are set forth for investigation. Subjects will be enrolled and treated in 
groups of at least 3, and up to 36 subjects will be enrolled in order to evaluate at least 9 subjects for 
MTD. Additional daily dose levels and/or dosing schedules (including BID regimen) may be studied 
based on clinical and PK data obtained during this study.  
Part 2: Phase 1b Safety and Efficacy Dose Expansion 
Bayesian optimal phase 2 design (Yuan, 2016; Zhou, 2017)will be applied to the Phase 1b dose 
expansion part to discover efficacy signals. Twenty subjects per cohort are planned to be enrolled and 
treated in 3 cohorts: R/R MM subjects with t(4;14), R/R MM subjects without t(4;14) and R/R 
DLBCL subjects. 
Number of Subjects (planned):  
Phase 1 dose escalation: up to 36 subjects 
Phase 1b dose expansion: up to 60 subjects 
Total: approximately 96 subjects 
Diagnosis and Main Criteria for Inclusion:  
1. 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. 
2. Subjects must be ≥18 years of age at the time of signing the ICF. 
3. Subjects must have an ECOG status of 0 – 2 (Appendix 3).  
4. For MM, subjects must have measurable disease by IMWG 2016 criteria (Kumar, 2016; 
Appendix 1) as defined by at least one of the following: 
• 
Serum monoclonal protein (M-protein) concentration ≥ 0.5g/dL. 
• 
Urine M-protein excretion of ≥ 200mg in 24 hours. 
• 
Serum free light chain concentration ≥10mg/dL with an abnormal (<0.26 or >1.65) κ:λ free 
light chain ratio. 
5. For DLBCL, subjects must have measurable disease by Lugano criteria (Cheson, 2014; 
Appendix 2).  
6. MM subjects who are relapsed/refractory to immune modulator, proteasome inhibitor and anti-
CD38 therapy. Subjects who could not tolerate a protease inhibitor (PI), immunomodulatory 
agent (IMiDs), and a CD38-directed cytolytic antibody are eligible to participate and R/R MM 
subjects who are intolerant of established therapies known to provide clinical benefit in multiple 
myeloma. 
7. DLBCL subjects who are relapsed or refractory with at least two prior line including treatment 
with R-CHOP, R-EPOCH, R-hyperCVAD and other standard of care therapies. Lines of therapy 
could have been discontinued due to completion of therapy, intolerance, or lack of response. 


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Note: Relapsed disease is defined as progression of disease, after initial response to previous 
treatment, more than six months after end of treatment. Refractory disease is defined as 
resistance to treatment due to lack of response or progression of disease during treatment or 
within six months after end of treatment. 
8. For dose expansion cohort 1 and 2 only; subjects must have local t(4;14) test results available 
for enrollment.  
9. At enrollment, subjects should have an estimated life expectancy ≥ 3 months in the opinion of 
the Investigator. 
10. Subjects must have sufficient organ and marrow function as defined below: 
• 
Hemoglobin ≥8g/ dL 
• 
Platelets >75x109/L (includes transfusion dependent subjects) 
• 
Absolute neutrophil count (ANC) ≥1000/mm3. Growth factors within 7 days of screening is 
not allowed to meet ANC eligibility criteria 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5xULN, or if 
attributed to tumor involvement, AST, and ALT <5x ULN. 
• 
Bilirubin ≤1.5xULN 
• 
Creatinine clearance ≥40 ml/min. Estimated creatinine clearance calculated using the 
Cockcroft-Gault formula 
• 
Coagulation parameters: prothrombin time/ international normalized ratio (PT/INR) 
<1.5xULN and activated partial thromboplastin (aPTT) < 1.5xULN. 
11. Females must not be breastfeeding or pregnant at screening (as documented by a negative beta-
human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 IU/L or 
equivalent units of β-hCG). A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study treatment. All 
female subjects will be considered to be of childbearing potential unless they are 
postmenopausal (at least 12 months consecutively amenorrheic, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral 
tubal ligation, total hysterectomy, and/or bilateral oophorectomy, with all surgery completed at 
least 1 month before the first dosing). 
12. Females of childbearing potential must not have had unprotected sexual intercourse within 30 
days prior to study entry and must agree to use a highly effective method of contraception, 
beginning at least 14 days prior to study entry, during treatment cycles, and for 30 days after the 
final dose of study treatment and have a male partner who uses a condom. Highly effective 
contraception includes: 
• 
Placement of an intrauterine device. 
• 
Established hormonal contraceptive methods: oral, injectable, or implant. Females who are 
using hormonal contraceptives must have been on a stable dose of the same hormonal 
contraceptive product while enrolled on trial and must continue to use the same 
contraceptive during the study and for one months after last dose of study drug. 
13. Male subjects must either practice complete abstinence or agree to use a latex or synthetic 
condom, even with a successful vasectomy (medically confirmed azoospermia), during study 
treatment and for 30 days after the final dose of study treatment.  
       Note: Male subjects must not donate semen or sperm from the first dose of study treatment, 
during study treatment (including during dose interruptions), and for 30 days after the final 
dose of study treatment. 
Diagnosis and Main Criteria for Exclusion:  
1. Subjects with plasma cell leukemia defined as a plasma cell count >2000/mm3. 


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2. Subjects with Waldenstrom’s macroglobulinemia or smoldering MM.  
3. Subjects with corrected serum calcium >14mg/dL (>3.5mmol/L) or free ionized calcium 
>6.5mg/dL (1.6mmol/L). 
4. Subjects with known systemic amyloidosis. 
5. Subjects who had prior treatment with SETD2 or NSD2 inhibitor. 
6. Prior cancer therapy for disease under study within the past 4 weeks or 5 half-lives, whichever 
is shorter. All prior treatment-related adverse events (AEs) must have resolved to Grade 1 or 
baseline per NCI CTCAE 5.0. 
7. Have known active central nervous system (CNS) or any leptomeningeal metastasis of primary 
extracranial tumor. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of 
study treatment and any neurologic symptoms have stabilized), have no evidence of new or 
enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7 days 
prior to first dose of study treatment.  
Note: Subjects with asymptomatic brain metastases found on screening magnetic resonance 
imaging (MRI) may be entered into the study without prior radiation therapy to the brain if they 
do not require immediate surgical or radiation therapy in the opinion of the treating Investigator 
and in the opinion of a radiation therapy or neurosurgical consultant. 
8. Subjects taking medications that are known as strong and moderate cytochrome P450 3A4 
(CYP3A4) and P-gp inducers/inhibitors (including St. John’s Wort). Subjects taking ARA, H2 
blockers and PPIs. Subjects must stop taking such medications and must not take them for the 
duration of their participation in the study. Washout of minimum 14 days or 5 half-lives 
(whichever is longer) prior to starting EZM0414 is required. 
9. Subjects unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from their diet 
and all foods that contain those fruits from time of enrolment to while on study. 
10. Have a known active infection with hepatitis B virus (HBV, as measured by positive hepatitis B 
surface antigen), hepatitis C virus (HCV, as measured by positive hepatitis C antibody). 
Exceptions: Subjects with a history of hepatitis B or C who have normal ALT AND are hepatitis 
B surface antigen negative and/or have undetectable HCV RNA are eligible.  
11. Known to be human immunodeficiency virus (HIV) seropositive. 
12. Subjects with active acute or chronic systemic infection requiring systemic treatment, including 
COVID-19. 
13. Has cardiovascular impairment: history of congestive heart failure greater than NYHA Class II, 
uncontrolled arterial hypertension (ie, systolic blood pressure (BP) >150 mm Hg and/or 
diastolic BP >110 mm Hg), unstable angina, myocardial infarction, or stroke within 6 months 
prior to the planned first dose of study drug; or ventricular cardiac arrhythmia requiring medical 
treatment (Appendix 4). 
14. Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to > 480 msec or 
history of long QT syndrome. A history or evidence of current clinically significant 
uncontrolled arrhythmias. History of additional risk factors for Torsade de Pointes including 
heart failure, hypokalemia, family history of Long QT Syndrome, and use of concomitant 
medications that are known to increase the risk of Torsade de Pointes (www.crediblemeds.org).  
15. Known left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or 
multigated acquisition (MUGA). 
16. Prior major surgery within 4 weeks of treatment start. 
17. Known hypersensitivity to components of the investigational product. 
18. Subjects who have received treatment with any unapproved drug product within 4 weeks prior 
to screening. 


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19. Current participation in any other interventional clinical study except for follow-up. 
20. Subjects with a history of or active malignancy other than disease under study, except for: 
• 
Cervical carcinoma Stage 1B or less. 
• 
Surgically treated non-invasive basal cell and squamous cell skin carcinoma. 
• 
Malignant melanoma with a complete response for more than 10 years. 
• 
Curable cancer and/or hematologic malignancies diagnoses with a complete response for 
more than 5 years. 
21. 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. 
22. 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. 
Investigational product, dosage, and mode of administration:  
EZM0414 will be administered orally once daily in continuous 28-day cycles. In dose escalation part, 
patient will not receive EZM0414 on Cycle 1 Day 2 and on Cycle 1 Day 3, all other days will follow 
daily dosing in cycle 1. Each subject will receive EZM0414 according to the dose level they are 
enrolled in. Intra-patient dose escalation will not be permitted. During the dose expansion part, 
subjects in cohorts 1-3 will receive EZM0414 at the MTD orally once daily. EZM0414 will be 
administered at approximately the same time once daily and without food, (no food two hours prior 
and one hour after EZM0414 dose, water is permitted without restrictions). 
Duration of treatment:  
Subjects will be treated continuously until consent withdrawal, unacceptable toxicity, disease 
progression, or need for treatment prohibited on this study. Each treatment cycle will be of 28-day 
duration. There will be a 30-day safety follow-up. 
Reference therapy, dosage, and mode of administration:  
Not applicable 
Criteria for evaluation: 
Safety: Clinical and laboratory safety will be assessed using NCI CTCAE 5.0 criteria (Appendix 5). 
Efficacy: IMWG 2016 will be used to evaluate response in MM subjects (Kumar, 2016; Appendix 1) 
and Lugano criteria will be used to assess response in DLBCL subjects (Cheson, 2014; Appendix 2).  
Pharmacokinetics: AUC0–t: area under the plasma concentration-time curve from time 0 to the time 
of the last quantifiable concentration; Cmax: observed maximum plasma concentration; Tmax: observed 
time at Cmax; λz: terminal phase elimination rate constant; t1/2: terminal elimination half-life. 
Biomarkers: H3K36me3 in tumor/bone marrow biopsy and blood collected at baseline and during 
treatment. Biomarkers such as histones and histone methylation, somatic mutations, DNA 
methylation and other DNA alterations such as t(4;14) and others, protein levels, RNA expression, 
immune cells in bone marrow aspirates, tumor biopsies, and/or blood samples. 
Statistical methods: 
This is an open-label study and there will be no randomization. Bayesian optimal interval design will 
be used for the Phase 1 dose escalation part of this study. Subjects with R/R MM or R/R DLBCL will 
be enrolled to determine MTD based on DLT and safety. The MTD will then be used for the 
subsequent Phase 1b dose expansion part of the study. In the dose expansion part, BOP2 design will 
be applied and the endpoints ORR, DOR, and PFS will be used to discover efficacy signals of 
EZM0414 treatment. The ORR, as the primary efficacy endpoint, will be summarized by cohort and 
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The secondary efficacy endpoint of PFS will be analyzed using Kaplan-Meier (KM) methodology. 
Median values along with two-sided 95% CIs will be calculated. KM based PFS at 6, 12, 18, and 24 
months will be estimated and associated two-sided 95% CIs will be provided.  
Analyses on DCR will be similar to the ones conducted on the ORR. 
DOR will be estimated using KM methodology for subjects who achieve CR, sCR, PR, or VGPR per 
IMWG 2016 Guidelines for MM or CR or PR per Lugano 2014 Guidelines for DLBCL. Median 
values along with two-sided 95% CIs will be calculated.  
The establishment of RP2D will be achieved based on the totality of the safety, efficacy data, target 
engagement (pharmacodynamic markers), and pharmacokinetic/pharmacodynamic (PK/PD) 
relationships. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
Details of Substantial Changes to the Protocol ................................................................................4 
Details of Non-substantial Changes to the Protocol ........................................................................5 
2. 
SYNOPSIS ...................................................................................................................7 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............18 
LIST OF TABLES .........................................................................................................................23 
LIST OF FIGURES .......................................................................................................................24 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................25 
5. 
INTRODUCTION ......................................................................................................29 
5.1. 
Background .................................................................................................................29 
5.1.1. 
Multiple Myeloma ......................................................................................................29 
5.1.2. 
Diffuse Large B Cell Lymphoma ...............................................................................30 
5.2. 
Investigational Product ...............................................................................................31 
5.2.1. 
EZM0414 ....................................................................................................................31 
5.2.2. 
EZM0414 Mechanism of Action ................................................................................32 
5.2.3. 
Nonclinical Experience ...............................................................................................32 
5.2.3.1. 
Nonclinical Pharmacology ..........................................................................................33 
5.2.3.2. 
Nonclinical Pharmacokinetics ....................................................................................33 
5.2.3.3. 
Drug-Drug Interaction ................................................................................................33 
5.2.3.4. 
Nonclinical Pharmacodynamics .................................................................................33 
5.2.3.5. 
Preclinical Safety ........................................................................................................34 
5.2.3.6. 
Preclinical Efficacy .....................................................................................................35 
5.2.3.7. 
Rationale for the Use of EZM0414 to Treat Multiple Myeloma and Diffuse 
Large B Cell Lymphoma ............................................................................................35 
5.2.4. 
Clinical Experience .....................................................................................................36 
5.2.5. 
Rationale for Starting Dose and Dosing Schedule .....................................................36 
5.2.6. 
Assessment of Response .............................................................................................37 


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5.2.6.1. 
Multiple Myeloma ......................................................................................................37 
5.2.6.2. 
Diffuse Large B Cell Lymphoma ...............................................................................37 
5.3. 
Conclusion ..................................................................................................................37 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................39 
7. 
INVESTIGATIONAL PLAN .....................................................................................42 
7.1. 
Overall Study Design ..................................................................................................42 
7.2. 
Number of Subjects ....................................................................................................47 
7.3. 
Treatment Assignment ................................................................................................47 
7.4. 
Duration of Treatment ................................................................................................47 
7.5. 
Dose Adjustment Criteria ...........................................................................................47 
7.5.1. 
Dose Limiting Toxicities ............................................................................................47 
7.5.2. 
Dose Reductions and Interruptions .............................................................................49 
7.5.3. 
Safety Management Guidelines ..................................................................................51 
7.5.4. 
Safety Stopping Rules .................................................................................................53 
7.5.5. 
Post-Treatment Monitoring for Hematologic Second Primary Malignancy ..............53 
7.5.6. 
Determination of Sample Size and Criteria for Early Stopping Due to 
Futility .........................................................................................................................53 
7.6. 
Criteria for Study Termination ...................................................................................54 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................63 
8.1. 
Subject Inclusion Criteria ...........................................................................................63 
8.2. 
Subject Exclusion Criteria ..........................................................................................65 
8.3. 
Subject Withdrawal Criteria .......................................................................................66 
9. 
TREATMENT OF SUBJECTS ..................................................................................68 
9.1. 
Description of Study Drug ..........................................................................................68 
9.2. 
Special Situations: Overdose, Misuse, Abuse and Medication Error .........................68 
9.3. 
Concomitant Medications ...........................................................................................69 
9.4. 
Treatment Compliance ................................................................................................70 
9.5. 
Randomization and Blinding ......................................................................................70 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................71 
10.1. 
Study Drug Packaging and Labeling ..........................................................................71 
10.2. 
Study Drug Storage .....................................................................................................71 
10.3. 
Study Drug Preparation ..............................................................................................71 
10.4. 
Administration ............................................................................................................71 


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10.5. 
Study Drug Accountability .........................................................................................71 
10.6. 
Study Drug Handling and Disposal ............................................................................72 
11. 
PHARMACOKINETIC ASSESSMENTS .................................................................74 
11.1. 
PK Window for Specific PK Timepoints ...................................................................75 
11.2. 
Determination of Drug Concentration in PK Samples ...............................................75 
11.3. 
Storage and Destruction of Pharmacokinetic Samples ...............................................75 
12. 
TRANSLATIONAL RESEARCH SAMPLES ..........................................................76 
12.1. 
Tumor Sampling .........................................................................................................76 
12.1.1. 
Archival Tumor, Tumor Biopsy and Bone Marrow Aspirates ...................................76 
12.1.2. 
Blood Samples ............................................................................................................76 
12.2. 
Sample Analysis .........................................................................................................76 
12.3. 
Future Use of Research Samples ................................................................................77 
13. 
ASSESSMENT OF SAFETY .....................................................................................78 
13.1. 
Safety Parameters .......................................................................................................78 
13.1.1. 
Demographic/Medical History ...................................................................................78 
13.1.2. 
Prior and Concomitant Medications ...........................................................................78 
13.1.3. 
Vital Signs ..................................................................................................................78 
13.1.4. 
Weight and Height ......................................................................................................79 
13.1.5. 
Eastern Cooperative Oncology Group Performance Status ........................................79 
13.1.6. 
Physical Examination .................................................................................................79 
13.1.7. 
Electrocardiogram (ECG) ...........................................................................................80 
13.1.8. 
Laboratory Assessments .............................................................................................80 
13.1.8.1. 
Hematology .................................................................................................................80 
13.1.8.2. 
Blood Chemistry .........................................................................................................80 
13.1.8.3. 
Coagulation Test .........................................................................................................80 
13.1.8.4. 
Urinalysis ....................................................................................................................81 
13.1.8.5. 
Creatinine Clearance ...................................................................................................81 
13.1.8.6. 
Virus Serology ............................................................................................................81 
13.1.8.7. 
Pregnancy Screen ........................................................................................................81 
13.1.8.8. 
Bone Marrow Assessments .........................................................................................83 
13.1.8.9. 
IgA, IgM, IgG (M-protein Serum, for MM Subjects Only) .......................................83 
13.1.8.10. M-protein (24-hour Urine, for MM Subjects Only) ...................................................83 
13.1.8.11. Serum Free Light Chain Ratio (MM Subjects Only) ..................................................83 


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13.2. 
Adverse Events ...........................................................................................................83 
13.2.1. 
Adverse Event (AE) ....................................................................................................83 
13.2.2. 
Serious Adverse Event (SAE) ....................................................................................84 
13.2.3. 
Disease-Related Events ..............................................................................................85 
13.2.4. 
Clinically Significant Assessments .............................................................................85 
13.2.5. 
Assessment of Severity ...............................................................................................85 
13.2.6. 
Relationship to Study Drug ........................................................................................86 
13.2.7. 
Test Abnormalities ......................................................................................................87 
13.2.7.1. 
Laboratory Abnormalities ...........................................................................................87 
13.2.7.2. 
Other Test Abnormalities ...........................................................................................87 
13.3. 
Recording Adverse Events .........................................................................................87 
13.4. 
Reporting Serious Adverse Events .............................................................................88 
13.5. 
Reporting of Pregnancy ..............................................................................................89 
13.6. 
Reporting of Special Situations ..................................................................................89 
13.6.1. 
Study Drug Overdose, Misuse, Abuse, or Medication Error without an 
Adverse Event .............................................................................................................90 
14. 
STATISTICS ..............................................................................................................91 
14.1. 
Study Design ...............................................................................................................91 
14.2. 
General Consideration for Statistical Analysis ...........................................................95 
14.3. 
Analysis Populations ..................................................................................................95 
14.4. 
Statistical Analysis Groups .........................................................................................96 
14.5. 
Interim Looks During the Phase 1b Dose Expansion Portion of the Trial and 
the Final Analysis .......................................................................................................96 
14.6. 
Safety Analyses ..........................................................................................................96 
14.6.1. 
DLT Evaluation and MTD Determination .................................................................96 
14.6.2. 
Adverse Events ...........................................................................................................97 
14.6.3. 
Deaths .........................................................................................................................97 
14.6.4. 
Laboratory Abnormalities ...........................................................................................98 
14.6.5. 
Other Safety Assessments ...........................................................................................98 
14.7. 
PK Data Analysis ........................................................................................................98 
14.8. 
Investigation of PK/PD Relationship ..........................................................................99 
14.9. 
Efficacy Analyses .......................................................................................................99 
14.9.1. 
Primary Efficacy Analyses .........................................................................................99 


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14.9.2. 
Secondary Efficacy Analyses .....................................................................................99 
14.9.2.1. 
Progression Free Survival ...........................................................................................99 
14.9.2.2. 
Disease Control Rate ..................................................................................................99 
14.9.2.3. 
Duration of Response ...............................................................................................100 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................101 
15.1. 
Study Site Monitoring Visits ....................................................................................101 
15.2. 
Protocol Compliance ................................................................................................102 
15.3. 
Audits and Inspections ..............................................................................................102 
15.4. 
Institutional Review Board (IRB) .............................................................................103 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................104 
16.1. 
Database Quality Assurance .....................................................................................104 
16.2. 
Bioanalytical Data Management and Quality Control ..............................................104 
17. 
ETHICS ....................................................................................................................105 
17.1. 
Ethics Review ...........................................................................................................105 
17.2. 
Ethical Conduct of the Study ....................................................................................105 
17.3. 
Written Informed Consent ........................................................................................105 
17.3.1. 
Subject Confidentiality and Access to Source Documents/Data ..............................106 
18. 
DATA HANDLING AND RECORD KEEPING ....................................................107 
18.1. 
Electronic Case Report Form ....................................................................................107 
18.2. 
Inspection of Records ...............................................................................................107 
18.3. 
Retention of Records ................................................................................................107 
18.4. 
Disclosure and Confidentiality .................................................................................108 
18.5. 
Discontinuation of Study ..........................................................................................108 
18.6. 
Subject Insurance and Indemnity ..............................................................................108 
19. 
PUBLICATION POLICY ........................................................................................109 
20. 
LIST OF REFERENCES ..........................................................................................110 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................25 
Table 2: 
Predicted Safe Starting Dose in Humans for EZM0414 Based on HED 
Relative to the Dog HNSTD .......................................................................................37 
Table 3: 
Dose Limiting Toxicities ............................................................................................49 
Table 4: 
Dose Modifications Instructions for Grade 1 – Grade 4 study drug-related 
Adverse Events* ..........................................................................................................51 
Table 5: 
Investigation: Hepatic .................................................................................................52 
Table 6: 
Investigation: Renal ....................................................................................................52 
Table 7: 
Investigation: Coagulation ..........................................................................................53 
Table 8: 
Schedule of Assessments for Dose Escalation and Dose Expansion .........................55 
Table 9: 
PK, Vitals and ECG schedule for Phase 1 (dose escalation) ......................................60 
Table 10: PK, Vitals and ECG Schedule for Phase 1b (dose expansion) ...................................62 
Table 12: Investigational Product/Study Drug ...........................................................................68 
Table 13: Prohibited Medications ...............................................................................................69 
Table 14: Assessment of Severity per Common Terminology Criteria for Adverse 
Events General Guidelines .........................................................................................86 
Table 15: Total Daily Dose and Respective Dose Level ............................................................91 
Table 16: Dose Escalation/de-escalation Rule for the BOIN Design .........................................92 
Table 17: Optimized Stopping Boundaries for R/R MM Cohort ...............................................94 
Table 18: Optimized Stopping Boundaries for R/R DLBCL Cohort .........................................95 
Table 19: Standard IMWG Response Criteria ..........................................................................113 
Table 20: Lugano Classification ...............................................................................................117 
Table 21: Drugs Known to be Inhibitors of CYP3A4 ..............................................................124 
Table 22: Drugs Known to be Inducers of CYP3A4 ................................................................125 
Table 23: Drugs known to be inhibitors or inducers of P-gp ....................................................125 


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LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................10 
Figure 2: 
Tumor Volume in MM and DLBCL Xenograft Models ............................................32 
Figure 3: 
Study Schema .............................................................................................................42 
Figure 4: 
Flowchart for Trial Conduct Using the BOIN design ................................................43 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
5-HT 
5-hydroxytryptamine 
AE 
Adverse event 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin 
ASCT 
Autologous stem cell transplantation 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BNP 
Brain natriuretic peptide 
BOIN 
Bayesian Optimal Interval 
BOP2 
Bayesian optimal phase 2 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CAR 
Chimeric antigen receptor 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Total clearance after intravascular dose 
Cmax 
Maximum observed plasma drug concentration 
CNS 
Central nervous system 
CNV 
Copy number variation 
CR 
Complete response 
CRF 
Case report form 
CS 
Clinically significant 
CSR 
Clinical study report 
CT 
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common terminology criteria for adverse events 
CV% 
Coefficient of variation 
CYP3A 
Cytochrome P450 3A 
CYP3A4 
Cytochrome P450 3A4 
DCR 
Disease Control Rate 
DLBCL 
Diffuse large B cell lymphoma 
DLT 
Dose limiting toxicities 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DRd 
Daratumumab, lenalidomide and dexamethasone 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 


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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOT 
End of treatment 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FIH 
First-in-human 
FISH 
Fluorescent-in situ hybridization 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
HMT 
Histone methyltransferase 
HNSTD 
Highest Non-severely Toxic Dose 
HTLV-1 
Human T-cell lymphotropic virus 1 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent ethics committee 
Ig 
Immunoglobulin 
IMWG 
International Myeloma Working Group 
ip 
Intraperitoneal 
IPI 
International Prognostic Index 
IRB 
Institutional review board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
KM 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
LDi 
Longest transverse diameter of a lesion 
LVEF 
Left ventricular ejection fraction 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple myeloma 
MMSET 
Multiple myeloma SET domain 


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M-protein 
Monoclonal protein 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
Next-generation sequencing 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamics 
PET-CT 
Positron emission tomography-computed tomography 
PFS 
Progression-free survival 
PI 
Protease inhibitor 
pj 
pj∼binomial 
PK 
Pharmacokinetics 
PPIs 
proton pump inhibitors 
PR 
Partial response 
PT 
Preferred term 
PT/INR 
Prothrombin time/international normalized ratio 
QSR 
Quarterly Safety Review 
R 
Renal insufficiency 
R/R 
Relapsed/refractory 
RBC 
Red blood cell 
REB 
Research ethics board 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAM 
S-adenosyl-methionine 
SAP 
Statistical analysis plan 
sCR 
Stringent complete response 
SD 
Standard deviation 
SDi 
Shortest perpendicular diameter 
SEER 
Surveillance, Epidemiology and End Results 
SOC 
Standard of care 
SRC 
Safety Review Committee 
SSD 
Safe Starting Dose 
SUSAR 
Serious adverse drug reactions 
t½ 
Half-life 
TEAE 
Treatment-emergent adverse events 


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TGI 
Tumor growth inhibition 
TK 
Toxicokinetics 
VGPR 
Very good partial response 
vs 
Versus 
WBC 
White blood cell 
 


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5. 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according 
to: United States and international standards of good clinical practice (GCPs), FDA Title 21 Part 
312, and International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines; applicable government regulations; and 
institutional research policies and procedures. 
5.1. 
Background 
5.1.1. 
Multiple Myeloma 
According to the United States Department of Health, National Cancer Institute (NCI) 
Surveillance, Epidemiology and End Results (SEER) program estimate, 34,920 new cases of 
multiple myeloma (MM) will be diagnosed in 2021 representing 1.8% of all new cancer case 
diagnoses (SEER database, NCI: SEER, 2018). Multiple myeloma is a neoplasm of the 
terminally differentiated clonal plasma cells and is cytogenetically heterogenous disease 
characterized by an abnormal proliferation of plasma cells in the bone marrow and usually 
accompanied by excessive production of monoclonal antibodies. 
Genetic abnormalities common in MM include hyperdiploidy, chromosomal translocations, 
deletions, duplications, and genetic mutations. Chromosomal translocations occur between the 
immunoglobulin heavy chain alleles at chromosome 14q32 and various partner chromosomes 
(Kuehl, 2002). These abnormalities form the basis for classification and risk stratification of MM 
subjects. High-risk MM is defined by the presence any of the following chromosomal 
abnormalities t(4;14), t(14;16), t(14;20), 17p deletion, 1q gain or p53 mutation. Some subjects 
may present with more than one high-risk abnormality (Kumar, 2018). These chromosomal 
translocations lead to overexpression of putative oncogenes and favor a pre-malignant state, 
which can ultimately lead to the plasma cell-derived, post-germinal center malignancy MM 
(Barwick, 2019). According to the International Myeloma Working Group (IMWG), events that 
define MM are hypercalcemia (C), renal insufficiency (R), anemia (A) and bone lesions (B), 
collectively referred to as CRAB features. 
National Comprehensive Cancer Network (NCCN) recommended treatment options for subjects 
with newly diagnosed MM are based on eligibility for autologous stem cell transplant (ASCT). 
Subjects who are candidates for ASCT, receive induction therapy with bortezomib (Velcade), 
lenalidomide (Revlimid) and dexamethasone (VRd), transplant followed by maintenance 
treatment with lenalidomide, and dexamethasone (Rd) based on S0777 study (Durie, 2020; 
Rajkumar, 2020). SWOG S0777, evaluated a combination of VRd vs Rd in previously untreated 
MM subjects and showed better progression free survival (PFS) and overall survival (OS) in 
VRd subjects as compared to Rd subjects. In subjects who are not candidates for ASCT, initial 
therapy options include VRd or alternatively daratumumab, lenalidomide and dexamethasone 
(DRd). MAIA study compared daratumumab plus lenalidomide and dexamethasone or 
lenalidomide and dexamethasone alone in transplant ineligible subjects. MAIA study showed 
that daratumumab plus lenalidomide and dexamethasone had significant efficacy in this patient 
population (Facon, 2019). VRd and DRd remain initial therapy options for subjects not eligible 
for transplant. These regimens are continued for 8-12 cycles for VRd followed by maintenance 
and until disease progression for DRd. 


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Additional treatment options include elotuzumab, SLAMF7-directed immunostimulatory 
antibody, in combination with lenalidomide and dexamethasone for MM after one to three prior 
therapies; Selinexor, a nuclear export inhibitor, in combination with dexamethasone for 
relapsed/refractory (R/R) MM after at least four prior therapies; Panobinostat, a histone 
deacetylase inhibitor, in combination with bortezomib and dexamethasone for MM after at least 
2 prior regimens. In 2020, multiple new treatment options for MM were approved by the Food 
and Drug Administration (FDA). Belantamab mafodotin-blmf (Blenrep) was approved for R/R 
MM subjects who received at least 4 prior therapies, including an anti-CD38 monoclonal 
antibody, a PI, and an IMiD. Isatuximab-irfc (Sarclisa), an anti-CD38 monoclonal antibody was 
approved for R/R MM, in combination with pomalidomide, and dexamethasone after 2 or more 
prior therapies, including lenalidomide and a PI. Subcutaneous daratumumab (daratumumab and 
hyaluronidase-fihj) in combination with other treatments was approved for adults with newly 
diagnosed MM or R/R MM. The first Chimeric antigen receptor (CAR) T-cell therapy 
idecabtagene vicleucel (ABCEMA) for was approved for R/R MM after 4 or more lines of prior 
therapy. Clinical trials are ongoing to investigate novel options such as bispecific antibodies or 
BiTE. 
After initial response, frontline treatment options eventually fail and almost all subjects with MM 
relapse. Relapsed/refractory MM is treated with combination regimens described above. 
Development of novel drugs has led to dramatic improvements in MM disease management and 
outcomes; however, majority of subjects with MM experience multiple remissions and relapses. 
Each subsequent remission after initial remission is of shorter duration (Kumar, 2017). Multiple 
myeloma subjects have a 5-year relative survival rate of 55.6% (SEER database, NCI: SEER, 
2018). Estimated deaths from MM in 2021 will be 12,410, representing 2% of all cancer related 
deaths (SEER database, NCI: SEER, 2018). Relapsed/refractory MM continues to remain an 
incurable disease and the need for targeted therapies to provide novel treatment options to 
subjects with R/R MM persists. 
5.1.2. 
 Diffuse Large B Cell Lymphoma 
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma 
in the United States. Based on 2014–2018 cases and deaths, the rate of new cases of DLBCL was 
5.6 per 100,000 persons per year (SEER database, NCI: SEER, 2017). Diffuse large B cell 
lymphoma is most frequently diagnosed among people aged 65-74 years old with median age at 
diagnosis being 66 years old, while 75% of the cases are diagnosed in persons 55 years old and 
older. Diffuse large B cell lymphoma is an aggressive neoplasm of the mature B cells and 
usually presents as asymptomatic disease with either nodal or extranodal lesions.  
Diffuse large B cell lymphoma is a clinically and genetically heterogeneous disease and based on 
cell of origin, can be classified into germinal center B-cell subtype (GCB-DLBCL), or activated 
B cell subtype (ABC-DLBCL). Detailed genetic analysis have identified five distinct clusters of 
the DLBCL subsets based on recurrent mutations, somatic copy number alterations and structural 
variants (Chapuy, 2018). These molecular signatures define genetic complexity and 
heterogeneity present in DLBCL that can be potentially targeted to develop novel treatment 
options. In the clinic, treatment decisions are made using the International Prognostic Index (IPI) 
to categorize prognosis in aggressive lymphomas based on five clinical factors: age, number of 
extranodal sites, performance status, disease stage at diagnosis, and LDH levels. 


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NCCN recommended frontline chemoimmunotherapy treatment is combination of rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) which leads to cure in 
50-60% of the subjects (Liu, 2019). R-CHOP may be combined with involved field radiation 
therapy (IFRT). Other regimens for advanced disease are combination of rituximab, etoposide, 
prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) or dose dense R-
CHOP-14. Subjects who have refractory disease or who experience relapse are candidates for 
salvage therapy followed by ASCT, if eligible. If ineligible for ASCT, treatment with 
chemotherapy is considered based on IPI. Second-line regimens for high dose chemotherapy 
include the following (which may be given with or without rituximab): DHAP (dexamethasone, 
cytarabine, cisplatin), ESHAP (methylprednisolone, etoposide, cytarabine, cisplatin), GDP 
(gemcitabine, dexamethasone, cisplatin), GemOx (gemcitabine and oxaliplatin), ICE 
(ifosfamide, carboplatin, etoposide), and MINE (mitoxantrone, ifosfamide, mesna, etoposide). 
Relapsed/refractory DLBCL subjects have poor outcomes in subsequent therapy, shorter 
duration between each line of treatment and very few subjects achieve remission. Recent FDA 
approvals for R/R DLBCL include Selinexor after at least 2 lines of systemic therapy. 
Tafasitamab-cxix, a CD19-directed cytolytic antibody, in combination with lenalidomide for R/R 
DLBCL subjects not eligible for ASCT. Polatuzumab, is a CD79b-directed antibody–drug 
conjugate, in combination with bendamustine and a rituximab product for R/R DLBCL after at 
least 2 prior therapies. Anti-CD19 directed CAR-T cell therapies include axicabtagene ciloleucel 
and tisagenlecleucel for adults with R/R DLBCL after two or more lines of systemic therapy. 
Clinical trials are ongoing to develop antibody drug conjugates, immunotherapies, and targeted 
therapies to provide better outcome for R/R DLBCL subjects. 
The 5-year relative survival rate for DLBCL subjects is 63.9%, however the stage of the disease 
at diagnosis has a strong influence on survival rate with 73.6 % in stage I subjects and 53.2% in 
stage IV subjects. (SEER database, NCI: SEER, 2017). Based on 2014–2018 cases and deaths, 
the death rate was 1.8 per 100,000 persons per year (NCI: SEER, 2017). Thus, medically unmet 
need for better and novel treatments for subjects with R/R DLBCL is high.  
5.2. 
Investigational Product 
5.2.1. 
EZM0414 
EZM0414 (also referred to as PH-EPZ-055-RS2-300, EPZ040414, or EPZ- 040414) is a potent 
and selective, orally bioavailable small molecule inhibitor of histone methyltransferase (HMT) 
Su(var)3-9, Enhancer of zeste, Trithorax domain containing 2 (SETD2), also known as KMT3A. 
Inhibition of SETD2 is expected to lead to decreased growth of MM tumors. In preclinical 
studies, inhibition of SETD2 by EZM0414 has demonstrated anti-proliferative activity in vitro in 
a panel of MM cell lines, with increased activity in the t(4;14) subset, and in vivo tumor growth 
inhibition (TGI) in multiple cell line-derived MM xenograft models (Figure 2). In addition, in 
vitro and in vivo EZM0414 treatment led to tumor growth inhibitory effects in DLBCL model 
systems (Figure 2). Therefore, EZM0414 is expected to have activity in t(4;14) as well as non-
t(4;14) R/R MM and R/R DLBCL patient populations.  
EZM0414 is orally bioavailable and formulated as tablets. Nonclinical safety studies completed 
in dogs and rats show EZM0414 is tolerated as evidence by the demonstration of no medical 
limiting clinical observations or clinical pathology findings. In GLP 28-day toxicity studies, 
animals were administered EZM0414 orally once daily for 28 consecutive days. The Safe 


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Starting Dose (SSD) in the planned FIH study with EZM0414 was determined based on the 
lowest human equivalent dose (HED) established in the most sensitive species. The dog was 
determined to be the most sensitive species; therefore, using the Highest Non-severely Toxic 
Dose (HNSTD) and the HED established for dogs, the SSD in a first-in-human (FIH) study with 
EZM0414 is 100 mg/60 kg patient.
Figure 2: 
Tumor Volume in MM and DLBCL Xenograft Models
(A) KMS-11 human t(4;14) MM xenograft model, (B) MM.1S human non-t(4;14) MM xenograft model, and (C) 
TMD8 human DLBCL xenograft model. Tumor volume was measured twice a week and mean tumor volumes were 
plotted over time. Data represent the mean ± SEM (n=10, KMS-11, and MM.1S or n=8, TMD8). * p <0.1 and **** 
p<0.0001 versus vehicle control at the end of the respective studies. p values were determined by one-way ANOVA 
followed by Tukey’s multiple comparison test. 
Abbreviations: ANOVA = analysis of variance; EZM0414 = EPZ-040414-6 (KMS-11); EZM0414 = EPZ-040414-4 
(MM.1S); EPZ-040414-5 (TMD8); SEM = standard error of the mean.
Source: EPZ-040414-PH-0009, EPZ-040414-PH-0004, EPZ-040414-PH-0008.
5.2.2.
EZM0414 Mechanism of Action 
EZM0414 (also referred to as PH-EPZ-055-RS2-300, EPZ040414, or EPZ-040414 in the 
nonclinical reports, but referred to as EZM0414 hereafter) is a potent and selective, orally 
bioavailable small molecule inhibitor of the enzymatic activity of histone methyltransferase 
(HMT) Su(var)3-9, Enhancer of zeste, Trithorax domain containing 2 (SETD2), also known as 
KMT3A. SETD2 catalyzes the S-(5′-Adenosyl)-L-methionine (SAM)-dependent deposition of 
the third or final methyl group onto the di-methylated state of lysine 36 of histone H3 
(H3K36me2) yielding the tri-methylated state of lysine 36 of histone H3 (H3K36me3) (Sun, 
2005). With the exception of PRDM9, which is expressed primarily in germ cells, SETD2 is the 
only known HMT capable of catalyzing H3K36me3 in vivo (Grey, 2017; Diagouraga, 2018). 
SETD2 also has been implicated in the methylation of non-histone proteins, including p53, 
STAT1 and α-tubulin (Carvalho, 2014; Park, 2016). It has several biological roles including 
transcriptional regulation and RNA splicing, DNA damage repair, and immune cell development 
and differentiation (Licht, 2017).
5.2.3.
Nonclinical Experience
EZM0414 is being developed as a potential treatment for adult patients with R/R MM 
specifically those with the (4;14) chromosomal translocation and R/R DLBCL. Studies in both 
t(4;14) and non-t(4;14) MM cell lines demonstrated marked anti-proliferative activity in 
response to EZM0414. Studies in DLBCL cells exhibited a wide range of sensitivity to 
EZM0414. In vivo, in 28-day studies using xenograft models, SCID mice bearing human MM 


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and DLBCL cell line-derived xenografts exhibited TGI and dose-dependent reductions in 
H3K36me3 levels. 
5.2.3.1. 
Nonclinical Pharmacology 
Cell-free in vitro experiments demonstrated potent inhibition of SETD2 methyltransferase 
activity. EZM0414 inhibited SETD2 enzymatic activity with a half maximal inhibitory 
concentration (IC50) of 18.3 ± 8.1 nmol/L with at least 11000 fold selectivity over 13 other 
related HMTs. The SETD2 IC50 value was dependent on substrate concentration, with a maximal 
intrinsic potency, as determined by inhibition constant (Ki), of 12.9 ± 1.5 nmol/L. Further, the 
mechanism of EZM0414 inhibition of SETD2 was mixed uncompetitive with respect to S-
adenosyl-methionine (SAM) and noncompetitive with respect to peptide, suggesting EZM0414’s 
potency cannot be abated by accumulating or high substrate concentrations in a cellular context. 
These results show that EZM0414 is a potent and selective inhibitor of SETD2 methyltransferase 
activity.  
5.2.3.2. 
Nonclinical Pharmacokinetics 
EZM0414 possesses favorable ADME properties with good probability to achieve efficacious 
exposure levels in humans. EZM0414 exhibited low to moderate CL and moderate to large Vss in 
mice, rats, dogs, and monkeys. EZM0414 displays good oral absorption in preclinical species (F: 
56% to 100%) and is a substrate for P-gp as detected by Caco-2 cells (ER: 7 at 1 µM); however, 
intrinsically, it is a highly permeable compound. EZM0414 is primarily metabolized by CYP3A 
enzymes and has negligible renal excretion. Metabolite identification conducted in vitro 
(hepatocytes), and ex vivo (rats and dogs) showed mainly oxidation followed by 
dehydrogenation or N-dealkylation on the piperazine moiety and indole moiety, with no unique 
human metabolites identified. Additionally, no metabolite was observed in sufficient quantities 
(> 10% EZM0414 plasma exposure) to require monitoring. 
5.2.3.3. 
Drug-Drug Interaction 
EZM0414 has a low potential of DDIs as a perpetrator. The IC50 of EZM0414 toward seven 
human CYP isozymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D, CYP3A) 
evaluated was ≥100 µmol/L except for CYP2C8 (IC50 = 6.80 µmol/L), and preincubation did not 
intensify the inhibitory potency for the majority of the CYPs except for CYP3A (IC50 was 
reduced from >100 µmol/L to 60.2 and 28.0 µmol/L with midazolam and testosterone as CYP3A 
substrates, respectively). EZM0414 may be a low CYP inducer, especially of CYP3A4; however, 
induction was observed based on mRNA levels only, whereas CYP activity was not induced. 
With respect to drug transporters, preliminary studies indicated the potential of EZM0414 to 
inhibit P-gp and breast cancer resistance protein (BCRP); (IC50 = 45.7 and 30.3 µmol/L, 
respectively). With respect to the potential of EZM0414 as victim in DDI scenarios, hepatic 
metabolism was predominantly mediated by CYP3A isozymes, rendering EZM0414 susceptible 
to concomitant drugs that are strong CYP3A modulators. 
5.2.3.4. 
Nonclinical Pharmacodynamics 
Secondary pharmacology and PD studies did not reveal significant potential for off-target 
toxicity. Two G-protein coupled receptors (GPCRs) that were targeted by EZM0414 included the 
DRD2 and the 5-HT1B receptors. The anticipated margin of exposure at the projected human 


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efficacious Cmax,u would be approximately 16- to 35-fold for the DRD2 receptor and 
approximately 4- to 9-fold for the 5-HT1B receptor, suggesting a low potential for adverse effects 
clinically. 
Two stand-alone CV safety pharmacology studies were performed in dogs as a result of the data 
obtained in the hERG and CiPA screening studies. Consistent findings between these studies 
included decreases in arterial and pulse pressure, possibly related to the decrease in systolic 
pressure. This was accompanied by a compensatory increase in heart rate. An increase in QTc 
was also observed at the same dose levels but was not considered clinically significant as it did 
not rise to the 10% threshold of concern. Although plasma concentration was not assessed 
directly, the GLP CV study was conducted at the same doses as the initial 28-day dog toxicity 
study using the same batch of API. Utilizing the Cmax,u values at equivalent doses in 28-day 
toxicity study, the CV effects observed in the GLP CV study began at approximately 1.2- to 
2.5-fold (50 mg/kg dose level) and were observed up to 3- to 6.6-fold (200 mg/kg dose level) the 
predicted human efficacious Cmax,u (0.4 μmol/L for a 120mg/60kg dose of EZM0414). Of 
interest, there were no ECG effects observed in the 28- day follow-up toxicity study in dogs.  
Central nervous system and respiratory safety pharmacology endpoints were included on the 28-
day rat study. Motor function effects and a reduced respiration rate were observed at the high 
dose (7- to 15-fold the predicted human efficacious Cmax,u), minute volume was reduced at ≥75 
mg/kg (≥ approximately 3- to 6.5-fold the predicted human efficacious Cmax,u), and tidal volume 
was reduced at all doses (0.2- to 0.5-fold the predicted human efficacious Cmax,u) at the end of 
exposure and into recovery. While these effects were considered drug-related, based on 
magnitude they were not considered adverse.  
5.2.3.5. 
Preclinical Safety 
The nonclinical safety profile of EZM0414 was evaluated in Sprague Dawley rats and Beagle 
dogs. In all studies, EZM0414 was delivered by oral gavage to simulate the oral route of 
administration proposed for the phase 1 clinical trials. The toxicity studies included a single 
escalating dose study in dogs, 7-day repeat-dose toxicity studies in rats and dogs, and 28-day 
GLP studies with 28-day recovery phases in rats (1 study) and dogs (2 studies, initial and 
follow-up). GLP genetic toxicity assessments were conducted to assess the mutagenicity 
potential of EZM0414. In addition, a thorough investigation was conducted to evaluate the 
differences in toxicity observed in the 7-day (non-GLP) and 28-day (GLP) repeat-dose toxicity 
studies in dogs, including additional single- and repeat-dose pharmacokinetic studies in rat and 
dog. 
Following repeat dosing of EZM0414 in rats and dogs, the primary target systems include the 
respiratory, immunology, coagulation, hepatic, kidney, and reproductive organs. Reduction in 
respiratory rate, tidal, and minute volume was seen in the 28-day GLP rat study, as well as 
depressed respiratory function during week 4 (males and females) and the recovery period (high 
dose males). Effects on lymphoid cellularity, particularly in the thymus and occasionally on 
germinal centers, were noted throughout the immune system in rats and dogs. Additionally, there 
were reproducible changes in the erythron and coagulation parameters in both species. 
Reproductive changes were evident in rats of both sexes in the 28-day rat study and in male dogs 
only in the follow-up 28-day dog study. At higher dose levels, there also was toxicity to the liver 
and gastrointestinal tract (rats and dogs), and the adrenal gland and skeletal muscle (rat). All 


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EZM0414-related effects, with the exception of reproductive effects, which minimally persisted 
through the recovery period, were reversible. A review of the literature suggests that the changes 
in the hematopoietic/immune system and the reproductive system of both sexes as well as those 
observed in the skeletal muscle of the rat may be the result of on-target pharmacology. 
The nonclinical safety profile of EZM0414 has been well characterized through the conduct of 
secondary pharmacology and PD studies, genetic toxicology, safety pharmacology, and repeat-
dose toxicity and TK studies in rats and dogs. Based on the available data, a potential clinical 
starting dose of 111 mg could be employed and is based on 1/6 of the HNSTD (20 mg/kg/day) in 
the dog, the more sensitive nonclinical species tested (Table 2). This approach is in line with the 
guidance provided by ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, and the 
accompanying Q&A document. A starting dose of 100 mg has been proposed and is supported 
by the data. Therefore, the nonclinical toxicology studies are considered adequate for supporting 
the proposed first-in-human study. 
These data support the clinical development plans for EZM0414 for the treatment of R/R MM 
and R/R DLBCL in adult patients. 
5.2.3.6. 
Preclinical Efficacy 
Preclinical efficacy studies with EZM0414 support the hypothesis that there is dependency on 
SETD2 for MM and DLBCL growth and survival, particularly in t(4;14) MM, and that SETD2 
inhibition leads to tumor cell growth inhibition. Oral administration of EZM0414 demonstrated 
significant antitumor activity in one t(4;14) MM, two non-t(4;14) MM, and four DLBCL cell 
line-derived xenograft models, with tumor regressions/growth stasis and dose-dependent TGI 
observable starting at 4 to 7 days of dosing initiation (Figure 2). In all models with more than 
one treatment group, the effects observed were dose-dependent and correlated well with 
reductions in tumor H3K36me3 levels, demonstrating on-target inhibition of SETD2 
methyltransferase activity in vivo. 
5.2.3.7. 
Rationale for the Use of EZM0414 to Treat Multiple Myeloma and Diffuse Large 
B Cell Lymphoma 
Data regarding the role of SETD2 in tumorigenesis demonstrates a variety of context-dependent 
mechanisms. While SETD2 may function as a classical tumor suppressor in the context of 
certain solid tumors, this is not true for SETD2’s role in the development of hematological 
malignancies. Several studies suggest that heterozygous loss of SETD2 acts to drive 
leukemogenesis, whereas homozygous loss slows disease progression. This suggests that 
complete loss of SETD2 is profoundly deleterious and provides strong rationale for use of 
SETD2 inhibitors against these hematological tumors (Hart, 2015; Shi, 2015; Wang, 2015; 
Tzelepis, 2016; Skucha, 2019).  
Importantly, several epigenetic mutations and dependencies have been identified in B-cell 
malignancies, including MM and DLBCL, providing therapeutic rationale for epigenetic 
inhibitors in these tumor types. As in the case of leukemia, SETD2 loss of function mutations 
found to date in DLBCL are also always heterozygous, suggesting that a similar 
haploinsufficient tumor suppressor role for SETD2 and therapeutic potential of SETD2 
inhibition may also exist in the setting of B-cell malignancies (Reddy, 2017).  


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In addition, SETD2 dependency also could manifest in other B cell malignancies where 
perturbation of H3K36 methylation plays a key role, including Histone H1 mutations and in the 
setting of (4;14) chromosomal translocations present in high-risk MM (Barwick, 2019; 
Yusufova, 2020). The (4;14) chromosomal translocation results in juxtaposition of IgH control 
elements with two genes on chromosome 4, fibroblast growth factor receptor 3 (FGFR3) and 
multiple myeloma SET domain (MMSET) (Chesi, 1997; Richelda, 1997; Chesi, 1998). MMSET, 
also known as WHSC1 or NSD2, is an HMT that catalyzes H3K36me1 and me2 formation and 
extensive scientific work has led to general agreement that high MMSET is the key factor in 
t(4;14) MM pathogenesis. MMSET has therefore been long recognized as a potential therapeutic 
target in t(4;14) MM; yet it has eluded drug discovery efforts to date (Lauring, 2008; Marango, 
2008; Brito, 2009; Kuo, 2011; Martinez-Garcia, 2011). However, since the (4;14) translocation 
results in high levels of the H3K36me2 substrate for SETD2, inhibiting SETD2 offers promise 
for targeting the underlying oncogenic mechanism driven by MMSET overexpression in t(4;14) 
MM subjects. 
Based on the in vitro and in vivo pharmacology studies EZM0414 shows selective and potent 
inhibitory activity for SETD2. In vitro studies show that EZM0414 reduces H3K36me3 levels 
and inhibits proliferation of MM and DLBCL cell lines in a dose-dependent manner. In vivo MM 
and DLBCL cell line-derived xenograft models demonstrated significant tumor growth inhibition 
by EZM0414. Nonclinical safety studies completed in dogs and rats show EZM0414 is tolerated 
as evidenced by no medically limiting clinical observations or clinical pathology findings. These 
results, coupled with the need for novel treatment options for R/R MM and R/R DLBCL, provide 
proof of concept for clinical exploration of EZM0414 in these B-cell malignancies. 
5.2.4. 
Clinical Experience 
This first-in-human study is being conducted to study the safety and efficacy of EZM0414 in 
R/R MM and R/R DLBCL subjects based on the results observed in pre-clinical studies 
supported by the mechanism of action. Details of currently approved therapies and novel agents 
in clinical trials are presented in Section 5.1.1 and Section 5.1.2. 
5.2.5. 
Rationale for Starting Dose and Dosing Schedule 
The nonclinical safety profile of EZM0414 has been well characterized through the conduct of 
secondary pharmacology and PD studies, genetic toxicology, safety pharmacology, and repeat-
dose toxicity and TK studies in rats and dogs. Based on the available data, a potential clinical 
starting dose of 111 mg could be employed and is based on 1/6 of the HNSTD (20 mg/kg/day) in 
the dog, the more sensitive nonclinical species tested (Table 2). This approach is in line with the 
guidance provided by ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, and the 
accompanying Q&A document. A starting dose of 100 mg has been proposed and is supported 
by the data. Therefore, the nonclinical toxicology studies are considered adequate for supporting 
the proposed first-in-human study. 
These data support the clinical development plans for EZM0414 for the treatment of R/R MM 
and R/R DLBCL in adult patients. 


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Table 2: 
Predicted Safe Starting Dose in Humans for EZM0414 Based on HED 
Relative to the Dog HNSTD  
Species Duration 
Route 
STD10/HNSTD 
(mg/kg/day) 
HEDa 
(mg/day) 
Supported 
FIH Starting 
Dose 
STD10/HNSTD 
AUC0-t (ng•h/mL) 
Rat 
4 weeks 
Oral 
150 
1452 
145 mg 
769,500b 
Dog 
4 weeks 
Oral 
20 
667 
111 mg 
72,900b 
FIH = first-in-human; HED = human equivalent dose; HNSTD = highest non-severely toxic dose; STD10 = severely 
toxic dose in 10% of animals. 
a HED was calculated by dividing the STD10 by 6.2 for rats and the HNSTD by 1.8 for dogs and then multiplying 
by average body weight of 60 kg.  
b Day 28; males and females combined.  
5.2.6. 
Assessment of Response 
All baseline local tumor assessments are to be performed within 28 days prior to the start of 
study treatment. Tumor response assessments at screening and during the trial will include whole 
body positron emission tomography-computed tomography (PET-CT), 18FDG-PET for PET avid 
disease OR contrast enhanced computed tomography (CT) of the neck, chest, abdomen and 
pelvis, and other applicable sites for PET non-avid disease. Radiologic disease assessments will 
occur as per Table 8. 
5.2.6.1. 
Multiple Myeloma 
Response will be assessed at every cycle using the IMWG 2016 consensus criteria that includes 
serum monoclonal protein (M-protein), 24-hour urine M-protein, serum free light chain kappa, 
lambda, and their ratio, bone marrow aspiration (CR), and bone marrow biopsy (sCR). Hence, 
subjects with MM would need to undergo a bone marrow biopsy or bone marrow aspiration for 
IMWG response assessment (Kumar, 2016; Appendix 1). If minimal residual disease (MRD) 
assessment or any molecular tumor assessments is performed as standard of care during the trial 
the results of these assessments will be shared with the sponsor. 
5.2.6.2. 
Diffuse Large B Cell Lymphoma 
A standard-of-care clinical examination for lymphoma, including assessment of B symptoms, 
will also be performed every 8 weeks at clinic visits. Response will be assessed using 2014 
Lugano classification (Cheson, 2014; Appendix 2). Hence subjects with a previously positive or 
unknown bone marrow biopsy at baseline would undergo a bone marrow biopsy in suspected 
CR. 
5.3. 
Conclusion 
Based on the available nonclinical data presented in Section 5.2, the potential risks include 
cardiovascular, respiratory, immunology, gastrointestinal, hematologic, hepatic, renal, and 
reproductive systems. 
Clinical subjects meeting protocol inclusion and exclusion criteria will be monitored rigorously 
for early signs of any of the potential risks noted in the nonclinical toxicology studies by 


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physician-performed history and physical examination as well as monitoring safety laboratory 
studies of the blood, urine, and serial time point-specific electrocardiogram (ECG). 
Epizyme’s assessment of the potential benefit:risk ratio is expected to be positive in human 
subjects with R/R MM and R/R DLBCL. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
Objectives 
Endpoints 
Part 1: Phase 1 Dose Escalation Phase 
Primary 
• To evaluate the safety and maximum 
tolerated dose (MTD) of EZM0414 when 
administered as monotherapy in subjects 
with R/RMM and R/R DLBCL. 
• Adverse event assessment according to 
Common Terminology Criteria for 
Adverse Events (CTCAE 5.0), physical 
examination, vital signs (blood pressure, 
heart rate, respiration rate, and body 
temperature), 12-lead ECG, clinical 
laboratory tests (hematology including 
coagulation profile, serum chemistries, 
and urinalysis), ECOG performance 
status, concomitant medication 
monitoring, and dose limiting toxicities 
(DLT). 
Exploratory 
• To investigate target engagement in 
samples collected before and during 
treatment with EZM0414. 
• To determine exploratory biomarkers such 
as histones and histone methylation, 
somatic mutations, DNA methylation, 
DNA alterations such as t(4;14) and 
others, protein levels, RNA expression, 
and immune cells in bone marrow 
aspirates, tumor/bone marrow biopsies, 
and blood samples.  
• To assess pharmacokinetics (PK) of 
EZM0414 when administered as 
monotherapy in subjects with R/R MM 
and R/R DLBCL. 
• H3K36me3 in tumor/bone marrow biopsy 
and blood collected at baseline and during 
treatment. 
• Biomarkers such as histones and histone 
methylation, somatic mutations, DNA 
methylation and other DNA alterations 
such as t(4;14) and others, protein levels, 
RNA expression, immune cells in bone 
marrow aspirates, tumor biopsies, and 
blood samples. 
• Pharmacokinetic parameters including but 
not limited to: AUC0–t: area under the 
plasma concentration-time curve from 
time 0 to the time of the last quantifiable 
concentration; Cmax: observed maximum 
plasma concentration; Tmax: observed time 
at Cmax; λz: terminal phase elimination rate 
constant; t1/2: terminal elimination half-
life. 


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Objectives 
Endpoints 
Part 2: Phase 1b Dose Expansion Phase 
Primary Safety 
• To determine the safety and tolerability of 
EZM0414 in subjects with R/R MM and 
R/R DLBCL. 
• Adverse event assessment according to 
CTCAE 5.0, assessment of changes in 
physical examination, vital signs (blood 
pressure, heart rate, respiration rate, and 
body temperature), 12-lead ECG, clinical 
laboratory tests (hematology including 
coagulation profile, serum chemistries, 
and urinalysis), ECOG performance 
status, and concomitant medication 
monitoring. 
• To establish the recommended Phase 2 
dose (RP2D). 
• Adverse events, clinical laboratory tests, 
and pharmacokinetic profile. 
Primary Efficacy 
• To determine the efficacy of EZM0414 as 
demonstrated by the effect on ORR in 
subjects with R/R MM and R/R DLBCL. 
• ORR defined as the proportion of 
responders as assessed by Investigator per 
IMWG 2016 guidelines for MM (sCR, 
CR, VGPR, and PR) or Lugano 2014 
guidelines for DLBCL (CR+PR). 
Secondary 
• To determine the efficacy of EZM0414 as 
demonstrated by the effect on ORR, PFS, 
and DOR in subjects with R/R MM and 
R/R DLBCL.  
• 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. 
• 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 scalation 


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Objectives 
Endpoints 
part and are rolled over to the dose 
expansion part). 
• 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.  
Exploratory 
• To determine H3K36me3 in tumor tissue 
biopsy and blood samples. 
• To determine exploratory biomarkers such 
as histones and histone methylation, 
somatic mutations, DNA methylation and 
other DNA alterations such as t(4;14) and 
others, protein levels, RNA expression, 
and immune cells in bone marrow 
aspirates, tumor/bone marrow biopsies, 
and blood samples.  
• To determine the pharmacokinetic profile 
of EZM0414. 
• H3K36me3 in tumor/bone marrow biopsy 
and blood collected at baseline and during 
treatment.  
• Biomarkers such as histones and histone 
methylation, somatic mutations, DNA 
methylation and other DNA alterations 
such as t(4;14) and others, protein levels, 
RNA expression, immune cells in bone 
marrow aspirates, tumor biopsies, and 
blood samples. 
• Pharmacokinetic parameters including but 
not limited to: AUC0–t: area under the 
plasma concentration-time curve from 
time 0 to the time of the last quantifiable 
concentration; Cmax: observed maximum 
plasma concentration; Tmax: observed time 
at Cmax; λz: terminal phase elimination rate 
constant; t1/2: terminal elimination half-
life, Cmax/D: maximum observed 
concentration normalized to the dose; and 
AUC/D: AUC normalized to the dose. 
 
 


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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design
This is a FIH, 2-part, multi-center, open-label Phase 1/1b safety, tolerability, PK, and efficacy 
study of oral SETD2 inhibitor, EZM0414, in subjects with R/R MM and R/R DLBCL. The first 
part of the study will be a Phase 1 dose-escalation designed to evaluate the safety, tolerability, 
and PK of EZM0414 in subjects with R/R MM and R/R DLBCL. 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) 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. 
Figure 3: 
Study Schema
Note: if needed, the Part 1: Phase 1 Dose Escalation may include an optional step-down dose level of 75 mg.
Abbreviations: DLBCL = diffuse large B cell lymphoma; DLT = dose limiting toxicities; MM = multiple myeloma; 
MTD = maximum tolerated dose; R/R = relapsed/refractory. 
Part 1: Phase 1 Safety Dose Escalation 
Part 1 is a safety dose escalation to determine the MTD for dose expansion in Part 2 of the study. 
Bayesian optimal interval design will be used to evaluate the safety and tolerability of EZM0414 
in subjects with R/R MM and R/R DLBCL. Six dose levels starting at 100 mg, and then 200 mg, 
300 mg, 400 mg, 600 mg, and 900 as well as an optional step-down dose level of 75 mg (if 
needed) will be tested in this dose escalation part of the study. Safety, tolerability, PK, and PD 
data will be reviewed, as available, initially after 4 planned dose levels (100 mg, 200 mg, 300 
mg, and 400 mg) are evaluable, then again when the 600 mg dose level is evaluable, then again 
when the 900 mg dose level is evaluable, and lastly when the MTD is determined. Subjects will 
be enrolled and treated in groups of at least 3 subjects, and up to 36 subjects (at least 3 subjects 
each with t(4;14) MM, non-t(4;14) MM and DLBCL) will be enrolled in order to evaluate at 


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least 9 subjects for MTD. Successive subjects within a given dose level will follow a staggered 
dose pattern with at least 48 hours between subjects. Additional daily dose levels and/or dosing 
schedules (including BID regimen) may be studied based on clinical safety, tolerability, and PK 
data obtained during this study.  
All subjects will be treated with the study drug in cycles of 28 days and the DLTs that occur 
within the first cycle will be used to determine MTD. Progression to the next dose level will be 
based upon the dose escalation/de-escalation/elimination rules (See Section 14.1) and SRC 
review of the safety and PK data (if available) of the current dose group. 
Figure 4: 
Flowchart for Trial Conduct Using the BOIN design 
 
A screening visit will occur within 28 days of signing an informed consent form (ICF). In 
Cycle 1 (except Day 2 and Day 3), EZM0414 will be administered orally once daily (QD) 
without food (no food two hours prior and one hour after EZM0414 dose, water is permitted 
without restrictions) in continuous 28-day cycles. Subjects will continue to receive treatment at 
the assigned dose level until disease progression, occurrence of unacceptable toxicity, 
withdrawal of consent, or need for treatment prohibited on this study. No intra-patient dose 
escalation will be permitted. DLT (as defined in Table 3) will be assessed during the first 
treatment cycle. Dose modifications for EZM0414 are discussed in Table 4. 


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Safety assessments will be performed throughout the study and at each study visit. Vital signs 
including blood pressure, respiration rate, heart rate, and temperature will be collected according 
to schedule of assessments (Table 8 and Table 9). 
A single 12-lead ECG will be collected at screening and triplicate ECGs 1-minute apart will be 
collected at all other time points mentioned in Table 8 and Table 9. Subjects should be rested in a 
sitting position for 10 min prior to collection of all study ECGs. 
Blood samples will be collected from all subjects for PK analyses at time points mentioned in 
Table 9. 
At time points where vital signs, ECG and PK blood samples are required, the following order of 
collection is recommended (1) vital signs, (2) ECG (3) Blood sample for PK analyses and 
biomarker analyses. 
Translational samples for research  
Tumor samples in MM subjects: Bone marrow aspirates and a bone marrow biopsy will be 
collected at screening or Cycle 1 Day 1 (pre-dose) in subjects with MM. For subjects with MM, 
a bone marrow biopsy and bone marrow aspirations will be performed on-treatment (Cycle 3 
Day 1). In subjects with MM a bone marrow biopsy and bone marrow aspirates will be 
performed at VGPR. A non-mandatory bone marrow biopsy and bone marrow aspirates can be 
performed at progression in MM subjects. If a standard of care (SOC) bone marrow will be 
performed, a bone marrow aspiration will be requested for research in MM subjects.  
Tumor samples in DLBCL subjects: In subjects with DLBCL, archival tissue sample not older 
than 6 months will be collected. In DLBCL subjects with not enough archival tissue available, an 
optional fresh biopsy is recommended at screening or Cycle 1 Day 1 (pre-dose). An on-treatment 
biopsy (Cycle 3 Day 1) will be optional for subjects with DLBCL. An optional tumor biopsy will 
be taken in subjects with DLBCL at PR. A non-mandatory tumor biopsy can be performed at 
progression in DLBC subjects. Biopsies in patients with DLBCL will be optional and a separate 
ICF will be provided.  
Blood samples for biomarker analyses in MM and DLBCL subjects: Blood samples for 
exploratory analyses will be collected pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 
1, Cycle 3 Day 1 and after that every other cycle until Cycle 26 and then every 4 Cycles after 
Cycle 26, at progression, and at any response event.  
Blood samples, tissue samples and bone marrow aspirates for biomarker analyses in MM and 
DLBCL subjects: In blood samples and tumor tissue/bone marrow aspirates/tumor cells DNA 
alterations such as mutations, copy number variation (CNV), and other DNA alterations will be 
assessed, RNA expression will be investigated in tumor tissue/bone marrow aspirates/tumor cells 
and/or blood samples (eg circulating tumor cells [CTCs] in the PBMC fraction/in PBMCs and/or 
the buffy coat) as well as protein expression and methylation status. Different assays such as 
next-generation sequencing (NGS), fluorescent-in situ hybridization (FISH), 
immunohistochemistry, and others will be performed to investigate translational research 
samples. 
Assessment of Safety 
In the Phase 1 safety portion, a Safety Review Committee (SRC) will monitor safety data on an 
ongoing basis. All dose escalation decisions will be made by the SRC upon review of all 


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available data. Determination of the MTD will be informed by all available data, including the 
overall tolerability of EZM0414. 
Assessment of response  
Assessment of response to treatment will be performed according to IMWG 2016 (Kumar, 2016; 
Appendix 1) consensus criteria in MM subjects and Lugano Classification (Cheson, 2014; 
Appendix 2) in DLBCL subjects. 
In MM: IMWG 2016 consensus criteria that includes serum M-protein, 24-hour urine M-
protein, serum free light chain kappa, lambda, and their ratio, bone marrow aspiration (complete 
response) and bone marrow biopsy (stringent complete response). Hence, subjects with MM 
would need to undergo a bone marrow biopsy or bone marrow aspiration for IMWG response 
assessment (Kumar, 2016; Appendix 1). 
In DLBCL: International Working Group consensus response evaluation criteria in lymphoma, 
Lugano Classification (Cheson, 2014; Appendix 2). Hence subjects with a previously positive or 
unknown bone marrow biopsy at baseline would undergo a bone marrow biopsy in suspected 
CR. 
Part 2: Phase 1b Safety and Efficacy Dose Expansion 
In the dose expansion phase, Bayesian optimal phase 2 (BOP2) design will be used to evaluate 
safety and efficacy in subjects with or without select genetic translocation in R/R MM and R/R 
DLBCL.  
In the dose expansion part, 60 subjects will be enrolled (20 subjects/cohort) and treated:  
• Cohort 1: R/R MM with t(4;14)  
• Cohort 2: R/R MM without t(4;14) 
• Cohort 3: R/R DLBCL 
During the treatment period, subjects will receive EZM0414 in continuous 28-day cycles. 
EZM0414 will be administered orally once daily (QD) without food (nothing to eat two hours 
prior and one hour after EZM0414 dose, water is permitted as needed). The subjects who receive 
EZM0414 at MTD and do not have DLT in the dose escalation part of the study will be rolled 
over to a cohort of this dose expansion part, depending on their condition (R/R MM or R/R 
DLBCL) and the select genetic translocation for R/R MM. All subjects will continue to receive 
treatment at the MTD in Phase 1b part until disease progression, occurrence of unacceptable 
toxicity, or withdrawal of consent, or need for treatment prohibited on this study. Subjects with 
R/R MM regardless of t(4;14) status will be enrolled first. Dose modifications for EZM0414 are 
discussed in Table 4. 
Safety assessments will be performed throughout the study and at each study visit. Vital signs 
including blood pressure, heart rate, respiration rate, and temperature will be collected according 
to schedule of assessments (Table 8 and Table 10). 
A single 12-lead ECG will be collected at screening and triplicate ECGs, 1-minute apart will be 
collected at time points mentioned in Table 8 and Table 10. 
Blood samples will be collected from all subjects for PK analyses at the time points mentioned in 
Table 10. 


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At time points where vital signs, ECG and PK blood samples are required, the following order of 
collection is recommended 1) vital signs, 2) ECG and 3) blood sample for PK analyses and 
biomarker analyses. 
Assessment of response  
Assessment of response to treatment will be performed according to IMWG 2016 consensus 
criteria (Kumar, 2016; Appendix 1) in MM subjects and Lugano Classification (Cheson, 2014; 
Appendix 2) in DLBCL subjects. To assess response according to IMWG 2016, subjects with 
MM will undergo bone marrow aspirates or biopsies to assess CR or stringent CR. respectively. 
To assess complete response according to Lugano Classification, subjects with DLBCL might 
undergo a bone marrow biopsy. In MM subjects, treatment response will include serum M-
protein, 24-hour urine M-protein, serum free light chain kappa, lambda, and their ratio. In 
DLBCL, imaging will be used to assess response. 
Translational samples for research  
Tumor samples in MM subjects: Bone marrow aspirates and a bone marrow biopsy will be 
collected from all MM subjects at baseline (at screening or Cycle 1 Day 1 pre-dose), on-
treatment (Cycle 3 Day 1) and at VGPR. A non-mandatory bone marrow biopsy and bone 
marrow aspirates will be taken for subjects with MM at disease progression. If a SOC bone 
marrow will be performed, a bone marrow aspiration will be requested for research in subjects 
with MM.  
Tumor samples in DLBCL subjects: In subjects with DLBCL, archival tissue sample not older 
than 6 months will be collected and if not available, an optional fresh biopsy will be performed at 
screening or Cycle 1 Day 1 (pre-dose). An optional on-treatment biopsy (Cycle 3 Day 1) and at 
PR will be performed in DLBCL subjects. Non-mandatory tumor biopsies in subjects with 
DLBCL will be taken at disease progression. All biopsies for subjects with DLBCL will be 
optional and a separate ICF will be provided. 
Blood samples for biomarker analyses in MM and DLBCL subjects: Blood samples will be 
collected predose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, after that at 
every other cycle until Cycle 26 and then every 4 cycles after Cycle 26, at progression, and at 
any response event.  
Blood samples, tissue samples and bone marrow aspirates for biomarker analyses in MM and 
DLBCL subjects: In blood samples and tumor tissue/bone marrow aspirates/tumor cells DNA 
alterations such as mutations, copy number variation (CNV), and other DNA alterations will be 
assessed, RNA expression will be investigated in tumor tissue/bone marrow aspirates/tumor cells 
and/or blood samples (eg circulating tumor cells [CTCs] in the PBMC fraction/in PBMCs and/or 
the buffy coat) as well as protein expression and methylation status. Different assays such as 
next-generation sequencing (NGS), fluorescent-in situ hybridization (FISH), 
immunohistochemistry, and others will be performed to investigate translational research 
samples. 
The translational research samples will be investigated for clones harboring t(4;14) translocation, 
somatic mutations such as SETD2, multiple myeloma SET domain (MMSET), expression of 
H3K36me2, and H3K36me3. Other markers and analysis might be performed as well.  


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Biomarker results including PD data will be correlated with PK data or outcome to investigate 
possible differences between subjects who respond to treatment versus those who do not 
respond. 
7.2. 
Number of Subjects 
Phase 1 dose escalation: up to 36 subjects. 
Phase 1b dose expansion: up to 60 subjects. 
Total: approximately 96 subjects. 
7.3. 
Treatment Assignment 
After obtaining written informed consent, subjects with R/R MM and R/R DLBCL will be 
screened according to the exclusion and inclusion criteria. Subjects who meet all selection 
criteria will receive a unique subject number upon enrollment in the study. Subject numbers will 
be allocated sequentially in the order in which subjects are enrolled. The Investigator or designee 
will enter the corresponding subject number in each subject’s electronic case report form 
(eCRF).  
In part 1, subjects will be administered EZM0414 based on the dose level they are enrolled in. 
Six dose levels starting at100 mg, 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) will be tested in this dose escalation part 
of the study. 
In part 2, subjects will be enrolled and treated with EZM0414 at the MTD in 3 cohorts:  
• Cohort 1: R/R MM with t(4;14)  
• Cohort 2: R/R MM without t(4;14) 
• Cohort 3: R/R DLBCL 
All subjects in this study will receive EZM0414 as monotherapy orally once daily (QD) in 28-
day cycles.  
7.4. 
Duration of Treatment 
Subjects will be treated continuously until consent withdrawal, unacceptable toxicity, disease 
progression, or need for treatment prohibited on this study. Each treatment cycle will be of 28-
day duration. There will be a 30-day safety follow-up. 
7.5. 
Dose Adjustment Criteria 
7.5.1. 
Dose Limiting Toxicities 
Any adverse event (AE) which meets the criteria of a DLT as assessed by the Investigator and 
warrants action as per Table 3, will be reviewed by the Safety Review Committee (SRC). No 
intra-patient dose reduction will be permitted in Cycle 1 of dose escalation. For subjects who 
require a dose interruption due to a DLT during cycle 1, the treatment will be restarted once the 
toxicity resolves to Grade ≤1 or baseline. However, an interruption in the administration of 
EZM0414, for more than 14 days will be discussed with the Sponsor’s or Designee Medical 


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Monitor before treatment can be resumed. The DLT evaluable subjects will consist of dose 
escalation dose level subjects who received at least 80% of planned study treatment during cycle 
1. If a subject is non evaluable, this subject will be replaced by a new subject. 
Safety assessments will be performed throughout the study and at each visit. DLT period is 28 
days of cycle 1 of the dose escalation part. AEs that are clearly and incontrovertibly due to the 
underlying disease or extraneous causes will not be considered as DLTs. All of the AEs of 
specified grades as listed in Table 3 will be classified as DLTs. Events will be assessed as DLTs 
according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0), as shown in 
Table 3 (Appendix 5). When a subject is assessed to be experiencing a DLT, study treatment will 
be interrupted and DLTs will be managed by concomitant medication (as appropriate), treatment 
discontinuation, or a combination of these. All dose escalation decisions will be made by the 
SRC and Sponsor upon review of all available data. Determination of the MTD will be informed 
by all available data, including the overall tolerability of EZM0414.  


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Table 3: 
Dose Limiting Toxicities 
Toxicity Category 
Dose-Limiting Toxicity/CTCAE (version 5.0) Grade 
Hematological toxicity 
• Grade 4 neutropenia lasting more than 5 days 
• Grade 3 febrile neutropenia (ANC <1.0 x 109/L fever ≥ 38.4°C or 
≥ 38°C for 1 hour)  
• Grade 3 thrombocytopenia with clinically significant bleeding  
• Grade 4 thrombocytopenia  
• Grade 4 Anemia unexplained by underlying disease 
Other non-
hematological toxicity 
• Any other non-hematologic toxicity ≥ 3 except: 
− Alopecia 
− Grade 3 nausea/vomiting or diarrhea for less than 3 days with 
adequate antiemetic and other supportive care 
− Grade 3 fatigue for less than one week 
− Grade 3 or higher isolated electrolyte abnormalities that last up to 3 
days, are not clinically complicated, and resolve spontaneously, or 
respond to conventional medical interventions 
− Grade 3 or higher amylase or lipase elevation that is not associated 
with symptoms or clinical manifestations of pancreatitis 
− Grade 3 tumor lysis syndrome (TLS) that lasts up to 3 days, is not 
clinically complicated, and resolves spontaneously, or responds to 
conventional medical interventions. 
• Any patient meeting Hy’s Law Criteria without alternate explanation, 
concurrent values of: 
− ALT or AST elevation of >3xULN, and 
− TBL elevation of >2xULN, and 
− Absence of initial findings of cholestasis (ie, absence of elevation of 
ALP to >2xULN) 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; ECOG = Eastern Cooperative 
Oncology Group (ECOG); TBL = total bilirubin; ULN = upper limit of normal 
Note: ALT is also referred to as serum glutamic pyruvic transaminase (SGPT); AST is also referred to as serum 
glutamic oxaloacetic transaminase (SGOT) 
7.5.2. 
Dose Reductions and Interruptions  
EZM0414 dose adjustments/reductions and interruptions will be allowed. However, an 
interruption in the administration of EZM0414, for more than 14 days must be discussed with 
the Sponsor’s or Designee Medical Monitor before treatment can be resumed. 
Toxicity will be managed by concomitant medication (as appropriate), treatment interruption, 
dose reduction, and treatment discontinuation, or a combination of these. During treatment with 
study drug, dose interruption and reduction for subjects who experience study drug-related 
toxicity will be in accordance with the Dose Modifications Instructions in Table 4.  


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For subjects who require dose interruption due to study drug-related toxicity, the treatment may 
restart once the toxicity has resolved to Grade ≤ 1 or baseline according to the Dose 
Modifications Instructions in Table 4. If clinically appropriate thereafter re-escalation can be 
considered in consultation with the Sponsor’s Medical Monitor. 
Based up on physical exam and respiration rate, follow-up examination should be performed as 
clinically indicated. For continuation of treatment for cycle 2 and beyond, subjects must meet the 
following retreatment criteria: 
• Platelet count must be ≥50 × 109/L, include transfusion dependent subjects  
• Absolute neutrophil count (ANC) must be ≥1.0 × 109/L if no lymphoma infiltration of 
bone marrow OR ANC must be ≥0.75 × 109/L with bone marrow infiltration, and 
• Any Grade 3 or higher toxicity must have resolved to Grade 1 or baseline, unless 
otherwise noted. 
The suggested dose reductions for the three lowest dose levels are as follows based on the dose 
reduction increments included in Table 4:  
• Starting dose: 100 mg QD EZM0414 
− 1st dose reduction 75 mg 
− 2nd dose reduction: 50 mg 
• Step down dose (if needed): 75 mg QD EZM0414: 1st dose reduction 50 mg and 2nd 
dose reduction: 25 mg 
• Starting dose: 200 mg QD EZM0414 
− 1st dose reduction 150 mg 
− 2nd dose reduction: 100 mg 
• Starting dose: 300 mg QD EZM0414 
− 1st dose reduction 200 mg 
− 2nd dose reduction: 100 mg 
All final decisions on dose reductions in response to drug-related AEs should be made after 
discussion with the Sponsor’s Medical Monitor. 


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Table 4: 
Dose Modifications Instructions for Grade 1 – Grade 4 study drug-related 
Adverse Events* 
Toxicitya 
During Therapy 
Approximate Study Drug Dose 
Adjustmentb 
Excluding fatigue, alopecia, nausea, vomiting, or diarrhea not receiving adequate medical treatment. 
For management of QTcF prolongation please refer to Section 7.5.3, AST/ALT elevations please refer 
to Table 5, creatinine elevations please refer to Table 6, and INR elevations please refer to Table 7. 
Grade 1 
All occurrences 
Continue study drug 
Maintain dose level 
Grade 2c 
Toxicity 
During therapy 
Approximate Study Drug Dose 
Adjustmentb 
1st occurrence 
Monitor as clinically indicated 
Maintain dose level 
2nd occurrence 
Interrupt study drug until 
resolved to Grade ≤1 or 
baselineb 
Maintain dose level 
3rd occurrence 
Restart at one lower dose level 
4th occurrence 
Discontinue study drug 
Not applicable 
Grade 3c,d 
Toxicity 
During therapy 
Approximate Study Drug Dose 
Adjustmentb 
1st occurrence 
Interrupt study drug until 
resolved to Grade ≤1 or 
baselineb 
Restart at one lower dose level 
2nd occurrence  
Restart at second lower dose level 
3rd occurrence 
Discontinue study drug 
Not applicable 
Grade 4 
Any occurrence 
Discontinue study drug 
Not applicable 
AST = aspartate aminotransferase; ALT = alanine aminotransferase; INR = international normalized ratio 
* Subjects diagnosed with a Covid-19 positive PCR test will be discontinued from treatment. 
a The term occurrences applies to same AE term and not any AE term. 
b An interruption of any study drug for more than 14 days due to any toxicity must be discussed with the Sponsor’s 
or Designee Medical Monitor before treatment can be resumed. 
c Excluding Grade 2 and 3 anemia: Subjects are allowed to continue study drug at their current dose level with 
transfusion per Investigator discretion. 
d Use of growth factors (G-CSF, GM-CSF) is permitted as per ASCO and ESMO guidelines 
7.5.3. 
Safety Management Guidelines 
Investigation: QTcF prolongation  
The QTcF is the QT interval corrected for heart rate according Fridericia’s formula (QTcF). For 
eligibility and withdrawal, subjects QTcF value will be used. For purposes of data analysis, 
QTcF values will be used. 


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If QTcF >500 msec or QTcF prolongation >60 msec from baseline is observed at any point 
during the study treatment and confirmed, the below guidance must be followed: 
1. Assess the quality of the ECG recording and the QT value and repeat if needed. 
2. Interrupt study treatment until confirmed resolution of QTcF and as per dose reduction 
guidelines in Table 4. 
3. Determine the serum electrolyte levels (in particular hypokalemia hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment. 
4. Review concomitant medication use for other causes for QT prolongation (refer to 
qtdrugs.org for known QT prolonging drugs), and for drugs with the potential to increase 
the risk of drug exposure related QT prolongation (e.g., concomitant use of CYP3A4 
inhibitors). 
5. Check study drug dosing diary and treatment compliance.  
6. Increased ECG safety monitoring is recommended during or in-between subsequent 
visits. 
Table 5: 
Investigation: Hepatic  
Liver function elevation management: Elevations in AST and/ or ALT 
Grade 1  
All occurrences  
Continue study drug 
Maintain dose level 
Grade 2 
1st occurrence  
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Maintain dose level 
 
2nd occurrence 
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Maintain dose level 
 
3rd occurrence 
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Restart at one lower 
dose level 
 
4th occurrence 
Discontinue study drug 
Not applicable 
Grade 3  
1st occurrence 
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Maintain dose level 
 
2nd occurrence  
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Restart at one lower 
dose level 
 
3rd occurrence 
Discontinue study drug 
Not applicable 
Grade 4 
Any occurrence  
Discontinue study drug 
Not applicable 
 
Table 6: 
Investigation: Renal 
Creatinine elevation management: 
Grade 1  
All occurrences  
Continue study drug 
Maintain dose level 
Grade 2 
1st occurrence  
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Maintain dose level 
 
2nd occurrence 
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Restart at one lower 
dose level 
 
3rd occurrence 
Discontinue study drug 
Not applicable 
Grade 3  
1st occurrence 
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Restart at one lower 
dose level 
 
2nd occurrence  
Discontinue study drug 
Not applicable 


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Grade 4 
Any occurrence  
Discontinue study drug 
Not applicable 
 
Table 7: 
Investigation: Coagulation 
INR management: 
Grade 1  
All occurrences  
Continue study drug 
Maintain dose level 
Grade 2 
1st occurrence  
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Maintain dose level 
 
2nd occurrence 
Interrupt study drug until resolved to 
Grade ≤1 or baseline 
Restart at one lower 
dose level  
 
3rd occurrence 
Discontinue study drug 
Not applicable 
Grade ≥3  
Any occurrence 
Discontinue study drug 
Complete safety 
assessments as 
clinically indicated 
7.5.4. 
Safety Stopping Rules 
Monitoring of all toxicity will be routinely performed by the SET-101 Safety Review Committee 
(SRC), composed of SET-101 investigators, Epizyme Medical Directors and Pharmacovigilance. 
Unacceptable toxicity is defined as those treatment-emergent adverse events that are at least 
possibly related to study drug, are of CTCAE Grade 4 or 5, and for which no other cause is 
identified. 
For unacceptable toxicities: If there are more than 25% (of the total number of subjects treated 
within the safety population [MM and DLBCL]) study drug withdrawals due to treatment related 
grade 4 or 5 toxicity at any point during the study, the SRC will escalate the safety findings to an 
ad hoc Epizyme Quarterly Safety Review (QSR) committee meeting. The QSR committee, an 
internal cross functional scientific and medical review board, will determine the final action for 
study SET-101. The decision will be communicated to investigators and health authorities, as 
applicable.  
For treatment related deaths: the SRC will also perform ongoing assessment and monitoring 
during routine data review meetings. All treatment-related deaths will trigger an ad hoc QSR 
meeting for full evaluation and decision with regard to continuing study SET-101. 
7.5.5. 
Post-Treatment Monitoring for Hematologic Second Primary Malignancy 
Post treatment monitoring as clinically indicated will be performed for those subjects who 1) do 
not enroll in a new clinical study, 2) do not withdraw consent and 3) do not begin a new anti-
neoplastic therapy. Monitoring will include a complete blood count with at least an automated 
differential or peripheral blood smear. 
7.5.6. 
Determination of Sample Size and Criteria for Early Stopping Due to Futility 
This is a FIH study. The objective of this study is to evaluate the safety, tolerability, and PK of 
EZM0414 in order to determine MTD in Phase 1 part, and safety, tolerability, PK, and efficacy 
to determine RP2D in Phase 1b part. 
This is an open-label study and there will be no randomization. Subjects will be enrolled based 
on their conditions. 


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The sample size of Phase 1 part is determined based on number of doses to be tested using BOIN 
design and there is no formal sample size estimation for the Phase 1b part of the study.  
The study will enroll approximately 96 subjects, of which up to 36 subjects will be enrolled in 
Phase 1 dose escalation part and 60 subjects (20 subjects/cohort) will be enrolled in Phase 1b 
dose expansion part. There will be 6 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 level of 75 mg (if needed) to be 
tested in Phase 1 dose escalation part to determine MTD, and additional daily dose levels and/or 
dosing schedules (including BID regimen) may be studied based on clinical and pharmacokinetic 
data obtained during this study. The sample size will therefore be adjusted accordingly. There 
will be 3 cohorts for the dose expansion part: 20 R/R MM subjects with t(4;14), 20 R/R MM 
subjects without t(4;14) and 20 R/R DLBCL subjects.  
The subjects who are treated at MTD in Phase 1 dose escalation part and do not experience any 
DLT will continue to receive the treatment beyond cycle 1 (be rolled over to the dose expansion 
part) until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent, or 
need for treatment prohibited on this study.  
There will be 3 looks performed in Phase 1b part when the data of 10, 15, and 20 subjects of a 
cohort have been available. The cohort will be terminated earlier if deemed futile by SRC and 
the study team. 
7.6. 
Criteria for Study Termination 
The Sponsor reserves the right to discontinue the study for medical reasons or for any other 
reason at any time. If the study is prematurely terminated or suspended, the Sponsor will 
promptly inform the Investigators/institutions and the regulatory authority(ies) of the termination 
or suspension and the reason(s) for the termination or suspension. The institutional review board 
(IRB)/independent ethics committee (IEC) should also be informed promptly and provided with 
the reason(s) for the termination or suspension by the Sponsor or by the Investigator/institution, 
as specified by the applicable regulatory requirement(s). 
The Investigator reserves the right to discontinue the study should his/her judgment so dictate. If 
the Investigator terminates or suspends a trial without prior agreement of the Sponsor, the 
Investigator should inform the institution where applicable, and the Investigator/institution 
should promptly inform the Sponsor and the IRB/IEC and should provide the Sponsor and the 
IRB/IEC with a detailed written explanation of the termination or suspension. Study records 
must be retained as noted in Section 18.3. 
 


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Table 8: 
Schedule of Assessments for Dose Escalation and Dose Expansion 
Assessment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Cycle 4 
Cycle 
5+ 
EOTa 
Safety 
Follow 
upb 
Study day 
(window) 
-28 to -1 
1c 
2 
3 
4 
8 
(±3D) 
15 
(±3D) 
22 
(±3D) 
1 
(±3D) 
2 
8 
(±3D) 
15 
(±3D) 
1 
(±3D) 
15 
(±3D) 
1 
(±3D) 
 
30 
(±3D) 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
(Complete) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical Exam 
(Symptom-
directed) 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
Height 
(screening 
only) and body 
weight 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
X 
Xd 
Xd 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
12-lead ECGe 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xe 
X 
 
Disease 
assessment for 
DLBCL 
subjects f 
X 
 
 
 
 
 
 
 
 
 
 
 
C3 
only 
 
Cycle 
5, 7, 9 
etc 
X 
 
Adverse 
Events 
X 


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Assessment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Cycle 4 
Cycle 
5+ 
EOTa 
Safety 
Follow 
upb 
Study day 
(window) 
-28 to -1 
1c 
2 
3 
4 
8 
(±3D) 
15 
(±3D) 
22 
(±3D) 
1 
(±3D) 
2 
8 
(±3D) 
15 
(±3D) 
1 
(±3D) 
15 
(±3D) 
1 
(±3D) 
 
30 
(±3D) 
Concomitant 
medications 
X 
Hematologyg,* 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood 
chemistryh 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
testi 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testj 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
EZM0414 oral 
administration 
 
Continuous oral administration in 28-day cycles per escalation schedule or expansion. 
In dose escalation: EZM0414 will be administered on C1D1 but will not be administered on C1D2 and 
C1D3. C1D4, C1D15 and C2D2 dose will be administered after PK sample collection. 
In dose expansion: C1D2 and C2D2 dose will be administered after PK sample collection. 
 
 
Bone marrow 
aspirates and 
bone marrow 
biopsyk 
Xl 
Xl 
 
 
 
 
 
 
 
 
 
 
Xm 
 
Xm 
 
 
Serum β2 
microglobulin 
(MM subjects 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum M-
protein serum 
(MM only) 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
24-hour urine 
sample for M-
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 


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Assessment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Cycle 4 
Cycle 
5+ 
EOTa 
Safety 
Follow 
upb 
Study day 
(window) 
-28 to -1 
1c 
2 
3 
4 
8 
(±3D) 
15 
(±3D) 
22 
(±3D) 
1 
(±3D) 
2 
8 
(±3D) 
15 
(±3D) 
1 
(±3D) 
15 
(±3D) 
1 
(±3D) 
 
30 
(±3D) 
protein (MM 
only) 
Serum free 
light-chain 
assay (MM 
only) 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
MM Disease 
assessment by 
IMWG 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
Skeletal 
survey (MM 
only)n 
X 
As clinically indicated and per the local standard of care for imaging (X-ray or MRI). The same 
methodology used at Screening should be used throughout the study for comparison purposes. 
 
 
CT or PET/CT 
for 
extramedullary 
soft tissue 
plasmacytoma 
(MM only) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
(Cycle 
3 
only) 
 
Xo 
 
 
Whole blood 
for exploratory 
analysisp 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Tumor tissue 
(DLBCL 
only)q 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
(cycle 
3 
only) 
 
X 
(optio
nal) 
 
 
PK 
 
Please refer to Table 9 for dose escalation PK and Table 10 for dose expansion PK collection schedule 
X 
 
Abbreviations: aPTT = activated partial thromboplastin; BNP = brain natriuretic peptide; C = Cycle; CR = complete response; CT = computed tomography; D 
= Day; DLBCL = diffuse large B cell lymphoma; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group status; EOT = end of treatment; 
FDG = fluorodeoxyglucose; IMWG = International Myeloma Working Group; INR = international normalized ratio; MM = multiple myeloma; M-protein = 


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Assessment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Cycle 4 
Cycle 
5+ 
EOTa 
Safety 
Follow 
upb 
Study day 
(window) 
-28 to -1 
1c 
2 
3 
4 
8 
(±3D) 
15 
(±3D) 
22 
(±3D) 
1 
(±3D) 
2 
8 
(±3D) 
15 
(±3D) 
1 
(±3D) 
15 
(±3D) 
1 
(±3D) 
 
30 
(±3D) 
monoclonal protein; PK = pharmacokinetics; PT = prothrombin time; sCR = stringent complete response complete response; VGPR = very good partial 
response  
a End of treatment visit should be completed within 7 days of the last dose of study drug. This visit may be completed at a scheduled visit when a decision to 
discontinue treatment is made. 
b 30-day safety follow-up should be completed 30 (±3) days after last dose of study drug or before start of a new anti-cancer therapy, whichever occurs first.  
c Cycle 1 Day 1 hematology, serum chemistries, coagulation and urinalysis may be performed on Cycle 1 Day -1. 
d Only in Part 1 dose escalation. 
e Collect single ECG at screening and triplicate ECGs at all other timepoints. ECGs during Cycle 1 and Cycle 2 are per Table 9 (dose escalation) and Table 10 
(dose expansion). Triplicate ECGs will also be collected at pre-dose (within 30 min of dose) and 2-hours post (± 10min) on Day 1 of every odd cycle starting at 
Cycle 3 Day 1, and at end of treatment.  
f Radiologic disease assessments at screening and every 8 weeks ±7 days. PET/CT whole body for FDG avid disease OR contrast enhanced CT of neck, chest, 
abdomen, and pelvis for subjects with non-FDG avid disease. Use the same modality for disease assessment through the study for each patient. 
g Hematology assessments will include red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, white blood cell count with differential, platelet count, peripheral blood smear, and reticulocyte count.                            
*  Post treatment monitoring as clinically indicated will be performed for those subjects who 1) do not enroll in a new clinical study, 2) do not withdraw 
consent and 3) do not begin a new anti-neoplastic therapy. Monitoring will include a complete blood count with at least an automated differential or peripheral 
blood smear. 
h Blood chemistry assessments will include sodium, potassium, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
albumin, calcium, glucose, total creatine kinase, total bilirubin, lactic dehydrogenase, creatinine, total protein, bicarbonate, phosphorus, magnesium, uric acid, 
amylase, lipase, cardiac markers- BNP, and Troponin. 
i Coagulation tests include aPTT, PT/INR, and fibrinogen. 
j Serum pregnancy test at screening and serum/urine pregnancy test at all other visits. Cycle 1 Day 1 pregnancy test does not need to be repeated if screening test 
performed within 72 hours of Cycle 1 Day 1. 
k Subjects with MM: Bone marrow aspirations and a bone marrow biopsy will be taken at screening/baseline (pre-dose), Cycle 3 Day 1, VGPR for translational 
studies. Bone marrow aspirates and bone marrow biopsies will be taken at CR and sCR to assess response according to IMWG 2016 criteria as per local 
institutional practice. If a SOC bone marrow will be performed a bone marrow aspiration will be taken for research in subjects with MM. A non-mandatory 
bone marrow biopsy and bone marrow aspirates can be taken at progression for research.  
l MM: Bone marrow aspirates and bone marrow biopsy are taken either at screening/baseline or at Cycle 1 Day1 (predose). 
m Translational research samples will be collected at Cycle 3 Day 1, VGPR and progression. A bone marrow aspirate will be collected for research if SOC biopsy 
will be performed for CR or sCR for MM. SOC samples will be taken at CR and sCR to assess ORR. 
n Skeletal surveys for sites that do not have CT/PET-CT capabilities. 
o Perform CT or PET/CT at screening, Cycle 3 Day 1 (±7 days) and then starting at cycle 6, every 3 cycles (±7 days) or sooner if clinically indicated. 


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p Whole blood will be collected for: Plasma and CTC in the PBMC fraction, PBMCs and/or buffy coat at Cycle 1 Day1 (pre-dose), Cycle 1 Day 15 (pre-dose), 
Cycle 2 Day 1 (pre-dose), Cycle 3 Day 1 (pre-dose), progression, or any response. After Cycle 3 Day 1 every other cycle until Cycle 26 and then every 4 
Cycles after Cycle 26. For exact sample collections see quick chart (Laboratory manual). 
q DLBCL subjects: Archival tissue or an optional fresh biopsy can be taken in subjects with DLBCL. An optional biopsy can be taken at PR. A non-mandatory 
biopsy can be taken at progression. An optional biopsy can be taken on-treatment at Cycle 3 Day 1. 
   Subjects with DLBCL: Bone marrow biopsy at suspected complete response if bone marrow status was unknown or positive at study entry. Bone marrow 
aspirate will be taken at CR if at baseline bone marrow status was unknown or positive. 
 
 
 
 


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Table 9: 
PK, Vitals and ECG schedule for Phase 1 (dose escalation) 
 
 
C1D1 
C1D2 
C1D3 
C1D4 
C1D8 
C1D15 
C1D22 
C2D1 
C2D2 
C2D8 
C2D15 
Day 1 of 
Odd cycles 
(C3, C5, C7 
etc.) 
PK 
Pre-dose (within 
30 min) 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
30min (±5min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
60min (±5min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
90min (±5min) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
3hr (±10min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
6hr (±10min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
10hr (±60min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
24hr (±60min) 
 
Xa 
 
 
 
 
 
 
Xb 
 
 
 
 
48hr (±2hr) 
 
 
Xa 
 
 
 
 
 
 
 
 
 
 
72hr (±2hr) 
 
 
 
Xb 
 
 
 
 
 
 
 
 
Vital signs 
Pre-dose (within 
30 min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
30min (±10min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
1hr (±10min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
2hr (±10min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
4hr (±10min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
6hr (±30min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
Triplicate 
ECGs 
Pre-dose (within 
30 min) 
X 
 
 
 
X  
X  
X 
X 
 
X 
X 
X  
 
30min (±5min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
1hr (±5min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
2hr (±10min) 
X 
 
 
 
X  
X  
X 
X 
 
X 
X 
X  
 
4hr (±10min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
6hr (±30min) 
X 
 
 
 
 
 
 
X 
 
 
 
 


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C1D1 
C1D2 
C1D3 
C1D4 
C1D8 
C1D15 
C1D22 
C2D1 
C2D2 
C2D8 
C2D15 
Day 1 of 
Odd cycles 
(C3, C5, C7 
etc.) 
 
24hr (±60min) 
 
X 
 
 
  
  
 
 
Xb 
 
 
 
C = Cycle; D = Day; ECG = electrocardiogram; PK = pharmacokinetics 
a Skip dosing with EZM0414 on C1D2 and C1D3. 
b PK sample must be collected prior to dosing with EZM0414 on C1D4 and C2D2. ECG must be collected prior to dosing with EZM0414 on Cycle 2 Day 2. 
 
 
 


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Table 10: 
PK, Vitals and ECG Schedule for Phase 1b (dose expansion) 
 
 
C1D1 
C1D2 
C2D1 
C2D2 
Day 1 of Odd cycles 
(C3, C5, C7, etc) 
PK 
Pre-dose (within 30 min) 
X 
 
X 
 
X 
 
30min (±5min)  
X 
 
X 
 
 
 
60min (±5min) 
X 
 
X 
 
 
 
90min (±5min) 
X 
 
X 
 
X 
 
3hr (±10min) 
X 
 
X 
 
 
 
6hr (±10min) 
X 
 
X 
 
 
 
10hr (±60min) 
X 
 
X 
 
 
 
24hr (±60min) 
 
Xa 
 
Xa 
 
Vital signs 
Pre-dose (within 30min) 
X 
 
X 
 
 
 
30min (±10min) 
X 
 
X 
 
 
 
1hr (±10min) 
X 
 
X 
 
 
 
2hr (±10min) 
X 
 
X 
 
 
 
4hr (±20min) 
X 
 
X 
 
 
 
6hr (±30min) 
X 
 
X 
 
 
Triplicate ECGs 
Pre-dose (within 30 min) 
X 
 
X 
 
 
 
30min (±5min) 
X 
 
X 
 
 
 
1hr (±5min) 
X 
 
X 
 
 
 
2hr (±10min) 
X 
 
X 
 
 
 
4hr (±10min) 
X 
 
X 
 
 
 
6hr (±30min) 
X 
 
X 
 
 
 
24hr (±60min) 
 
Xa 
 
Xa 
 
C = Cycle; D = Day; ECG = electrocardiogram; PK = pharmacokinetics 
a PK and ECG must be collected prior to dosing on C1D2 and C2D2. 
 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
To be eligible for inclusion in the trial, the subject has to meet all inclusion criteria and must not 
violate any of the exclusion criteria. Deviations to the protocol inclusion and exclusion criteria 
will not be allowed. If there is a question about eligibility, the investigator should consult with 
the sponsor’s medical monitor. 
Investigators should ensure that all study enrolment criteria have been met at screening. If a 
subject’s status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of study drug is given such that they no longer meet all 
eligibility criteria, he or she should be excluded from participation in the study. 
8.1. 
Subject Inclusion Criteria 
1. 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. 
2. Subjects must be ≥18 years of age at the time of signing the ICF. 
3. Subjects must have an ECOG status of 0 – 2 (Appendix 3).  
4. For MM, subjects must have measurable disease by IMWG 2016 criteria (Kumar, 2016; 
Appendix 1) as defined by at least one of the following: 
• Serum monoclonal protein (M-protein) concentration ≥ 0.5g/dL. 
• Urine M-protein excretion of ≥ 200mg in 24 hours. 
• Serum free light chain concentration ≥10mg/dL with an abnormal (<0.26 or >1.65) 
κ:λ free light chain ratio. 
5. For DLBCL, subjects must have measurable disease by Lugano criteria (Cheson, 2014; 
Appendix 2).  
6. MM subjects who are relapsed/refractory to immune modulator, proteasome inhibitor 
and anti-CD38 therapy. Subjects who could not tolerate a PI, IMiDs, and a CD38-
directed cytolytic antibody are eligible to participate and R/R MM subjects who are 
intolerant of established therapies known to provide clinical benefit in multiple myeloma. 
7. DLBCL subjects who are relapsed or refractory with at least two prior line including 
treatment with R-CHOP, R-EPOCH, R-hyperCVAD and other standard of care therapies. 
Lines of therapy could have been discontinued due to completion of therapy, intolerance, 
or lack of response. 
Note: Relapsed disease is defined as progression of disease, after initial response to 
previous treatment, more than six months after end of treatment. Refractory disease is 
defined as resistance to treatment due to lack of response or progression of disease during 
treatment or within six months after end of treatment. 
8. For dose expansion cohort 1 and 2 only; subjects must have local t(4;14) test results 
available for enrollment.  


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9. At enrollment, subjects should have an estimated life expectancy ≥ 3 months in the 
opinion of the Investigator. 
10. Subjects must have sufficient organ and marrow function as defined below: 
• Hemoglobin ≥8g/ dL 
• Platelets >75x109/L (includes transfusion dependent subjects) 
• ANC≥1000/mm3. Growth factors within 7 days of screening is not allowed to meet 
ANC eligibility criteria 
• AST and ALT <2.5xULN, or if attributed to tumor involvement, AST, and ALT <5x 
ULN 
• Bilirubin ≤1.5xULN 
• Creatinine clearance ≥40 ml/min. Estimated creatinine clearance calculated using the 
Cockcroft-Gault formula 
• Coagulation parameters: prothrombin time/ international normalized ratio (PT/INR) 
<1.5xULN and activated partial thromboplastin (aPTT) < 1.5xULN. 
11. Females must not be breastfeeding or pregnant at screening (as documented by a negative 
beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 IU/L 
or equivalent units of β-hCG). A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of study 
treatment. All female subjects will be considered to be of childbearing potential unless 
they are postmenopausal (at least 12 months consecutively amenorrheic, in the 
appropriate age group, and without other known or suspected cause) or have been 
sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, and/or bilateral 
oophorectomy, with all surgery completed at least 1 month before first dosing). 
12. Females of childbearing potential must not have had unprotected sexual intercourse 
within 30 days prior to study entry and must agree to use a highly effective method of 
contraception, beginning at least 14 days prior to study entry, during treatment cycles, 
and for 30 days after the final dose of study treatment and have a male partner who uses a 
condom. Highly effective contraception includes: 
• Placement of an intrauterine device. 
• Established hormonal contraceptive methods: oral, injectable, or implant. Females 
who are using hormonal contraceptives must have been on a stable dose of the same 
hormonal contraceptive product while enrolled on trial and must continue to use the 
same contraceptive during the study and for one months after last dose of study drug. 
13. Male subjects must either practice complete abstinence or agree to use a latex or 
synthetic condom, even with a successful vasectomy (medically confirmed azoospermia), 
during study treatment and for 30 days after the final dose of study treatment.  
      Note: Male subjects must not donate semen or sperm from the first dose of study 
treatment, during study treatment (including during dose interruptions), and for 30 days 
after the final dose of study treatment. 


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8.2. 
Subject Exclusion Criteria 
1. Subjects with plasma cell leukemia defined as a plasma cell count >2000/mm3. 
2. Subjects with Waldenstrom’s macroglobulinemia or smoldering MM. 
3. Subjects with corrected serum calcium >14mg/dL (>3.5mmol/L) or free ionized calcium 
>6.5mg/dL (1.6mmol/L). 
4. Subjects with known systemic amyloidosis. 
5. Subjects who had prior treatment with SETD2 or NSD2 inhibitor. 
6. Prior cancer therapy for disease under study within the past 4 weeks or 5 half-lives, 
whichever is shorter. All prior treatment-related AEs must have resolved to Grade 1 or 
baseline per NCI CTCAE 5.0. 
7. Have known active central nervous system (CNS) or any leptomeningeal metastasis of 
primary extracranial tumor. Subjects with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging 4 weeks 
prior to the first dose of study treatment and any neurologic symptoms have stabilized), 
have no evidence of new or enlarging brain metastases, and are on stable or tapering 
doses of steroids for at least 7 days prior to first dose of study treatment.  
Note: Subjects with asymptomatic brain metastases found on screening MRI may be 
entered into the study without prior radiation therapy to the brain if they do not require 
immediate surgical or radiation therapy in the opinion of the treating Investigator and in 
the opinion of a radiation therapy or neurosurgical consultant. 
8. Subjects taking medications that are known as strong and moderate CYP3A4 and P-gp 
inducers/inhibitors (including St. John’s Wort). Subjects taking ARA, H2 blockers and 
PPIs. Subjects must stop taking such medications and must not take them for the duration 
of their participation in the study. Washout of minimum 14 days or 5 half-lives 
(whichever is longer) prior to starting EZM0414 is required. 
9. Subjects unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from 
their diet and all foods that contain those fruits from time of enrolment to while on study. 
10. Have a known active infection with hepatitis B virus (HBV, as measured by positive 
hepatitis B surface antigen), hepatitis C virus (HCV, as measured by positive hepatitis C 
antibody).  
Exceptions: Subjects with a history of hepatitis B or C who have normal ALT AND are 
hepatitis B surface antigen negative and/or have undetectable HCV RNA are eligible.  
11. Known to be human immunodeficiency virus (HIV) seropositive. 
12. Subjects with active acute or chronic systemic infection requiring systemic treatment, 
including COVID-19. 
13. Has cardiovascular impairment: history of congestive heart failure greater than NYHA 
Class II, uncontrolled arterial hypertension (ie, systolic blood pressure (BP) >150 mm Hg 
and/or diastolic BP >110 mm Hg), unstable angina, myocardial infarction, or stroke 
within 6 months prior to the planned first dose of study drug; or ventricular cardiac 
arrhythmia requiring medical treatment (Appendix 4). 


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14. Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to > 480 msec 
or history of long QT syndrome. A history or evidence of current clinically significant 
uncontrolled arrhythmias. History of additional risk factors for Torsade de Pointes 
including heart failure, hypokalemia, family history of Long QT Syndrome, and use of 
concomitant medications that are known to increase the risk of Torsade de Pointes 
(www.crediblemeds.org).  
15. Known left ventricular ejection fraction (LVEF) < 50% by either echocardiogram 
(ECHO) or multigated acquisition (MUGA). 
16. Prior major surgery within 4 weeks of treatment start. 
17. Known hypersensitivity to components of the investigational product. 
18. Subjects who have received treatment with any unapproved drug product within 4 weeks 
prior to screening. 
19. Current participation in any other interventional clinical study except for follow-up. 
20. Subjects with a history of or active malignancy other than disease under study, except 
for: 
• Cervical carcinoma Stage 1B or less. 
• Surgically treated non-invasive basal cell and squamous cell skin carcinoma. 
• Malignant melanoma with a complete response for more than 10 years. 
• Curable cancer and/or hematologic malignancies diagnoses with a complete response 
for more than 5 years. 
21. 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. 
22. 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. 
8.3. 
Subject Withdrawal Criteria 
Subjects have the right to withdraw from the study at any time and for any reason without 
penalty or prejudice to future medical care by the physician or institution. The Investigator is 
also free to terminate a subject’s study drug treatment at any time if the subject’s clinical 
condition warrants it. Subject data up to withdrawal of consent will be included in the analysis of 
the study, and where permitted, publicly available data can be included after withdrawal of 
consent (eg, death records). 
Subjects (or legally authorized representatives) can decline to continue receiving any study 
treatment and/or other protocol-required procedures at any time during the study but can 
continue participation in the study (eg, for follow-up information). If this occurs, the Investigator 
is to discuss with the subject (or legally authorized representatives) appropriate processes for 
discontinuation and the options for procedures that may continue such as collection of data, 
including endpoints and AEs. The Investigator must document the agreement in the procedures 
that the subject will continue with and the level of follow-up that is agreed to by the subject (eg, 


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in person, by telephone/mail, through family/friends, in correspondence/communication with 
other physicians, from review of the medical records.) If a subject voluntarily withdraws from 
the study, the investigator should attempt to contact the subject to determine the reason(s). 
The primary reasons for discontinuation or withdrawal of a subject from protocol-required 
treatment or procedures must be determined using the following categories: 
• Confirmed disease progression by Investigator 
• Death 
• Subject request to end study treatment and/or procedures 
• Withdrawal of consent 
• AE 
• Pregnancy 
• Noncompliance with study drug 
• Lost to follow-up 
• Physician decision 
• Termination of study by Sponsor 
• Any other reason that, in the opinion of the Investigator, would justify removing the 
subject from the study drug, based on the interest of the subject. 
 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
A description of the investigational product/study drug is provided in Table 11.  
Table 11: 
Investigational Product/Study Drug 
 
Investigational Product/Study Drug 
Product Name: 
EZM0414 
Dosage Form: 
Immediate-release Tablet 
Unit Dose 
25 mg or 200 mg 
Route of Administration 
Oral  
Physical Description 
25 mg: White to off-white, round, biconvex, coated 
tablets  
200 mg: White to off-white, capsule-shaped, 
biconvex, coated tablets  
Manufacturer 
Pharmaron Beijing, Co., Ltd. 
9.2. 
Special Situations: Overdose, Misuse, Abuse and Medication Error 
Definitions, reporting, and management of overdose, misuse, abuse, and medication errors are 
presented below and refer to EZM0414. 
• Overdose: An overdose is defined, regardless of any associated AEs or sequelae, as: 
− On a per dose basis, any amount of the orally administered drug(s) that is over the 
protocol-specified dose assigned to a given subject. 
− On a schedule or frequency basis, anything taken more frequently than the 
protocol-required schedule or frequency. 
• Misuse: Intentional and inappropriate use of study drug not in accordance with the 
protocol. 
• Abuse: Sporadic or persistent intentional excessive use of study drug accompanied 
by harmful physical or psychological effects. 
• Medication error: Any unintentional event that causes or leads to inappropriate 
study drug use or subject harm while the study drug is in the control of site personnel 
or the subject. 
These occurrences must be reported on the dosing administration eCRF. Adverse events 
associated with these occurrences are to be captured on the AE eCRF.  
All instances of special situations are to be reported using the special situations form regardless 
of presence or absence of an associated AE. Refer to Section 13.6 for detailed instructions on 
how to handle the reporting of special situations.  


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In the event of a special situation, the Investigator should immediately contact the Sponsor’s or 
Designee Medical Monitor or their designee and closely monitor the subject for AEs/SAEs and 
laboratory abnormalities. 
9.3. 
Concomitant Medications 
Unless clinically indicated, subjects should avoid taking additional non-study medications that 
may interfere with study treatments. Any medication or vaccine, including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements that the patient is receiving at the 
time of enrolment or receives during the study must be recorded in the CRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Details of prohibited medications are detailed in Table 12 and Appendix 6. 
Table 12: 
Prohibited Medications 
 
Unless stated otherwise, these medications are prohibited from the time that subjects enter the main 
screening period until the last dose of study treatment. The pre-screen may be done whilst on prior 
therapy. 
Any investigational anti-cancer therapy other than 
those under investigation in this study 
Should not be given concomitantly whilst the 
patient is on study treatment 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, biologic or hormonal therapy, or 
any other novel agent for cancer treatment other 
than those under investigation in this study 
 
Should not be given concomitantly whilst the 
patient is on study treatment. 
Palliative radiotherapy may be used for the 
treatment of pain, provided the Investigator does 
not consider these are indicative of clinical 
progression. Study treatment should 
be discontinued a minimum of 3 days before a 
patient undergoes palliative radiotherapy, and 
study treatment restarted within 4 weeks 
(provided any bone marrow toxicity has 
recovered). 
Herbal medications and supplements 
 
Should not be given concomitantly unless agreed 
by the Sponsor. This is due to their potential to 
modulate CYP3A4 or activity of other enzymes 
which are not well characterized (see also below), 
and further details in Appendix 6. 
Concomitant medications known to significantly 
modulate CYP3A4 activity 
 
The principal enzyme for metabolizing EZM0414 
is CYP3A4/5. Subjects should avoid concomitant 
medications and foods known to significantly 
modulate CYP3A4/5 activity (potent/moderate 
inhibitors or inducers of CYP3A4). The required 
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minimum 14 days or 5 half-lives (whichever is 
longer). See Appendix 6. 
Concomitant medications known to significantly 
modulate P-gp activity 
 
 
EZM0414 is also P-gp substrates. Co-
administration of P-gp inhibitors or inducers may 
affect exposure to EZM0414, and it is 
recommended that these are not co-administered 
with EZM0414. See Appendix 6. 
Concomitant medications known to significantly 
alter gastric pH 
EZM0414 has pH-dependent solubility. The 
EZM0414 has potential interact with gastric pH-
dependent acid-reducing agents, such as antacids, 
histamine H2-receptor antagonists (H2 blockers), 
and proton pump inhibitors (PPIs). 
Live virus and bacterial vaccines 
Prohibited whilst the patient is receiving study 
medication and during the 30-day follow-up 
period. 
Anti-cancer therapy like chemotherapy, 
immunotherapy, hormonal therapy, radiotherapy 
(except palliative), biological therapy, and other 
novel agents 
Not permitted whilst the patient is receiving study 
medication. 
CYP = Cytochrome P450; P-gp = P-glycoprotein 
9.4. 
Treatment Compliance 
Compliance for doses taken outside of the clinic may be assessed by a count of the tablets 
returned to the study trial site and accounted for by the subject diary. 
9.5. 
Randomization and Blinding 
Not applicable.  
 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug Packaging and Labeling 
25 mg: Thirty (30) EZM0414 tablets in individually labelled 45 mL heat sealed HDPE bottles 
with child resistant, tamper-evident polypropylene screw cap, containing a desiccant cartridge. 
200 mg: Thirty (30) EZM0414 tablets in individually labelled 75 mL heat sealed HDPE bottles 
with child resistant, tamper-evident polypropylene screw cap, containing a desiccant cartridge. 
10.2. 
Study Drug Storage 
Do not store above 30°C (86°F), Store in original package. 
10.3. 
Study Drug Preparation 
EZM0414 drug product is formulated as 25 mg and 200 mg immediate-release film-coated 
tablets. 
10.4. 
Administration 
EZM0414 tablets are intended for oral administration only. Study drug tablets should be 
swallowed whole and may not be crushed. EZM0414 will be administered at approximately the 
same time each day and should be taken on an empty stomach with nothing to eat two hours 
prior and one hour after the EZM0414 dose. Water may be consumed at will. 
Missed or vomited dose: If a dose is missed (ie, not within 6 hours of the scheduled dosing time), 
do not take the dose. Resume dose administration at the next scheduled dose. If a subject vomits 
after EZM0414 administration, do not take an additional dose. Resume dose administration at the 
next scheduled dose. 
All doses of study drug administered, missed, and vomited (as applicable) are to be recorded in 
the eCRF. 
10.5. 
Study Drug Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
Investigator until the following documentation has been received by the Sponsor: 
• A signed and dated confidentiality agreement 
• A copy of the final protocol signature page signed and dated by the Investigator 
• Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC/REB for the institution where the study is to 
be conducted 
• A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study 
• A copy of the regulatory authority approval for the country in which the study is 
being conducted (if required) and the import license (if required) 


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• An Investigator-signed and dated Form Food and Drug Administration (FDA) 1572 
(or Investigator ICH GCP Statement for ex-US sites), a signed and dated curriculum 
vitae for the Principal Investigator (PI) including a copy of the PI’s current medical 
license (required in the US) or medical registration number on curriculum vitae 
• Financial disclosure form for the PI listed on Form FDA 1572/Investigator ICH GCP 
Statement 
• A signed and dated clinical trials agreement. 
The Investigator and study staff will be responsible for the accountability of all clinical supplies 
(dispensing, inventory, and record keeping) following the Sponsor’s instructions and adherence 
to GCP guidelines as well as local and regional requirements. 
Under no circumstances will the Investigator allow the study drugs to be used other than as 
directed by this protocol. Clinical supplies will not be dispensed to any individual who is not 
enrolled in the study. An accurate and timely record of the receipt of all clinical supplies, 
dispensing of study drugs to the subject, collection and reconciliation of used and unused 
supplies that are either returned by the subject or shipped to the site but not used, subsequent 
return of unused study drugs to the Sponsor or designated central or local depot, and (where 
applicable) destruction of study drugs at the site must be maintained. This includes but may not 
be limited to: (a) documentation of receipt of clinical supplies, (b) study drugs dispensing/return 
reconciliation log, (c) study drugs accountability log, (d) all shipping service receipts, (e) 
documentation of drug returned to the Sponsor, and (f) certificates of destruction for any 
destruction that occurs at site. All forms will be provided by the Sponsor. Any comparable forms 
that the investigational site wishes to use must be approved by the Sponsor. 
The supplies and inventory records must be made available, upon request, for inspection by the 
designated representative of the Sponsor or a representative of any national health authority. All 
used and unused study drugs provided by the Sponsor, including empty containers, are to be 
returned to the Investigator by the subject then potentially to the Sponsor’s designated contractor 
or depot by the conclusion of the study, unless approval is given by the Sponsor for destruction 
of supplies and containers at the investigational site. Upon completion of drug accountability and 
reconciliation procedures by investigational site personnel and documentation procedures by the 
Sponsor’s personnel, study drugs that are to be returned to the Sponsor’s approved contract 
vendor must be boxed and sealed and shipped back to the Sponsor’s approved contract vendor 
following all local regulatory requirements. 
Study drug accountability will be reviewed during investigational site visits and at the 
completion of the study. 
10.6. 
Study Drug Handling and Disposal 
Study drugs will be stored in accordance with the labeled storage conditions. Refer to the 
pharmacy manual for details.  
All study drug will be supplied to the PI (or a designated pharmacist) by the Sponsor except in 
the US. Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored 
according to the conditions specified on the drug label. The Investigator (or a designated 
pharmacist) must maintain an accurate record of the shipment and dispensing of the study drug 


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in a drug accountability log, a copy of which must be given to the Sponsor at the end of the 
study. An accurate record of the date and amount of study drug dispensed to each subject must 
be available for inspection at any time. Once study drug has been received by the investigational 
site, the assigned clinical research associate will review these documents along with all other 
study conduct documents at appropriate intervals during investigational site visits. 
All drug supplies are to be used only for this study and not for any other purpose. The 
Investigator (or a designated pharmacist) must not destroy any drug labels or any partly used or 
unused drug supply before approval to do so by the Sponsor. At the conclusion of the study, and 
as appropriate during the course of the study, the Investigator (or a designated pharmacist) will 
either return all used and unused drug containers, drug labels, and a copy of the completed drug 
disposition form to the Sponsor’s designated contractor, or where approval is given by the 
Sponsor, destroy supplies and containers at the investigational site. 


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11. 
PHARMACOKINETIC ASSESSMENTS 
Blood samples (4 mL) will be obtained for the determination of EZM0414 concentration 
according to the schedule of assessments presented in Table 8, Table 9, and Table 10. The date 
and time of collection of each sample will be recorded. 
The timing of the PK samples may be adjusted during the study, dependent on emerging data, in 
order to ensure appropriate characterization of the plasma concentration-time profiles. The 
timing of later PK samples will be reassessed based on emerging PK data and the desire to 
characterize 80% of the AUC in all subjects. The total number of samples and the total volume 
of blood taken from each patient will not exceed than that of planned collection. 
If a patient misses any doses of EZM0414 within 3 days of PK sampling, please contact the 
Epizyme PK representative as to any effect on the changes required on the timing of the PK 
assessments. All other assessments, including laboratory safety assessments, vital signs and 
radiologic assessments should continue to be performed as per study plan, relative to baseline 
assessments. Samples will be collected, labelled, stored, and shipped as detailed in the 
Laboratory Manual. Any residual sample remaining after PK analysis has been performed may 
be used for exploratory biomarker research and characterization of metabolites, if consent for 
this exploratory research has been obtained. 
In dose escalation, a screening visit will occur within 28 days of signing an ICF. Subjects will 
visit the clinical study unit on an out-patient basis from day 1 to day 4, day 8, day 15 and day 22 
in cycle 1. Prior to dosing on cycle 1 day 1, subject eligibility will be reconfirmed. A single oral 
dose of EZM0414 will be administered on day 1. Blood samples for PK analysis will be obtained 
predose (0 hour), 0.5, 1, 1.5, 3, 6, 10, 24, 48 and 72 hours postdose. The subjects will not be 
dosed on cycle 1 day 2 and cycle 1 day 3. After the 72-hour PK sample collection conducted on 
day 4 and the subjects will receive EZM0414 tablets to be taken once daily from day 4 to day 28. 
Subjects will return to the clinical study unit on an out-patient basis on day 8, day 15, and day 22 
for safety monitoring and PK blood sample on cycle 1 day 15. On day 29, subjects will return to 
out-patient clinic for Cycle 2 Day 1 safety assessment and in clinic administration of EZM0414. 
Blood samples for PK analysis will be obtained predose (0 hour), 0.5, 1, 1.5, 3, 6, 10 and 24-
hours postdose. 24-hour post PK sample will be collected prior to cycle 2 day 2 dose of 
EZM0414. Vital signs and ECGs will be collected as indicated in Table 9. Subjects will dose 
with EZM0414 once daily after Cycle 2 Day 1 (Table 8). 
In dose expansion, a screening visit will occur within 28 days before day 1 and after signing an 
informed consent form (ICF). Subjects will visit the clinical study unit on an out-patient basis 
from day 1 to day 2, day 8, day 15, and day 22 in cycle 1. Prior to dosing on cycle 1 day 1, 
subject eligibility will be reconfirmed. A single oral dose of EZM0414 will be administered on 
day 1. Blood samples for PK analysis will be obtained predose (0 hour), 0.5, 1, 1.5, 3, 6, 10, and 
24 hours postdose. After the 24-hour PK sample collection conducted on cycle 1 day 2, subjects 
will receive EZM0414 tablets to be taken once daily from day 2 to day 28. Subjects will return to 
the clinical study unit on an out-patient basis on day 8, day 15, and day 22 for safety monitoring. 
On day 29, subjects will return to out-patient clinic for Cycle 2 Day 1 safety assessment and in 
clinic administration of EZM0414. Blood samples for PK analysis will be obtained predose (0 
hour), 0.5, 1, 1.5, 3, 6, 10 and 24 hours postdose. 24-hour post PK sample will be collected prior 


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to cycle 2 day 2 dose of EZM0414. Vital signs and ECGs will be collected as indicated in 
Table 10. Subjects will dose with EZM0414 once daily after Cycle 2 Day 1 (Table 8). 
11.1. 
PK Window for Specific PK Timepoints 
Unless a specific range is specified, a 5-minute window will be allowed for samples taken up to 
1-hour post-dose; a 10 minute window for samples taken between 2-9 hours; a 1 hour window 
for samples taken between 10-24 hours post-dose, and a 2 hour window between 25-72 hours. 
11.2. 
Determination of Drug Concentration in PK Samples 
Samples for determination of EZM0414 concentrations in plasma will be analyzed by Charles 
River Laboratories, Inc., on behalf of Epizyme, using appropriate bioanalytical methods. Full 
details of the analytical methods used will be described in a separate bioanalytical report. All 
samples still within the known stability of the analytes of interest (ie, EZM0414) at the time of 
receipt by the bioanalytical laboratory will be analyzed. 
In addition, the PK samples may be subjected to further analyses in order to investigate the 
presence and/or identity of drug metabolites. Any results from such analyses will be reported 
separately from the Clinical Study Report (CSR). 
11.3. 
Storage and Destruction of Pharmacokinetic Samples 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 6 
months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling. 
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be reported 
separately from the CSR. 
 


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12. 
TRANSLATIONAL RESEARCH SAMPLES 
12.1. 
Tumor Sampling 
12.1.1. 
Archival Tumor, Tumor Biopsy and Bone Marrow Aspirates 
Multiple myeloma subjects will undergo a bone marrow biopsy and bone marrow aspirate at 
screening or Cycle 1 Day 1. All MM subjects will undergo an on-treatment bone marrow biopsy 
and bone marrow aspirates at Cycle 3 Day 1 and at VGPR. A non-mandatory bone marrow 
biopsy and bone marrow aspirates can be taken at progression. If a SOC bone marrow will be 
performed, a bone marrow aspiration will be requested for research as well. 
For subjects with DLBCL, unstained slides containing tumor tissue are required (>90% tumor 
cellularity and min. 5x5mm of tumor area). The archival tissue should not be older than 6 months 
prior to study enrollment. For subjects without sufficient archival tissue, an optional fresh biopsy 
is recommended at screening or Cycle 1 day 1 (pre-dose). DLBCL subjects can undergo an 
optional on-treatment biopsy at Cycle 3 Day 1. Subjects can also have an optional biopsy at PR 
and at progression. Tumor biopsies should be taken from the same lesion (non-target lesion). 
A non-mandatory tumor biopsy for R/R DLBCL subjects can be taken at progression. A bone 
marrow biopsy and non-mandatory bone marrow aspirations for R/R MM subjects can be taken 
at progression. 
No biopsies, bone marrow aspirates or blood samples can be taken under this study for research 
under another IRB protocol (eg, institutional IRB protocol of the site to take research samples).  
12.1.2. 
Blood Samples 
Subjects will have pre-dose blood draws at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 
3 Day 1 and after that day 1 of every other cycle until Cycle 26 and then day 1 of every 4 cycles 
after Cycle 26, at progression, and at any response event. The blood samples will be processed 
for plasma and PBMC and/or buffy coat. We expect that circulating tumor cells (CTC) will be 
collected/within in the PBMC fraction. 
12.2. 
Sample Analysis 
For R/R MM subjects central confirmatory testing will be performed for t(4;14) but for study 
entry, local testing will be accepted. The t(4;14) translocation will be assessed at different time 
points (eg, baseline, on-treatment). Our preclinical data indicated an increased activity in t(4;14) 
(Section 5.2.3). Therefore changes (decrease, increase) in the t(4;14) cell clone population during 
the disease course in heavily pretreated R/R MM subjects (most likely genomically very 
complex) will be assessed.  
SETD2 catalyzed the tri-methylation of H3K36 using di-methylated H3K36 as a substrate. It is 
expected that EZM0414 will inhibit this process and therefore a decrease in tri-methylated 
H3K36 (H3K36me3) levels. Hence, the assessment of H3K36me3 is the key pharmacodynamic 
(PD) marker in this study and will be assessed in the tumor tissue/tumor cell and/or blood (eg, 
PBMCs, plasma). Tumor tissue/tumor cells will be investigated for somatic mutations such as 
SETD2, MMSET and others that might be of interest. To assess target engagement, expression 
of H3K36me3 and additional histone and histone methylation markers will be assessed in tumor 


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tissue/tumor cells as well as in blood (eg, PBMCs, plasma). The relationship between the PD 
marker H3K36me3 and plasma PK will be of special interest in this study. 
It is described that SETD2 and MMSET can harbor gene mutations and/or CNV. Therefore, 
somatic mutations that will occur in these 2 genes will be assess in our cohort and correlated 
with the outcome. Certain mutations could impact responsiveness to EZM0414 such as certain 
SETD2 truncating mutations (no SET domain) or activating MMSET(NDS2) mutations. 
Therefore, mutation and CNV analysis will be performed in tumor tissue/tumor cells and/or 
blood (eg, CTC in the PBMC fraction). 
Additional analysis to assess protein and/or RNA expression might be performed on tumor 
tissue/tumor cells, the tumor microenvironment, PBMCs, buffy coat or from the plasma to better 
understand mechanism of action, tumor changes, and responsiveness. More extended DNA and 
other analysis might follow (eg, methylation, mutations, CNV, clonal analysis, and others) for 
the same reason. 
12.3. 
Future Use of Research Samples 
Not all of the tissue, bone marrow aspirates and blood components obtained during this study 
may be required for the tests that are part of the clinical trial. Following the conclusion of the 
study, the samples may be used for additional research. These samples will be held for a 
maximum of 15 years. This research will help to understand disease subtypes, drug response and 
toxicity, and possibly identify new drug targets or biomarkers that predict subject response to 
treatment. The use of the samples for internal research will be done according to the guidelines 
defined by the FDA guidance for In Vitro Diagnostic Device Studies Using Leftover Human 
Specimens that are Not Individual Identifiable (issued 25 April 2006) and the European 
Medicines Agency (EMA) Reflection Paper on Pharmacogenetic Samples, Testing and Data 
Handling (EMA/CHMP/PGxWP/201914/2006). If a subject requests destruction of their tissue 
and blood samples and the samples have not yet been de-identified, the Sponsor will destroy the 
samples as described in this FDA guidance. The Sponsor will notify the Investigator in writing 
that the samples have been destroyed. The Sponsor reserves the right to destroy the biosamples 
for any reason during the storage period without further notice. Selected de-identified trial and 
sample data will be uploaded to Epizyme’s sample tracking system. 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
Unless stated otherwise, all assessments should be performed, and results reviewed before 
administration of EZM0414 to start a new cycle. 
13.1.1. 
Demographic/Medical History 
Demographic information will be collected at the Screening Visit. Standard demography 
parameters will include age, gender, and race/ethnicity (recorded in accordance with prevailing 
regulations). The screening visit will occur within 28 days prior to the first dose of study drug to 
confirm that the subjects meet the selection criteria for the study. The assessments to be 
conducted at screening are provided in Table 8 (Schedule of Assessments for Dose Escalation 
and Dose Expansion). Medical and surgical histories will be obtained at the Screening Visit, 
along with a record of prior concomitant medications and/or procedures. Significant findings 
before the start of study drug will be recorded on the Medical History and Current Medical 
Conditions eCRF. A standard of-care clinical examination for MM and lymphoma, including 
assessment of B symptoms, will also be performed at the screening visit and at all disease 
assessments. 
13.1.2. 
Prior and Concomitant Medications 
Prior and concomitant medications include all prescription and nonprescription medications, 
vitamins, herbals (including medical marijuana), and transfusions. 
All prior medications (including over-the-counter medications) administered 30 days before the 
first dose of study drug will be recorded. Any concomitant therapy administered to the subject 
during the course of the study (starting at the date of informed consent) until 30 days after the 
final dose of study drug will be recorded. Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded. 
13.1.3. 
Vital Signs 
Vital signs will be performed after the subject is seated for 5 minutes and will include the 
following: 
• Blood pressure 
• Respiration rate 
• Heart rate 
• Temperature 
Vitals signs will be collected at screening. Serial vital signs will be collected at pre-dose, 30 
minutes, 60 minutes, 2 hours, 4 hours, and 6 hours post oral dose of EZM0414 on Cycle 1 Day 1 
(Table 9 and Table 10); pre-dose, 30 minutes, 60 minutes, 2 hours, 4 hours, and 6 hours post oral 
dose of EZM0414 on Cycle 2 Day 1. One set of vital signs will be collected at day 1 of each 
cycle, at end of treatment and at follow-up visit (Table 8). Vital signs will be documented in 
source documents and captured in the relevant eCRF. Any clinically significant changes noted by 


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the Investigator should be reported as an AE. Timing window allowances can be found in 
respective tables for serial and one-time vitals. 
At time points where vital signs, ECG and PK blood samples are required, the following order of 
collection is recommended 1) vital signs, 2) ECG and 3) PK blood sample. 
13.1.4. 
Weight and Height 
Height measurement is required at screening only. 
Body weight will be measured at screening, Cycle 1 Day 1, day 1 of each new cycle, at the end 
of study treatment and at follow-up (Table 8). 
13.1.5. 
Eastern Cooperative Oncology Group Performance Status 
An ECOG performance status assessment will be completed at the visits designated in the Study 
Design and Schedule of Assessments (Table 8). The ECOG performance scale will be used 
(Appendix 3). 
13.1.6. 
Physical Examination 
A complete physical examination is required at screening, on Cycle 1 Day 1, end of treatment, 
and at safety follow-up. A symptom-directed physical examination is required at Cycle 1 Day 8, 
Cycle 1 Day 15, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 3 Day 
15, Cycle 4 Day 1, Cycle 4 Day 15, day 1 of each new cycle thereafter.  
A complete physical examination of all body systems must be performed at screening by a 
qualified licensed individual. A review of body systems will include the following: 
• General appearance 
• Skin 
• Head, Ears, Eyes, Nose, Throat (HEENT) 
• Respiratory 
• Cardiovascular 
• Abdomen (including liver and kidneys) 
• Neurological examination with sensory testing and seizure status, if applicable 
• Musculoskeletal 
Any abnormalities or changes in intensity noted during the review of body systems should be 
documented in the source document and reported appropriately in the eCRF. If a new clinically 
significant finding (eg, not noted at screening) occurs from the initial EZM0414 administration 
until the end of the study, an AE must be documented. In addition, resolution of any abnormal 
findings during the study will be noted in source document and the eCRF if clinically significant. 
These assessments will be completed as indicated in the Schedule of Assessments in Table 8. 
It is unknown if EZM0414 will react with exposure to sunlight. Subjects should be advised to 
take measures to avoid UV exposure including tanning beds. Use sunscreen, protective clothing, 
and sunglasses whenever outside. 


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13.1.7. 
Electrocardiogram (ECG) 
Single ECG will be collected at screening. Subjects should be seated resting for 10 minutes prior 
to collection of all study ECGs. 
Triplicate ECGs one-minute apart will be collected at pre-dose, 30 minutes, 60 minutes, 2 hours, 
4 hours, and 6 hours post oral dose of EZM0414 on Cycle 1 Day 1, 24 hours post oral dose on 
Cycle 1 Day 2. On Cycle 2 Day 1 pre-dose, 30 minutes, 60 minutes, 2 hours, 4 hours, and 6 
hours post oral dose of EZM0414, and 24 hours post oral dose on Cycle 2 Day 2. Triplicate 
ECGs will be collected pre-dose and 2 hours post on Day 1 of every odd cycle starting at Cycle 3 
Day 1, and at end of treatment visit (Table 8). Machine read ECGs should be reviewed by the 
Investigator within 24 hours. ECGs will be read by a Central Reader within 72 business hours. 
At time points where vital signs, ECG and PK blood samples are required, the following order of 
collection is recommended 1) vital signs, 2) ECG and 3) PK blood sample. 
13.1.8. 
Laboratory Assessments 
Safety laboratory testing at screening and during study will be performed at local labs according 
to institutional procedures. Reference ranges will be supplied by the laboratory and used to 
assess the laboratory data for clinical significance and out of range pathological changes. 
Abnormal laboratory values which are unexpected or not explained by the subject’s clinical 
condition should be repeated until confirmed, explained, or resolved. Laboratory value changes 
starting from the initial EZM0414 exposure will be recorded in the eCRF as an AE if clinically 
significant per investigator.  
Specific clinical laboratory tests for hematology including coagulation profile, serum 
chemistries, urinalysis, and viral serology are detailed in Appendix 7. 
13.1.8.1. Hematology 
Hematology tests will be performed during screening, Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 
Day 15, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 3 
Day 15, Cycle 4 Day 1, Cycle 4 Day 15, and day 1 of each new cycle thereafter, at the end of 
study, and at follow-up (Table 8).  
13.1.8.2. Blood Chemistry 
Blood chemistry tests will be performed during screening, Cycle 1 Day 1, Cycle 1 Day 8, Cycle 
1 Day 15, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 
3 Day 15, Cycle 4 Day 1, Cycle 4 Day 15, and day 1 of each new cycle thereafter, at the end of 
study, and at follow-up (Table 8).  
13.1.8.3. Coagulation Test 
Coagulation test will be performed during screening, Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 
15, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 3 Day 
15, Cycle 4 Day 1, Cycle 4 Day 15, and day 1 of each new cycle thereafter, at the end of study, 
and at follow-up (Table 8).  


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13.1.8.4. Urinalysis 
Urinalysis will be performed during screening, Cycle 1 Day 1, day 1 of each new cycle 
thereafter, at the end of study, and at follow-up (Table 8).  
13.1.8.5. Creatinine Clearance 
Creatinine clearance will be calculated by Cockcroft-Gault formula (Appendix 8) and must be 
≥40 ml/min at enrollment. 
13.1.8.6. Virus Serology 
Viral serology testing, if indicated per eligibility criteria, will be performed at screening for 
HBV, HCV, HIV, and human T-cell lymphotropic virus 1 (HTLV-1). 
13.1.8.7. Pregnancy Screen 
In women of childbearing potential, a serum pregnancy test is required at screening and 
serum/urine pregnancy test at time points indicated in Table 8. Cycle 1 Day 1 pregnancy test 
does not need to be repeated if screening test is performed within 72 hours of Cycle 1 Day 1. 
13.1.8.7.1. Definition of Childbearing Potential: Female Subjects 
A female subject is considered of childbearing potential if she: 
• Is anatomically and physiologically capable of becoming pregnant, and 
• Will be or could possibly be sexually active with a male while undergoing study 
treatment. 
A female subject is considered to be of non-childbearing potential (ie, physiologically incapable 
of becoming pregnant) if she: 
• Is naturally postmenopausal (at least 12 months consecutively amenorrhoeic 
[amenorrhea following cancer therapy does not rule out childbearing potential] and 
without other known or suspected cause) 
• Is surgically sterilized (ie, bilateral tubal ligation, total hysterectomy, and/or bilateral 
oophorectomy) with surgery completed at least 1 month before the first dose of study 
drug 
• Has a documented congenital or acquired disorder that is incompatible with 
pregnancy. 
13.1.8.7.2. Definition of Childbearing Potential: Male Subjects 
A male subject is considered of childbearing potential if he: 
• Is anatomically and physiologically capable of causing a pregnancy in a female 
partner, AND 
• Will be or could possibly be sexually active with a female (who is or may become 
pregnant) while undergoing study treatment. 
A male subject is considered to be of non-childbearing potential if he: 


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• Has a documented successful vasectomy (with medically confirmed azoospermia). 
However, even with a successful vasectomy, male subjects must either practice 
complete abstinence or agree to use a latex or synthetic condom during sexual contact 
with a pregnant female or FCBP from first dose of study drug, during study treatment 
(including during dose interruptions), and for 30 days after study drug 
discontinuation. 
13.1.8.7.3. Prevention 
Female Subjects 
Females of childbearing potential (FCBP) enrolled must either practice complete abstinence or 
agree to use two reliable methods of contraception simultaneously. This includes ONE highly 
effective method of contraception and ONE additional effective contraceptive method. 
Contraception must begin at least 14 days prior to first dose of study drug, continue during study 
treatment (including during dose interruptions), and for 30 days after study drug discontinuation. 
Female subjects must also refrain from breastfeeding for 30 days following last dose of study 
drug. The following are examples of highly effective and additional effective methods of 
contraception: 
• Examples of highly effective methods: 
− Intrauterine device (IUD) 
− Hormonal (ovulation inhibitory combined [estrogen and progesterone] birth 
control pills or intravaginal/transdermal system, injections, implants, 
levonorgestrel-releasing intrauterine system [IUS], medroxyprogesterone 
acetate depot injections, ovulation inhibitory progesterone-only pills [eg, 
desogestrel]) 
− Partner’s vasectomy (if medically confirmed [azoospermia] and sole sexual 
partner) 
• Examples of additional effective methods: 
− Male latex or synthetic condom 
− Diaphragm 
− Cervical Cap 
If the above contraception methods are not appropriate for the FCBP, she must be referred to a 
qualified contraception provider to determine the medically effective contraception method 
appropriate for the subject. 
Note: Female subjects of childbearing potential exempt from these contraception requirements 
are subjects who practice complete abstinence from heterosexual sexual contact. True abstinence 
is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
Male Subjects 
Male subjects must either practice complete abstinence or agree to use a latex or synthetic 
condom, even with a successful vasectomy (medically confirmed azoospermia), during sexual 


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contact with a pregnant female or FCBP from first dose of study drug, during study treatment 
(including during dose interruptions), and for 30 days after study drug discontinuation. 
Note: Male subjects must not donate semen or sperm from first dose of study drug, during study 
treatment (including during dose interruptions), and for 30 days after study drug discontinuation. 
13.1.8.8. Bone Marrow Assessments 
Bone marrow biopsy and aspirate performed as per institutional practice are to be evaluated 
histologically for plasma cells percentage and monoclonality and determination of other cells in 
the marrow (Table 8). An aspirate is to be evaluated by flowcytometry as per institutional 
guidelines to characterize myeloma cells. These results will be reported on the eCRF.  
13.1.8.9. IgA, IgM, IgG (M-protein Serum, for MM Subjects Only) 
A blood sample will be drawn for protein electrophoresis for quantification of M-protein. 
Subsequent Ig identification will be done by immunofixation (Table 8). 
13.1.8.10. M-protein (24-hour Urine, for MM Subjects Only) 
Twenty hour-hour urine will be collected for urine protein electrophoresis and quantitation of M-
protein (not total protein alone) and for immunofixation (Table 8). 
13.1.8.11. Serum Free Light Chain Ratio (MM Subjects Only) 
A blood sample will be drawn for quantification of free light chain (Table 8). 
13.2. 
Adverse Events 
13.2.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IP, whether or not related to the IP. This includes any newly occurring event or 
previous condition that has increased in severity or frequency after the ICF is signed. 
Worsening of a pretreatment event, after initiation of the study drug, must be recorded as a new 
AE. For example, if a subject experience a mild intermittent dyspepsia prior to dosing of study 
drug, but the dyspepsia becomes severe and/or more frequent after the first dose of study drug, a 
new AE of worsening dyspepsia (with the appropriate date of onset) should be recorded in the 
eCRF. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the subject was screened in the study and progression of underlying disease are not to be 
considered AEs unless the condition deteriorated in an unexpected manner during the study (eg, 
surgery was performed earlier than planned). 
“Lack of efficacy” or “failure of an expected pharmacological action” per se is not to be reported 
as an AE. However, any signs and symptoms and/or clinical sequelae resulting from “lack of 


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efficacy” will be reported as an AE and assessed for seriousness accordingly if it meets the 
definition of an AE. 
Diagnostic and therapeutic procedures must not be reported as AE verbatim terms. However, the 
medical condition for which the procedure was performed must be reported if it meets the 
definition of an AE. 
Elective surgeries or procedures must not be reported as AEs but must be documented on the 
appropriate eCRF page. 
Each AE must be assessed immediately to determine if it meets the definition of serious 
(Section 13.2.2). If an SAE occurs, expedited reporting must follow local and international 
regulations, as appropriate. Refer to Section 13.2.5 (assessment of severity) for additional details. 
13.2.2. 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose meets any of the following: 
• Results in death (regardless of cause, that occurs during participation in the study or 
occurs after participation in the study and is suspected of being a delayed toxicity due 
to administration of study drug) 
• Is life-threatening (an event/reaction in which the subject was at risk of death at the 
time of the event/reaction; it does not refer to an event/reaction which hypothetically 
might have caused death if it were more severe). 
Note: Life-threatening AE or life-threatening suspected adverse reaction: An AE or 
suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death. 
It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
• Requires in-subject hospitalization or prolongation of hospitalization 
• Results in persistent or significant disability or incapacity, or 
Note: the term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent 1 of the outcomes listed in the definition. 
• All SAEs that occur after any subject has been enrolled, before treatment, during 
treatment, or within 30 days following the cessation of treatment, whether or not they 
are related to the study, must be recorded on forms provided by Epizyme, Inc. 


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13.2.3. 
Disease-Related Events 
Events that meet the criteria for an SAE but are thought to be due to the underlying malignancy 
or associated with progression of disease under study should only be reported as SAE if 
untoward.  
Note: Disease progression should not be reported as an SAE term in and of itself. Report the 
SAE term that is untoward in the context of disease progression. 
13.2.4. 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, physical examinations, and vital signs must 
be assessed and those assessed as clinically significant by the treating clinician must be 
documented as an AE. When possible, a clinical diagnosis for the study assessment must be 
provided rather than the abnormal test results alone (eg, urinary tract infection, anemia). In the 
absence of a diagnosis, the abnormal study assessment itself may be listed as the AE (eg, bacteria 
in urine or decreased hemoglobin). 
The abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Worsening, from baseline, concomitant signs or symptoms related to the abnormal 
study assessment 
• Further diagnostic testing or medical/surgical intervention is required 
• A change in the dose of study drug, if study drug is withheld, or discontinued from 
study drug occurs. 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant must be made by the Investigator. 
13.2.5. 
Assessment of Severity 
The Investigator must determine and record the severity of all AEs. Adverse events will be 
graded on a 5-point scale according to CTCAE Version 5.0 (Appendix 5). Investigators will 
collect all CTCAE grades for AEs (for both increasing and decreasing severity). All AEs 
reported using CTCAE classification and graded as 4 or 5 are to be considered SAE. Every effort 
must be made by the Investigator to categorize each AE according to its severity. In the event 
that an AE is not covered by the CTCAE scale, the assessment of severity will be determined by 
using the CTCAE general guidelines presented in Table 13. 


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Table 13: 
Assessment of Severity per Common Terminology Criteria for Adverse 
Events General Guidelines 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
ADL = activities of daily living; AE = adverse event 
a Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADLs refer to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
An AE that is assessed as severe should not be confused with an SAE. Severity is a category 
used for rating the intensity of an event (as in “mild,” “moderate,” or “severe”). Refer to 
Section 13.2.2 for the definition of an SAE. 
All AEs that occur after any subject has been enrolled, before treatment, during treatment, or 
within 30 days following the cessation of treatment, whether or not they are related to the study, 
must be recorded on the appropriate eCRF forms provided by Epizyme, Inc. 
13.2.6. 
Relationship to Study Drug 
A qualified Investigator must make the determination of relationship to EZM0414 for each AE. 
The Investigator should decide whether, in his or her medical judgment there is a reasonable 
possibility that the event may have been caused by EZM0414. 
• The following should be considered when assessing the relationship of an AE to 
study treatment: 
• Temporal relationship of the onset of the event to the first dose of study drug 
• The course of the event, considering especially the effect of discontinuation of study 
treatment or the reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• The presence of risk factors in the study subject known to increase the occurrence of 
the event 
• The presence of non-study treatment-related factors that are known to be associated 
with the occurrence of the event. 


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Investigators must also systematically assess the causal relationship of AEs to the IP using the 
following definitions (the decisive factor being the temporal relationship between the AE and 
administration of the IP): 
• Probable: A causal relationship is clinically/biologically highly plausible, there is a 
plausible time sequence between onset of the AE and administration of the IP, and 
there is a reasonable response on withdrawal. 
• Possible: A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the IP. 
• Unlikely: A causal relationship is improbable, and another documented cause of the 
AE is most plausible. 
• Unrelated: A causal relationship can be definitively excluded, and another 
documented cause of the AE is most plausible. 
13.2.7. 
Test Abnormalities 
13.2.7.1. Laboratory Abnormalities 
The Investigator should decide, based upon the AE criteria and the clinical condition of the 
subject, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. 
A clinical laboratory AE is any laboratory value that is considered clinically significant (CS) by 
the Investigator and has caused a medical intervention or is accompanied by clinical symptoms. 
Laboratory abnormalities that have not required medical intervention should not be recorded as 
AEs and will be captured and reported in the laboratory section of the CSR. If a medical 
intervention occurs, it should be recorded as a treatment with the abnormal laboratory finding as 
the AE (eg, anemia with treatment required and blood transfusion recorded as a procedure, 
hyperglycemia with treatment required and change in insulin dose recorded as concomitant 
medications). 
 If, at the end of the treatment, there are pathological laboratory values which were not present at 
baseline, further laboratory evaluations should be performed until the values return to within 
reference range or until a plausible explanation (ie, concomitant disease) is found. 
13.2.7.2. Other Test Abnormalities 
Other safety assessments (eg, ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline and events in the medical and scientific judgment of the 
Investigator are considered to be clinically significant, are to be recorded as an AE in accordance 
with the definitions provided in Section 13.2.1 and Section 13.2.2 respectively. 
Any other safety assessment that led to an intervention, including permanent discontinuation of 
study treatment, dose reduction, and/or dose interruption/delay should also be recorded as an AE. 
13.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be collected from the time the subject 


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signs the informed consent form until the end of the safety reporting period (or until screen 
failure). The safety reporting period ends at the time of the safety follow-up visit, 30 days after 
the last dose of study drug, or initiation of an investigational agent or anticancer therapy, 
whichever occurs first.  
The AE term should be reported in standard medical terminology when possible. For each AE, 
the Investigator will evaluate and report the onset (date and time), resolution (date and time), 
intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the subject to discontinue the study. 
Subjects who experience death while on treatment or within 30 days of study drug 
discontinuation (‘deaths on study’ hereafter) will have a Grade 5 SAE reported in electronic data 
capture (EDC) system and an SAE form submitted UNLESS the only known cause of death is 
progressive disease. Attempts should be made to specify a cause of death. However, if 
progressive disease or the indication of the study is the only known cause of death, the death is 
not untoward and should be recorded on the Death eCRF as progression of disease is a key 
efficacy criterion.  
All deaths on study, regardless of cause, or if meeting the criteria for a reportable SAE will be 
reported on the Death eCRF. 
Should a pregnancy occur, it must be reported and recorded on Epizyme, Inc.’s pregnancy form. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should reported 
as AEs but recorded as planned procedures within the eCRF. 
13.4. 
Reporting Serious Adverse Events 
All SAEs will be reported within 24 hours of the Investigator becoming aware of the event. The 
Investigator must promptly notify the Sponsor or its designee of all SAEs in order that the legal 
obligations and ethical responsibilities of the Sponsor or its designee are met. 
If an AE is considered serious, the AE page/screen of the eCRF must be completed. 
For each SAE, the Investigator will provide information on severity, start, and stop dates, 
relationship to IP, action taken regarding IP, and outcome. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the IP under clinical investigation. The Sponsor and its 
designee will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. 
Any AE that is both unexpected is at least possible related per investigator and meets the 
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An Investigator who receives an Investigator safety report describing a SUSAR or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements. 
13.5. 
Reporting of Pregnancy 
Pregnancy will not be considered an SAE. However, any pregnancy occurring in a female 
subject, or a female partner of a male subject should be reported to Epizyme. To ensure subject 
safety, each pregnancy must be reported to the Sponsor or its designee within 2 weeks of 
learning of its occurrence using a SET-101 Pregnancy Report Form. A Pregnancy Report Form 
should be completed and submitted by email as is done for SAE. 
The pregnant female subject must be withdrawn from the study treatment.  
Every effort should be made to gather information regarding the pregnancy outcome until 8 
weeks postpartum. It is the responsibility of the Investigator to obtain all pregnancy outcome 
information, and information regarding the health status of the baby. Submit this information to 
the Sponsor or its designee as is done for paper SAE forms. 
Pregnancy complications and elective terminations for medical reasons must be reported as an 
AE and assessed for seriousness per usual. Spontaneous abortions must be reported as SAE 
under “medically significant”. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention after 
the subject has completed the study and considered by the Investigator as possibly related to the 
study treatment, must be promptly reported to the Sponsor. 
The Investigator also must attempt to collect and report to the Sponsor or its designee pregnancy 
information on any female partner of male study subjects who become pregnant while the subject 
is enrolled in the study. 
13.6. 
Reporting of Special Situations 
Report the special situation(s) of overdose, misuse, abuse, and/or medication error (described in 
Section 9.2) using one of the following sets of instructions according to whether the special 
situation occurred without any associated AEs, with an associated AE, or with an associated 
SAE: 
Special situation(s) without associated AE(s): 
• Report to Epizyme using a Special Situations Form following the procedures for 
reporting SAE (Section 13.4).  
Special situation(s) with an associated AE: 
• Enter the event on the AE eCRF and mark the SAE field, “no”. Serious adverse 
events related narrative fields should not be completed. 
• Report to Epizyme using a Special Situations Form following the procedures for 
reporting SAE (Section 13.4).  
 
 


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Special situation(s) with an associated SAE: 
• Complete the AE eCRF per protocol for the associated SAE term ONLY (Special 
situations are not adverse event terms in and of themselves); complete eCRF SAE 
fields. 
• Report to Epizyme using a paper Special Situations Form following the procedures 
for reporting SAE (Section 13.4).  
13.6.1. 
Study Drug Overdose, Misuse, Abuse, or Medication Error without an Adverse 
Event 
Overdose and medication errors with no clinical consequences, need to be reported in the same 
manner. The report must indicate that there was no associated AE with the overdose or 
medication error. 
 


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14. 
STATISTICS 
14.1. 
Study Design and Sample Size Justification 
This study is a first-in-human, 2-part, multi-center, open-label Phase 1/1b safety, tolerability, PK, 
and efficacy study of oral SETD2 inhibitor, EZM0414, in subjects with R/R MM and R/R 
DLBCL. The first part of the study will be Phase 1 dose escalation designed to evaluate safety, 
tolerability, and PK of EZM0414 in subjects with R/R MM and R/R DLBCL. The second part of 
the study is the Phase 1b dose expansion designed to evaluate safety and efficacy at MTD in 
subjects with R/R DLBCL, or R/R MM with or without select genetic translocation. The dose 
expansion part 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.  
Part 1: In the dose escalation Phase 1 part, subjects diagnosed with R/R MM or R/R DLBCL 
will receive EZM0414 as monotherapy orally once daily (QD) in 28-day cycles according to the 
escalation schedule Table 14 below.  
Table 14: 
Total Daily Dose and Respective Dose Level 
Dose Level 
Total Daily Dose (mg) 
-1 
(optional) 
75 
1 
100 
2 
200 
3 
300 
4 
400 
5 
600 
6 
900 
Additional daily dose levels and/or dosing schedules (including BID regimen) may be studied based on clinical and 
pharmacokinetic data obtained during this study. 
Bayesian optimal interval design (Liu, 2015; Yuan, 2016; Zhou, 2017) will be used for this dose 
escalation part. Similar numbers of subjects with R/R MM or R/R DLBCL will be enrolled to 
determine MTD. The target toxicity rate (∅𝑇𝑇) for the MTD is set at 0.25 for both R/R MM and 
R/R DLBCL. The maximum number of subjects for determination of MTD is 9. A total of 6 dose 
levels (𝑗𝑗= 6, ie, starting at100 mg, then 200 mg, 300 mg, 400 mg, 600 mg, and 900 mg) as well 
as an optional step-down dose level of 75 mg will be investigated. We will enroll and treat 
subjects in groups of at least 3, and up to 36 subjects will be enrolled in this dose-escalation part 
of the study in order to evaluate at least 9 subjects for MTD. Dose limiting toxicities are defined 
in Section 7.5.1, and only those DLTs that occur within the first cycle will be used for safety 
assessment. The BOIN design uses the following rules, optimized to minimize the probability of 
incorrect dose assignment, to guide dose escalation/de-escalation: 
• 
if the observed DLT rate at the current dose is ≤ 0.197, escalate the dose to the next higher 
dose level; 
• 
if the observed DLT rate at the current dose is ≥ 0.298, de-escalate the dose to the next 
lower dose level; 


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• 
otherwise, stay at the current dose. 
For the purpose of overdose control, the current dose 𝑗𝑗 and higher levels will be eliminated from 
further examination if Pr(𝑝𝑝𝑗𝑗> 0.25 data) > 0.8 and at least 3 subjects have been treated at the 
current dose level 𝑗𝑗, where 𝑝𝑝𝑗𝑗 is the true DLT rate of dose level 𝑗𝑗, 𝑗𝑗= 1,⋯, 6. This posterior 
probability is evaluated based on the beta-binomial model 𝑦𝑦𝑗𝑗∣𝑝𝑝𝑗𝑗∼binomial(𝑝𝑝𝑗𝑗) with 𝑝𝑝𝑗𝑗∼
uniform(0,1), where 𝑦𝑦𝑗𝑗 is the number of subjects experienced DLT at dose level 𝑗𝑗. When the 
lowest dose is eliminated, stop the trial for safety. The probability cut-off 0.8 is chosen to be 
consistent with the common practice when the target DLT rate ≤1/6, a dose with 2/3 subjects 
experienced DLT is eliminated. The above dose escalation/de-escalation and elimination rule can 
be equivalently presented in Table 15, which will be used to conduct the trial. 
Table 15: 
Dose Escalation/de-escalation Rule for the BOIN Design 
Target 
Toxicity 
Rate 
Pr (pj > target 
toxicity rate | 
data)  
Actions 
The number of evaluable patients at the 
current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
0.25 
0.8 
Escalate if # of DLT ≤ 
0 
0 
0 
0 
0 
1 
1 
1 
1 
De-escalate if # of DLT ≥ 
1 
1 
1 
2 
2 
2 
3 
3 
3 
Eliminate if # of DLT ≥ 
NA NA 
2 
2 
2 
3 
3 
3 
4 
BOIN = Bayesian Optimal Interval Design; DLT = Dose Limiting Toxicity; NA = Not Applicable 
* When none of the actions (ie, escalate, de-escalate, or eliminate) is triggered, stay at the current dose for treating 
the next group of subjects. Note that “# of DLT” is the number of subjects with at least 1 DLT, and “NA” means that 
a dose cannot be eliminated before treating 3 evaluable subjects. 
Maximum tolerated dose will be determined based on isotonic regression as specified in Liu and 
Yuan (2015). When the isotonic estimate of toxicity rate 𝑝𝑝෤j* is closest to pre-set target DLT rate 
(∅𝑇𝑇=0.25 for this study). If there are ties for 𝑝𝑝෤j* the higher dose with 𝑝𝑝෤j* < the target toxicity rate 
will be selected as MTD. Alternatively, the lower dose with 𝑝𝑝෤j* > ∅𝑇𝑇 will be selected. 
Part 2: Bayesian Optimal Phase 2 Design (BOP2) 
Justification for response rates that will be considered futile 
Based on previous publications and scientific review (in the table below), the response rate of 
20-35% for R/R MM and 25-45% for R/R DLBCL has been used in the SET-101 protocol. For 
R/R MM, an objective response rate of 20-35% has been reported for monotherapies 
(Richardson, 2009; Siegel, 2012; Lonial, 2020). For R/R DLBCL, an objective response rate of 
25-45% has been reported for monotherapies (Mondello, 2016; Davids, 2017; Kalakonda, 2020) 
that are not CAR-T or bi-specifics and are not known to cause cytokine release syndromes. 
 
Study 
ORR 
Number of Subjects 
R/R MM 
Carfilzomib 
(Siegel et al 2012) 
23.7% (95% CI, 18.7-29.4) 
257 
Lenalidomide 
(Richardson et al 2009) 
26% (95% CI, 25.7-26.5) 
222 
Belantamab mafodotin 
(Lonial et al, 2020) 
34% (97.5% CI, 23.9-46.0) 
99 


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Study 
ORR 
Number of Subjects 
R/R DLBCL 
Venetoclax 
(Davids et al 2017) 
22% 
41 
Selinexor 
(Kalakonda et al 2020) 
28% (95% CI, 20.7-37.0) 
127 
Lenalidomide 
(Mondello et al 2016) 
37% 
123 
Using meta-analysis with fixed effect model for 3 MM studies, the lower 95% CI is 22.5%. 
Therefore, 20% response rate was selected that will be considered futile. Using meta-analysis 
with fixed effect model for 3 DLBCL studies, the lower 95% CI is 25.6%. Therefore, 25% 
response rate was selected that will be considered futile in this proof of concept Phase 1b dose 
expansion part of the study. 
In the dose expansion part of the study, the following cohorts of subjects will receive EZM0414 
monotherapy at MTD orally once daily (QD) in 28-day cycles: 
• Cohort 1: R/R MM with t(4;14) translocation  
• Cohort 2: R/R MM without t(4;14) translocation 
• Cohort 3: R/R DLBCL 
Subjects treated at MTD in Phase 1 dose escalation part of the study will continue to receive the 
treatment beyond cycle 1 (be rolled over to this dose expansion part) until disease progression, 
occurrence of unacceptable toxicity, or withdrawal of consent, or need for treatment prohibited 
on this study.  
Bayesian optimal phase 2 design (Yuan, 2016; Zhou, 2017) will be applied to the Phase 1b dose 
expansion part to discover efficacy signals. Twenty (20) subjects/cohort are planned to be 
enrolled and 3 looks will be performed when the data of 10, 15 and 20 subjects have been 
available. The cohort will be terminated if deemed futile. 
For R/R MM 
There will be 2 cohorts of R/R MM subjects enrolled in this part of the study. They are with and 
without t(4;14), respectively. Relapsed/refractory MM subjects treated at MTD in the dose 
escalation part will be rolled over to either Cohort-1 R/R MM with t(4;14) or Cohort-2 R/R MM 
without t(4;14) depending on their translocation status. 
For either of these 2 cohorts let 𝑛𝑛𝑀𝑀 denote the interim sample size and 𝑁𝑁𝑀𝑀 denote the maximum 
sample size. Also let 𝑝𝑝𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 denote the objective response rate (ORR) and define the null 
hypothesis. 𝐻𝐻0: 𝑝𝑝𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀≤0.2, under which the treatment is deemed as unacceptable. We will stop 
enrolling subjects and claim that the treatment is futile if 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀> 0.2|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆𝑀𝑀൬𝑛𝑛𝑀𝑀
𝑁𝑁𝑀𝑀
൰
𝛼𝛼𝑀𝑀
 


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where 𝜆𝜆𝑀𝑀=0.84 and 𝛼𝛼𝑀𝑀=1 are design parameters optimized to maximize power under the 
alternative hypothesis 𝐻𝐻1: 𝑝𝑝𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀= 0.35, (ie, the probability of correctly claiming that the 
treatment is acceptable under 𝐻𝐻1), while controlling the type I error rate (ie, the probability of 
incorrectly claiming that the treatment is acceptable under 𝐻𝐻0) at 0.084. This optimization is 
performed assuming a vague prior Beta (0.2, 0.8) for 𝑝𝑝𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀. The above decision rule leads to the 
following stopping boundaries and yields a statistical power of 0.571 under 𝐻𝐻1: 
Table 16: 
Optimized Stopping Boundaries for R/R MM Cohort 
Sample size for interim looks 
Stop if # Response ≤ 
10 
1 
15 
3 
20 
6 
ORR = Objective response rate; R/R = Relapsed/refractory; MM = Multiple myeloma. 
𝐻𝐻0: ORR (Futile)=0.2; 𝐻𝐻1: ORR (Promising)=0.35; Type I Error Rate=0.1 
 
Based on Table 16, futility assessments will be conducted for each R/R MM cohort when 
response assessment data become available (ie, minimum 5 cycles or if all subjects progressed) 
in the first 10 enrolled subjects, and again in the first 15 enrolled subjects. Enrolment will not 
cease during the assessment periods. When the response assessment data are available for the 
total number of 20 subjects, we reject the null hypothesis for the cohort and conclude that the 
treatment is promising (go) if the number of responses is more than 6 (>6); otherwise, we 
conclude that the treatment is futile (no-go). The go/no-go criteria in Table 16 are non-binding. 
For R/R DLBCL  
One cohort of 20 subjects with R/R DLBCL will be enrolled in the dose expansion part of the 
study following BOP2 design. The subjects with R/R DLBCL treated at MTD in the dose 
escalation part of the study will be rolled over to this dose expansion part until disease 
progression, occurrence of unacceptable toxicity or withdrawal of consent occurred.  
Let 𝑛𝑛𝐷𝐷 denote the interim sample size and 𝑁𝑁𝐷𝐷 denote the maximum sample size for this cohort. 
Also let 𝑝𝑝𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 denote the ORR and define the null hypothesis 𝐻𝐻0: 𝑝𝑝𝐷𝐷𝐷𝐷𝐷𝐷𝑓𝑓≤0.25, under which the 
treatment is deemed as futile. We will stop enrolling subjects and claim that the treatment is 
unacceptable if 
𝑃𝑃𝑃𝑃(𝑝𝑝𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷> 0.25|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆𝐷𝐷൬𝑛𝑛𝐷𝐷
𝑁𝑁𝐷𝐷
൰
𝛼𝛼𝐷𝐷
, 
where 𝜆𝜆𝐷𝐷=0.82 and 𝛼𝛼𝐷𝐷=0.51 are design parameters optimized to maximize power under the 
alternative hypothesis 𝐻𝐻1: 𝑝𝑝𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷= 0.4, (ie, the probability of correctly claiming that the 
treatment is acceptable under 𝐻𝐻1), while controlling the type I error rate (ie, the probability of 
incorrectly claiming that the treatment is acceptable under 𝐻𝐻0) at 0.093. This optimization is 
performed assuming a vague prior Beta (0.25, 0.75) for 𝑝𝑝𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷. The above decision rule leads to 
the following stopping boundaries and yields a statistical power of 0.555 under 𝐻𝐻1: 


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Table 17: 
Optimized Stopping Boundaries for R/R DLBCL Cohort 
Sample size for interim looks 
Stop if # Response ≤ 
10 
2 
15 
4 
20 
7 
ORR = Objective response rate; R/R = Relapsed/refractory; DLBCL = diffuse large B cell lymphoma 
𝐻𝐻0: ORR (Futile)=0.25; 𝐻𝐻1: ORR (Promising)=0.4; Type I Error Rate=0.1 
 
Based on Table 17, futility assessments will be conducted when response assessment data 
become available (ie, minimum 5 cycles or if all subjects progressed) in the first 10 enrolled 
subjects, and again in the first 15 enrolled subjects. Enrolment will not cease during the 
assessment periods. When the total number of subjects reaches the maximum sample size of 20, 
we reject the null hypothesis and conclude that the treatment is acceptable (go) if the number of 
responses is more than 7 (>7); otherwise, we conclude that the treatment is unacceptable (no-go). 
The go/no-go criteria in Table 17 are non-binding. 
14.2. 
General Consideration for Statistical Analysis 
This section is a summary of the planned statistical analyses of the most important endpoints 
including safety, PK, primary, and key secondary efficacy endpoints. A statistical analysis plan 
(SAP) will be finalized prior to final database lock. Should the SAP and the protocol be 
inconsistent with respect to any further planned analyses, the language of the SAP is governing. 
In general, the data from Phase 1 dose escalation part and Phase 1b dose expansion part will be 
analyzed separately except the efficacy data from the subjects who receive the study drug at 
MTD in dose escalation part and are rolled over to the dose expansion part. Their efficacy data in 
Phase 1 part will be integrated in Phase 1b efficacy data analysis unless otherwise specified. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated. All tests of interactions will be conducted at a 2-sided alpha level of 0.1, and all 
confidence intervals (CIs) will be given at a 2-sided 95% level, unless otherwise stated. 
14.3. 
Analysis Populations 
Safety Population: Safety analyses will be composed of all subjects who receive at least 1 dose 
of the study drug in Phase 1 (dose escalation part) or Phase 1b (dose expansion part). 
Dose-limiting toxicity (DLT) Evaluable Population: The DLT evaluable population will 
consist of dose escalation dose level subjects in the Safety Population who received at least 80% 
of planned study treatment during cycle 1. 
Intent-to-Treat (ITT) Population (Phase 1b Dose Expansion Portion): The ITT Population is 
defined as all subjects enrolled in corresponding cohorts of Phase 1b part, regardless of their 
adherence with the entry criteria, the treatment they actually received, and subsequent 
withdrawal from treatment or deviation from the protocol. The ITT Population includes the 
subjects who received the study treatment at MTD in Phase 1, dose escalation part and are rolled 
over to the corresponding cohorts of the Phase 1b, dose expansion part. 


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PK Analysis Population: will include all subjects in the Safety Analysis population who have 
sufficient post-dose blood sample collected to allow estimation of the PK parameters. 
14.4. 
Statistical Analysis Groups 
The Safety Population, DLT Population and PK Analysis Population of Phase 1 part (dose 
escalation) of the study will be categorized to 6 dose groups (starting at 100 mg, then 200 mg, 
300 mg, 400 mg, 600 mg, and 900 mg) as well as an optional step-down dose level of 75 mg. In 
addition, 2 summary groups for R/R MM and R/R DLBCL will be created regardless of the dose 
levels and an overall group will also be created including all Phase 1 subjects for DLT and safety 
data analysis. 
Similarly the Safety Population, PK Analysis Population, and ITT Population of Phase 1b 
portion (dose expansion) will be categorized to 3 groups according to the cohorts for relevant 
data analysis. ITT Population will include the subjects who receive EZM0414 at MTD in the 
dose escalation part of the study and are rolled over to the dose expansion part. In addition the 
cohorts of R/R MM with and without t(4;14) will be combined to form a R/R MM group and all 
3 cohorts will be combined to form an overall group for summary statistics presentation. 
14.5. 
Interim Looks During the Phase 1b Dose Expansion Portion of the 
Trial and the Final Analysis 
There will be 2 interim looks in the dose expansion part of the trial when the data from 10 and 15 
subjects of the cohort are available. A final analysis will be conducted when all data collection is 
completed, and database is locked. All ORR data from both the dose escalation part and the dose 
expansion part will be analyzed in this final analysis. 
14.6. 
Safety Analyses 
Safety of EZM0414 including DLT for the Phase 1 dose escalation part and all safety events data 
in both Phase 1 and Phase 1b dose expansion part. 
DLT evaluation will be performed based on the DLT Population (Section 14.3) and the other 
safety analysis will be conducted on the Safety Population.  
In general safety parameters will be summarized by the analysis group (see Section 14.4) 
according to the different phases of the trial. These parameters will consist of the incidence of 
deaths, adverse events, serious adverse events (SAE), adverse events leading to discontinuation, 
adverse events leading to dose modification, ECOG, ECGs, physical examination, vital signs, 
and specific laboratory abnormalities (worst grade). 
14.6.1. 
DLT Evaluation and MTD Determination 
Dose limiting toxicities occurred in the first cycle of the study treatment in the dose escalation 
part will be specifically reported by the dose level group (see Section 14.4) on DLT Population. 
A listing will be generated presenting the detailed information including the sequential order of 
these DLTs. The DLTs that lead to the determination if the dose levels starting at 100 mg, then 
200 mg, 300 mg, 400 mg, 600 mg, and 900 mg QD as well as an optional step-down dose level 
of 75 mg QD are safe and tolerable, as well as the determination of MTD for the Dose Expansion 
part will be evaluated and described in the CSR (not included in any statistical analysis output).  


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14.6.2. 
Adverse Events 
Treatment-emergent adverse events (TEAE) is defined as AEs that started or worsened in 
severity on or after the date of the first dose of the study drug through 30 days after the end of 
treatment. 
The reported AE term will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version in effect at the time of the database lock. The severity of each AE and 
abnormal laboratory tests will be graded by the site investigator based on version 5.0 of the NCI 
CTCAE. If a severity grading scale does not exist for an AE, the investigator will classify the 
severity as mild, moderate, severe, life-threatening/debilitating, or fatal based on the criteria 
described in the study protocol. The causal relationship between the occurrence of an AE and 
study drug will be judged by the investigator as “probable”, “possible”, “unlikely”, or 
“unrelated”. 
Incidence of TEAEs will be summarized for all analysis groups (see Section 14.4) in dose 
escalation part and cohort groups in dose expansion part, and by MedDRA system organ class 
(SOC) and preferred term (PT) within each SOC. Overall incidence will also be presented for 
each part. TEAEs will also be summarized by severity, and by relationship to study intervention. 
If a subject experience repeat episodes of the same AE (as defined by the MedDRA SOC and 
PT), then the event with the highest reported severity grade and the strongest causal relationship 
(“related”) to study drug will be used for purposes of the incidence tabulations. 
All AEs including TEAEs will be presented in study phase specific listings (Phase 1 dose 
escalation part and Phase 1b dose expansion part). 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each group (the analysis groups in dose 
escalation part or cohort groups in dose expansion part). Subject data listings of all AEs leading 
to discontinuation from study drug will also be provided for the phases. 
Serious adverse events will be summarized as for TEAE, ie, by the analysis group, SOC and PT, 
and by severity and relationship to the study drug. All SAEs will also be presented in listings. 
14.6.3. 
Deaths 
Deaths will be summarized by phase (Phase 1, dose escalation portion or Phase 1b, dose 
expansion portion) and group (see group definitions in Section 14.4) as follows:  
• Summary of subjects who died during treatment and till 30 days after last dose of 
study drug  
• Summary of subjects who died during treatment and till 30 days after last dose of 
study drug with treatment-related TEAEs  
• Summary of subjects who died after 30 days after the last dose of study drug with 
treatment-related AEs.  
Listings will be created to present detailed death related information including date, cause of the 
death and AE/TEAE related to the death, etc. 


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14.6.4. 
Laboratory Abnormalities 
Abnormal clinical laboratory values will be noted as either high or low based on the normal 
ranges for each laboratory parameter. Changes from pre-treatment in laboratory parameters will 
be summarized. 
14.6.5. 
Other Safety Assessments 
Listings of ECOG, ECG and vital signs data will be created with change from baseline 
presented. 
14.7. 
PK Data Analysis 
PK data Analysis will use the PK Analysis Population. At minimum, the following PK 
parameters will be determined for EZM0414 based on the available blood samples collected 
during the dose escalation and dose expansion portions: 
• Maximum plasma concentration (Cmax) 
• Time to Cmax (Tmax) 
• Terminal elimination half-life (T½) 
• AUC0-t  
• Area under the concentration-time curve from time zero to 24 hours post-dose (AUC0-
24) 
• Area under the concentration-time curve from time zero to 24 hours post-dose (AUC0-
last) 
• Apparent volume of distribution during the terminal (λz) phase (Vz/F) 
• Maximum observed concentration normalized to the dose (Cmax/D) 
• AUC0-24 normalized to the dose (AUC0-24/D) 
• AUClast normalized to the dose (AUClast/D) 
• Kel: elimination rate constant 
• λz  
Individual plasma concentrations and concentration-time data will be presented and summarized 
both graphically and in tabular format with descriptive statistics (n, arithmetic mean, standard 
deviation [SD], percent coefficient of variation [CV%], median, minimum, and maximum) 
according to nominal (protocol-specified) sampling times. Pharmacokinetics parameters will be 
calculated using noncompartmental analysis, based on actual elapsed time from dosing to each 
post-dose time point. Pharmacokinetics parameters will be summarized by the analysis group 
(see Section 14.4) using descriptive statistics (n, arithmetic mean, SD, CV%, median, minimum, 
maximum, and geometric mean if applicable). Individual patient level data listings of all PK 
parameters will be prepared.  


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14.8. 
Investigation of PK/PD Relationship 
Where possible, modelling and simulation methods may be used as part of the evaluation to 
assess relationships between emerging safety, tolerability, PK and PD and covariates data. 
Clinical pharmacology department will be responsible for these analyses and, if conducted, will 
be reported separately from the CSR. 
14.9. 
Efficacy Analyses 
All efficacy data analyses, unless otherwise specified, will be performed on the ITT Population. 
The ITT Population is composed of the subjects who had received EZM0414 at MTD in the dose 
escalation part and rolled over to the dose expansion part, and the subjects enrolled in the Phase 
1b dose expansion part of the study. 
No multiplicity adjustment will be made. 
14.9.1. 
Primary Efficacy Analyses 
 The primary efficacy endpoint for this study is ORR, defined as the proportion of responders  in 
subjects with R/R MM (CR + sCR + PR + VGPR) and (CR+PR) in subjects with R/R DLBCL. 
The response will be determined based on IMWG 2016 Guidelines for R/R MM and on Lugano 
2014 Guidelines for R/R DLBCL. 
Objective response rate and the associated 95% confidence intervals (CI) will be calculated for 
each dose expansion cohort.  
14.9.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints for this study include progression free survival (PFS), disease 
control rate (DCR), and duration of response (DOR). All of these secondary efficacy analyses 
will also be performed on the ITT Population. 
14.9.2.1. Progression Free Survival  
PFS is defined as the time from the date of the first dose of the study drug administration to the 
first observation of documented disease progression or death, whichever occurs first. 
PFS will be summarized descriptively using the Kaplan-Meier (KM) method. The KM estimate 
along with the corresponding 95% CI will be computed using the Brookmeyer and Crowley 
method and the median will be provided. The event-free rate with corresponding 95% CI will be 
calculated using Greenwood’s formula and will be provided at 6, 12, 18, and 24 months. Median 
follow-up for PFS will be estimated according to the KM estimate of potential follow-up.  
KM curves will also be provided. In cases where PD or death has not been reached, censoring 
rules will be applied, detailed censoring rules will be pre-specified in the SAP. 
14.9.2.2. Disease Control Rate  
Disease control rate (DCR) in this study is 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 


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subjects who receive EZM0414 at MTD in the dose scalation part and are rolled over to the dose 
expansion part). DCR will be calculated and summarized by cohort. The associated 95% 
confidence intervals (CI) for each cohort will be tabulated. 
14.9.2.3. Duration of Response 
Duration of response (DOR) is defined as the time from initial response to documented 
progression or death, whichever comes first, as assessed by Investigator per IMWG 2016 
guidelines for MM or Lugano 2014 guidelines for DLBCL. 
 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
As described in the ICH GCP Guidelines (ICH E6 Section 8.3), ‘essential documents’, including 
eCRFs, source documents, consent forms, laboratory test results, and the IP inventory records 
must be maintained by the Investigator. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with the US Code 
of Federal Regulations (CFR), 21 CFR 312.68, or other local regulatory authorities in accordance 
with regulatory requirements. 
15.1. 
Study Site Monitoring Visits 
Before an investigational site can enter a patient into the study, a representative of Epizyme, Inc. 
will visit the investigational study site to: 
• Determine the adequacy of the facilities. 
• Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Epizyme, Inc. or its representatives. 
This will be documented in a Clinical Study Agreement between Epizyme, Inc. and 
the investigator. 
During the study, a monitor(s) from Epizyme, Inc. or representative will have regular contacts 
with the investigational site and staff, for the following to occur: 
• Ensure that each patient has been properly consented by reading and reviewing the 
Inform Consent Form (ICF) with them. The patient is to ask the Investigator or Nurse 
any questions to ensure the appropriate understanding and risks of participation in the 
study. Take the ICF home to discuss with family. Once this is done, document this 
process in the source documents accordingly. 
• Regular contact visits: on site or virtual (depending on COVID-19 restrictions) will 
be between every 4-6 weeks as deemed appropriate, based on the workload and 
patient number enrolled in the study at each site. 
• Provide information and support to the investigator(s) and participating site team. 
They will make themselves available to meet with the Site Monitor at each scheduled 
visit. 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is ensuring patient safety is paramount, each 
patient is properly consented, and properly documented in the source documents, 
adhering to the protocol, that data are being accurately recorded in the case report 
forms, and that investigational product accountability checks are being performed 
regularly. 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records for 
each patient (eg, clinic charts) at each scheduled visit. The site will enter the patient’s 


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data regularly and on time as deemed appropriate in the corresponding Monitoring 
Plan. 
• Record and report any protocol deviations/violations not previously sent to Epizyme, 
Inc. 
• Confirm Adverse Events (AEs) and Serious Adverse Events (SAEs) have been 
properly documented on Case Report Forms (CRFs) and confirm any SAEs have 
been forwarded to Epizyme, Inc. and those SAEs that met criteria for reporting have 
been forwarded to the IRB and followed until resolved. 
• The monitor will ensure all queries are resolved in a timely manner and look to 
identify any trends that require resolution. 
• The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
15.2. 
Protocol Compliance 
The Investigator must conduct the study in compliance with the protocol provided by the 
Sponsor and given approval/favorable opinion by the IRB/IEC/research ethics board (REB) and 
the appropriate regulatory authorities. Modifications to the protocol must not be made without 
required written agreement between the Investigator and the Sponsor. Changes to the protocol 
will require written IRB/IEC/REB and the appropriate regulatory authority(ies) 
approval/favorable opinion prior to implementation, except when the modification to eliminate 
an immediate hazard(s) to the subject. The IRB/IEC/REB may provide, if applicable regulatory 
authority(ies) permit, expedited review, and approval/favorable opinion for minor changes 
during study that have the approval/favorable opinion of the IRB/IEC/REB. The Sponsor must 
ensure that all protocol modifications are submitted to the regulatory authority(ies) in accordance 
with the governing regulations. 
If other unexpected circumstances arise that require deviation from protocol-specified procedures 
the Investigator must consult with the Sponsor (and IRB, IEC, or REB, as required) to determine 
the appropriate course of action. 
The site must document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site must notify the Sponsor or its designee (and IRB, IEC, or REB, 
as required). Significant deviations include, but not limited to, those that involve fraud or 
misconduct, dosing errors, increase the health risk to the subject, or confound interpretation of 
primary study assessments. 
15.3. 
Audits and Inspections 
Authorized representatives of Epizyme, Inc., a regulatory authority, an IEC or an Institutional 
Review Board may visit the site to perform audits or inspections, including source data 
verification. The purpose of an Epizyme, Inc. audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, Good Clinical Practice guidelines of the International Conference on 


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Harmonization, and any applicable regulatory requirements. The investigator should contact 
Epizyme, Inc. immediately if contacted by a regulatory agency about an inspection. 
15.4. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
16.1. 
Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures. Data queries requiring 
clarification will be generated and addressed by the investigational site timely. Only authorized 
personnel will make corrections to the clinical database, and all corrections will be documented 
in an audit trial. 
16.2. 
Bioanalytical Data Management and Quality Control 
Samples will be shipped according to the Laboratory Manual. EZM0414 will be quantified using 
a validated liquid chromatography/mass spectrometry/mass spectrometry method. Before the 
analysis of study samples, the assay sensitivity, specificity, linearity, and reproducibility will be 
documented. Details on the analytical methodology, the method of validation, and the analytical 
within-study quality control procedures will be included in the CSR for this protocol. 
 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved, or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The investigator must submit 
written approval from IRB/IEC to Epizyme, Inc. before he or she can enroll any subject into the 
study. 
The Principal Investigator (PI) is responsible for informing the IRB or IEC of any amendment to 
the protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
information and materials (including advertising in any form) used to recruit subjects for the 
study. The protocol must be re-approved by the IRB or IEC upon receipt of amendments and 
annually, as local regulations require. 
The PI is also responsible for providing the IRB with reports of any reportable serious adverse 
drug reactions (SUSAR) from any other study conducted with the IP. Epizyme, Inc. will provide 
this information to the PI. 
Progress reports and notifications of Suspected Unexpected Serious Adverse Reaction(s) 
(SUSARs) will be provided to the IRB or IEC according to local regulations and guidelines. 
17.2. 
Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
GCP as described in the ICH Tripartite Guideline E6 (R1): GCP: Consolidated Guideline. 
Compliance with these regulations also constitutes compliance with the ethical principles 
described in the current revision of the Declaration of Helsinki. The study will also be carried out 
in keeping with all applicable country and local legal and regulatory requirements. 
17.3. 
Written Informed Consent 
Informed consent will be obtained, and protocol eligibility will be established during the 
Screening Visit. Informed consent will be obtained after the study has been fully explained to the 
subject and before the conduct of any screening procedures or assessments. For research biopsies 
a separate consent form will be provided for DLBCL subjects. 
It is the responsibility of the Investigator to obtain written informed consent from each subject 
before any protocol-specific assessments and/or procedures are performed. All consent 
documentation must be written in the source documents, approved, used, and maintained in 
accordance with applicable regulations and GCP. If applicable, an ICF will be provided in a 
certified translation of the subject’s local language. 
Each Investigator will provide the Sponsor or its designee with a copy of the IRB/IEC approved 
ICF(s), and a copy of the IRB/IEC written approval, prior to the start of the study. Additionally, 
if the IRB/IEC requires modification of the sample subject information and the model ICF 
provided by the Sponsor, the documentation supporting this requirement must be provided to the 
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Each subject or the subject’s legally authorized representative is requested to sign the approved 
ICF after the subject has received and read the written subject information and received an 
explanation of what the study involves, including but not limited to: the objectives, potential 
benefits and risk, inconveniences, and the subject’s rights and responsibilities. The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. A copy of the ICF (subject information sheet and the ICF, as applicable) must be given 
to the subject or the subject’s legally authorized representative. 
Original, signed ICFs must remain in each subject’s study file and must be available for 
inspection at any time. 
The Sponsor reserves the right to delay initiation of the study at a site where the ICF(s) do not 
meet the standards of applicable regulations and ICH GCP. 
17.3.1. 
Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the Sponsor and/or their designee(s), 
participating Investigators, and any staff. This confidentiality includes the clinical information 
relating to participating subjects, as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
The Study Monitor or other authorized representatives of the Sponsor may inspect all documents 
and records required to be maintained by the Investigator regularly, including but not limited to, 
paper or electronic medical records (office, clinic, or hospital), and pharmacy records for the 
subjects in this study. The clinical study site will permit access to such records accordingly. 


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18. 
DATA HANDLING AND RECORD KEEPING 
18.1. 
Electronic Case Report Form 
The Sponsor or designee will provide the study sites with secure access to and training on the 
EDC application sufficient to permit site personnel to enter or correct information in the eCRFs 
on the subjects for which they are responsible. 
An eCRF is required and must be completed for each randomized subject. The Investigator has 
ultimate responsibility for the accuracy, authenticity, and timely collection and reporting of all 
clinical, safety, and laboratory data entered on the eCRFs and any other data collection forms. 
Source documentation supporting the eCRF data must indicate the subject’s participation in the 
study and must document the dates and detail of study procedures, AEs, other observations, and 
subject’s status. 
The Investigator, or designated representative, must complete the eCRF as soon as possible after 
information is collected (preferably within 24 hours). 
The audit trail will show the user’s identified information and the date and time of any 
correction. The eCRFs must be signed electronically by the Investigator to attest that the data 
contained on the eCRFs including any changes made to the eCRFs, is correct and endorse the 
final submitted data for the subjects for whom the Investigator is responsible. 
The completed eCRFs are the sole property of the Sponsor and must not be made available in 
any form to third parties, except for authorized representatives of the Sponsor or appropriate 
regulatory authorities, without written permission from the Sponsor. 
The Sponsor will retain the eCRF data and corresponding audit trails. A copy of the final 
archival eCRF in the form of a Compact Disc or other electronic storage media will be provided 
to the site for placement in the Investigator’s study file. 
18.2. 
Inspection of Records 
The Sponsor or designee will be allowed to conduct site visits to the Investigational facilities for 
the purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor 
to inspect the drug storage area, study treatment stocks, drug accountability records, subject 
paper or electronic medical charts and study source documents, and other records relative to 
study conduct. 
To ensure compliance with relevant regulations, data generated by this study will be available for 
inspection upon request by representatives of the US FDA as well as other national and local 
regulatory authorities, the Sponsor and/or its designee, interested commercial parties, and the 
IRB/IEC/REB for each study site. 
18.3. 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, eg, eCRFs and hospital records), all original signed ICFs, eCRFs, SAE forms, 
source documents, detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, telephone calls reports). The records must 


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be retained by the Investigator according to the ICH, local regulations, or as specified in the 
Clinical Study Agreement, whichever is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), the Sponsor must be prospectively notified. The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor. The Investigator must obtain the Sponsor’s 
written permission before disposing of any records, even if retention requirements have been 
met. 
18.4. 
Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the course of this 
study will be kept confidential by the Investigator, the Investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study without the written consent of the Sponsor. No data collected as part of this 
study will be utilized in any written work, including publications, without the written consent of 
the Sponsor. These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in the Confidentiality Agreement between the Sponsor and the 
Investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the Confidentiality Agreement between the Investigator 
and the Sponsor (provided by the Sponsor). 
18.5. 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or for valid 
administrative reasons at any time. If the study is prematurely terminated or suspended, the 
Sponsor will promptly inform the Investigators/institutions and the regulatory authority(ies) of 
the termination or suspension and the reason(s) for the termination or suspension. The 
Investigator must contact all participating subjects within a time period specified by the Sponsor 
to inform them of the decision to discontinue the study. The IRB/IEC should also be informed 
promptly and provided with the reason(s) for the termination or suspension by the Sponsor or by 
the Investigator/institution, as specified by the applicable regulatory requirement(s). 
The Investigator reserves the right to discontinue the study should his/her judgment so dictate. If 
the Investigator terminates or suspends a trial without prior agreement of the Sponsor, the 
Investigator should inform the institution where applicable, and the Investigator/institution 
should promptly inform the Sponsor and the IRB/IEC and should provide the Sponsor and the 
IRB/IEC with a detailed written explanation of the termination or suspension. Study records 
must be retained as noted above. 
18.6. 
Subject Insurance and Indemnity 
The Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in this study. 
 


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19. 
PUBLICATION POLICY 
Clinical study results will be made publicly available in compliance with local legislation and 
guidelines. 
If a manuscript is published in a peer-reviewed journal, then that initial release may be an 
abstract that meets the requirements of the International Committee of Medical Journal Editors. 
All manuscripts, abstracts or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the Sponsor, in advance of submission. The review 
is aimed at protecting the Sponsor’s proprietary information existing either at the date of the 
commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each Investigator and the Sponsor. 


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Yusufova N, Kloetgen A, Teater M, et al. Histone H1 loss drives lymphoma by disrupting 3D chromatin 
architecture. Nature. 2020;589:299-305. 
Zhou H, Lee JJ, Yuan Y. BOP2: Bayesian optimal design for phase II clinical trials with simple and complex 
endpoints. Statistics in Medicine. 2017;36(21):3302-3314. 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
V 1.0, 23 July 2024 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol SET-101 
A phase 1a/1b, open-label, multi-centre, two-part study of 
IPN60210, a SETD2 inhibitor, in participants with 
relapsed/refractory multiple myeloma (MM) or 
relapsed/refractory diffuse large B cell lymphoma (DLBCL) 
 
 
Ipsen, Inc. 
One main Street 
Cambridge, MA 02142 
 
 
 
Version 1.0 
23 July 2024 
 




 
Statistical A nal ysis Pla n  
 
V 1. 0, 2 3 J ul y 2 0 2 4  
E piz y me, I nc.  
C o nfi de ntial  
Pa ge 3  of 1 8  
M O DI FI C A TI O N HI S T O R Y   
After a p pr o val of versi o n 1. 0 of t he statistical a nal ysis pla n, s u bse q ue nt versi o ns s h o ul d be 
d oc u me nte d bel o w wit h a brief des cri pti o n of t he c ha n ge fr o m t he pre vi o us versi o n, as well as t he 
rati o nale f or t h e c ha n g e. 
 
Versi o n, D ate  
M a de b y  
Brief Descri pti o n of C h a n ge a n d R ati o n ale  
1. 0, 2 3 J U L 2 0 2 4 
 
I nitial Versi o n 
 
 
 
 
 
 
P P D


 
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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
MODIFICATION HISTORY ..........................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
OVERALL STUDY DESIGN ......................................................................................8 
2.1. 
GENERAL DESCRIPTION .........................................................................................8 
2.2. 
CHANGES TO ANALYSIS FROM PROTOCOL ......................................................9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
4. 
INTERIM ANALYSIS ...............................................................................................11 
5. 
SAMPLE SIZE DETERMINATION AND JUSTIFICATION .................................11 
5.1. 
SAMPLE SIZE DETERMINATION .........................................................................11 
5.2. 
SAMPLE SIZE JUSTIFICATION .............................................................................11 
6. 
ANALYSIS POPULATIONS ....................................................................................12 
6.1. 
DEFINITION OF ANALYSIS POPULATIONS ......................................................12 
6.1.1. 
ANALYSIS POPULATION IN PART 1A DOSE ESCALATION PART ...............12 
6.1.2. 
PHARMACOKINETIC (PK) POPULATION IN BOTH PHASE 1A ......................12 
6.2. 
STATISTICAL ANALYSIS GROUPS .....................................................................12 
7. 
DEFINITIONS AND CONVENTIONS ....................................................................13 
7.1. 
STUDY DAY .............................................................................................................13 
7.2. 
BASELINE ASSESSMENTS ....................................................................................13 
7.3. 
MULTICENTRE STUDIES .......................................................................................13 
7.4. 
MULTIPLE COMPARISONS/MULTIPLICITY ......................................................13 
7.5. 
COMMON CONVENTIONS ....................................................................................13 
7.6. 
MISSING DATA ........................................................................................................14 
7.7. 
STATISTICAL ANALYSIS SOFTWARE ................................................................14 
8. 
STATISTICAL ANALYSIS ......................................................................................14 
8.1. 
DISPOSITION OF SUBJECTS .................................................................................14 
8.2. 
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS ................14 
8.2.1 
PRIOR ANTI-CANCER THERAPIES ......................................................................15 


 
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8.2.2 
MEDICAL HISTORY ................................................................................................15 
8.3. 
EFFICACY ANALYSES ...........................................................................................15 
8.3.1 
ANALYSIS OF PRIMARY EFFICACY ENDPOINT ..............................................15 
8.3.2 
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS .....................................15 
8.4. 
SAFETY ANALYSES ...............................................................................................15 
8.4.1 
GENERAL CONSIDERATIONS ..............................................................................15 
8.4.2 
STUDY DRUG EXPOSURE .....................................................................................16 
8.4.3 
ADVERSE EVENTS..................................................................................................16 
8.4.4 
LABORATORY VALUES ........................................................................................16 
8.4.5 
VITAL SIGNS ............................................................................................................17 
8.4.6 
ELECTROCARDIOGRAMS (ECGS) .......................................................................17 
8.4.7 
ECOG .........................................................................................................................17 
8.4.8 
PHYSICAL EXAMINATION ...................................................................................17 
8.4.9 
PRIOR AND CONCOMITANT MEDICATIONS AND PROCEDURES ...............17 
8.4.10 
SUBSEQUENT ANTICANCER THERAPY ............................................................17 
9. 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS ....................18 
9.1. 
ANALYSIS OF PHARMACOKINETICS.................................................................18 
9.2. 
ANALYSIS OF PHARMACODYNAMICS .............................................................18 
10. 
REFERENCES ...........................................................................................................18 
LIST OF TABLES 
Table 1: 
Dose Escalation/de-escalation Rule for the BOIN Design .........................................12 
 
LIST OF FIGURES 
Figure 1: 
Study Schema ...............................................................................................................8 
Figure 2: 
Flowchart for Trial Conduct Using the BOIN Design ..................................................9 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AEs 
adverse events 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0–t 
area under the plasma concentration-time curve from time 0 to the time 
of the last quantifiable concentration 
QD 
once daily 
BMI 
body mass index 
BOR 
best overall response 
BOIN 
Bayesian optimal interval  
BOP2 
Bayesian optimal phase 2 
CI 
confidence intervals 
Cmax 
maximum plasma concentration 
CSR 
clinical study report  
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
diffuse large B cell lymphoma 
DLTs 
dose-limiting toxicities 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report forms 
EZM0414 
PH-EPZ-055-RS2-300, EPZ040414, or EPZ- 040414 
FIH 
first-in-human 
GI 
gastrointestinal 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLGT 
high-level group term 
HR 
heart rate 
HTLV-1 
human T-cell lymphotropic virus 1 
INR 
international normalized ratio 
IMWG 
International Myeloma Working Group 
IV 
intravenously 
LVEF 
left ventricular ejection fraction 


 
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MedDRA 
Medical Dictionary for Regulatory Activities 
λz 
terminal phase elimination rate constant 
MM 
multiple myeloma 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition 
NCI 
National Cancer Institute 
NE 
not evaluable 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
preferred term 
PTT 
partial thromboplastin time 
RECIST 
response evaluation criteria in solid tumors 
RP2D 
recommended phase 2 dose 
R/R 
relapsed/refractory 
SAEs 
serious adverse events 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
SD 
stable disease 
SETD2 
Su(var)3-9, Enhancer of zeste, Trithorax domain containing 2 
SI 
standardized using International System of Units 
SOC 
system organ class 
SRC 
Safety Review Committee 
StdDev 
standard deviation 
t(4;14) translocation 
part of chromosome 4 has swapped places with chromosome 14 
TEAE 
treatment-emergent adverse event 
T-LBL/T-ALL 
T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia 
t1/2 
terminal elimination half-life 
Tmax 
time at Cmax 
VGPR 
very good partial response 
WBC 
white blood cell 
WHO 
World Health Organization 
 


 
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1. 
INTRODUCTION 
Study SET-101 is a first in human (FIH), 2-part (Phase 1a: dose escalation; Phase 1b: dose 
expansion), open-label, multi-centre study in adult participants with R/R MM or R/R DLBCL. In 
the middle of phase 1a (dose escalation) conduct, this study was terminated by May 2024 based 
on a business decision.  
This statistical analysis plan (SAP) is limited to the planned analyses for the phase 1a portion of 
Protocol SET-101 Amendment 3.0. Of note, this SAP should be read in conjunction with the study 
protocol and the electronic case report forms (eCRFs).  
A clinical study report (CSR) will be prepared based on this SAP. Any deviations from this SAP, 
will be fully documented in the CSR with justification.  
2. 
OVERALL STUDY DESIGN 
2.1. 
General Description 
This is a FIH, open-label, multi-centre, Phase 1a/1b study to evaluate the safety, tolerability, PK, 
and efficacy of the oral SETD2 inhibitor, IPN60210, in adult participants with R/R MM or R/R 
DLBCL. The study schema is displayed in Figure 1 (See further details in Protocol Amendment 3).  
Figure 1: 
Study Schema 
 
Approximately 96 participants (Phase 1a: 36; Phase 1b: 60) were planned to be enrolled into the 
study. All participants in this study would receive IPN60210 as monotherapy orally once daily 
(QD) in 28-day cycles. 
In the Phase 1a dose escalation portion of the study, participants were to receive one of six planned 
dose levels: 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, and 900 mg, or optional step-down dose 
level of 75 mg (if applicable). Participants would be treated continuously until consent withdrawal, 
unacceptable toxicity, disease progression, or need for treatment prohibited on this study. 


 
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Part 1: Phase 1a (Dose Escalation) 
Part 1 is a safety dose escalation study to determine the MTD for dose expansion in Part 2 of the 
study. Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015; Yuan et al, 2016; Zhou, et 
al, 2017) would be used to evaluate the safety and tolerability of EZM0414 in participants with 
R/R MM and R/R DLBCL. The flowchart for trial conduct using the BOIN design is displayed in 
Figure 2. 
Figure 2: 
Flowchart for Trial Conduct Using the BOIN Design 
 
Note: Additional daily dose levels and/or dosing schedules (including BID regimen) may be studied based on 
clinical safety, tolerability, and PK data obtained during this study. 
2.2. 
Changes to Analysis from Protocol 
The study was terminated early based on a business decision. Only selected analysis detailed in 
the phase 1a portion of the protocol will be conducted.  


 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives  
Endpoints  
Part 1: Phase 1a Dose Escalation Phase  
Primary  
•  
To evaluate the safety and MTD of 
IPN60210 when administered as monotherapy 
in participants with R/R MM or R/R DLBCL.  
•  
Adverse event assessment according to 
CTCAE 5.0, physical examination, vital signs 
(blood pressure, heart rate, respiration rate, and 
body temperature), 12-lead ECG, clinical 
laboratory tests (haematology including 
coagulation profile, serum chemistries, and 
urinalysis), ECOG performance status, 
concomitant medication monitoring, and DLTs.  
Exploratory  
•  
To investigate pharmacodynamic 
biomarkers of target engagement in 
tumour/bone marrow biopsy and/or blood.  
•  
Change from baseline of H3K36me3 in 
tumour/bone marrow biopsy and/or blood.  
•  
To explore potential predictive 
biomarkers of response and other biomarkers 
associated with mechanism of action or 
resistance in bone marrow aspirates, 
tumour/bone marrow biopsies, and/or blood 
samples.   
•  
Determination of biomarkers of response  
such as histones and histone methylation markers, 
genomic alterations such as somatic mutations, 
DNA methylation and other DNA alterations 
such as t(4;14), protein and gene expression, 
immune cells in bone marrow aspirates, tumour 
biopsies, and/or blood samples.  
•  
To assess PK of IPN60210 when 
administered as monotherapy in participants 
with R/R MM or R/R DLBCL.  
•  
PK parameters including but not limited to: 
AUC0–t, Cmax, Tmax, and λz:   
Abbreviations: λz: terminal phase elimination rate constant; AUC0–t: area under the plasma concentration-time curve 
from time 0 to the time of the last quantifiable concentration; Cmax: observed maximum plasma concentration; CR = 
complete response; CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control rate; 
DLBCL = diffuse large B cell lymphoma; DLT = dose limiting toxicity; DNA = deoxyribonucleic acid; DOR = 
duration of response; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; H3K36me3 = 
histone 3 trimethylation at lysine 36; IMWG = International Myeloma Working Group; MM = multiple myeloma; 
MTD = maximum tolerated dose; ORR = objective response rate; PD = progressive disease; PFS = progression-free 
survival; PK = pharmacokinetics; PR = partial response; R/R = relapsed/ refractory; sCR = suspected complete 
response; SD= stable disease; t1/2: terminal elimination half-life. Tmax: observed time at Cmax; VGPR = very good 
partial response. 


 
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4. 
INTERIM ANALYSIS 
Not applicable (NA). 
5. 
SAMPLE SIZE DETERMINATION AND JUSTIFICATION 
5.1. 
Sample Size Determination 
The sample size of Phase 1a part was based on number of doses to be tested. Approximately 
36 participants were planned to be enrolled in Phase 1a. 
5.2. 
Sample Size Justification 
Bayesian optimal interval design (Liu, 2015; Yuan, 2016; Zhou, 2017) was to be used in the dose 
escalation part. Similar numbers of participants with R/R MM or R/R DLBCL were to be enrolled 
to determine the MTD. The target toxicity rate (∅்) for the MTD was set at 0.25 for both R/R MM 
and R/R DLBCL participants. The maximum number of participants for determination of the MTD 
will be 9 participants. A total of 6 dose levels (𝑗= 6, ie, starting at 100 mg, then 200 mg, 300 mg, 
400 mg, 600 mg, and 900 mg) as well as an optional step-down dose level of 75 mg will be 
investigated. Participants would be enrolled and treated in groups of at least 3, and up to 
36 participants were to enrol into the dose-escalation part of the study so that it can evaluate at 
least 3 and up to 9 participants per dose level. At least 6 participants would be needed to determine 
the MTD. Dose limiting toxicities are defined in Section 7.5.1 of the protocol, and only those DLTs 
that occur within the first cycle will be used for dose escalation-related safety assessments. The 
BOIN design uses the following rules, optimized to minimize the probability of incorrect dose 
assignment, to guide dose escalation/de-escalation: 
• if the observed DLT rate at the current dose is ≤ 0.197, escalate the dose to the next 
higher dose level; 
• if the observed DLT rate at the current dose is ≥ 0.298, de-escalate the dose to the 
next lower dose level; 
• otherwise, stay at the current dose. 
For the purpose of overdose control, the current dose 𝑗 and higher levels will be eliminated from 
further examination if Pr(𝑝௝> 0.25| data) > 0.8 and at least 3 participants have been treated at the 
current dose level 𝑗, where 𝑝௝ is the true DLT rate of dose level 𝑗, 𝑗= 1,⋯, 6. This posterior 
probability is evaluated based on the beta-binomial model 𝑦௝∣𝑝௝∼binomial(𝑝௝) with 𝑝௝∼
uniform(0,1), where 𝑦௝ is the number of participants experienced DLT at dose level 𝑗. When the 
lowest dose is eliminated, stop the trial for safety. The probability cut-off 0.8 is chosen to be 
consistent with the common practice when the target DLT rate ≤1/6, a dose with 2/3 participants 
experienced DLT is eliminated. The above dose escalation/de-escalation and elimination rule can 
be equivalently presented in, which will be used to conduct the trial. 


 
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Table 1: 
Dose Escalation/de-escalation Rule for the BOIN Design 
Target 
Toxicity 
Rate 
Pr (pj > 
target 
toxicity rate | 
data)  
Actions 
The number of evaluable patients at the 
current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
0.25 
0.8 
Escalate if # of DLT ≤ 
NA NA 
0 
0 
0 
1 
1 
1 
1 
De-escalate if # of DLT ≥ 
NA NA 
1 
2 
2 
2 
3 
3 
3 
Eliminate if # of DLT ≥ 
NA NA 
2 
2 
2 
3 
3 
3 
4 
BOIN = Bayesian Optimal Interval Design; DLT = Dose Limiting Toxicity; NA = Not Applicable 
* When none of the actions (ie, escalate, de-escalate, or eliminate) is triggered, stay at the current dose for treating 
the next group of subjects. Note that “# of DLT” is the number of participants with at least 1 DLT, and “NA” means 
that a dose cannot be eliminated before treating 3 evaluable subjects. 
Maximum tolerated dose will be determined based on isotonic regression as specified in Liu and 
Yuan (2015). When the isotonic estimate of toxicity rate 𝑝෤j* is closest to pre-set target DLT rate 
(∅்=0.25 for this study). If there are ties for 𝑝෤j* the higher dose with 𝑝෤j* < the target toxicity rate 
will be selected as MTD. Alternatively, the lower dose with 𝑝෤j* > ∅் will be selected. 
6. 
ANALYSIS POPULATIONS 
6.1. 
Definition of Analysis Populations 
6.1.1. Analysis Population in Part 1a Dose Escalation Part  
Safety Population 
The safety population is defined as all participants who have received at least one dose of study 
drug in Phase 1a (dose escalation part). The safety population will be used for all safety analysis 
in part 1a.  
Dose-Limiting Toxicity (DLT) Evaluable Population  
The DLT evaluable population is consist of dose escalation dose level participants in the Safety 
Population who received at least 80% of planned study treatment during cycle 1. Participants will 
be analysed according to the assigned dose level for the respective dose escalation cohort. 
6.1.2. Pharmacokinetic (PK) Population in Both Phase 1a   
Pharmacokinetic (PK) Population 
The PK population will include all participants in the Safety population who have sufficient post-
dose blood sample collected. 
6.2. 
Statistical Analysis Groups 
The Safety population of the study will be categorized to the 3 conducted dose levels (100 mg, 
200 mg, 300 mg).  


 
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7. 
DEFINITIONS AND CONVENTIONS 
7.1. 
Study Day 
Study day will be calculated in reference to the first dose date of study drug as follows: 
• Assessment date is on/after first dose date of study drug: 
Study Day = (date of event – first dose date of study drug) + 1 
• Assessment date is prior to first dose date of study drug: 
Study Day = date of event – first dose date of study drug 
 
For partial dates, Study Day will be missing in the listings.   
7.2. 
Baseline Assessments 
Unless otherwise specified, baseline is defined as the last non-missing (including unscheduled) 
assessment value prior to the initial administration of the study drug. If an assessment is performed 
on the same day as the first dose of study drug, and time is not collected, the assessment will be 
considered baseline. If there is more than one value on or prior to the initial administration of the 
study drug, the value closest to and prior to the receipt of the first dose, whether scheduled or 
unscheduled, will be used as the baseline value.   
AEs and medications reported with a start date on the date of first dose will be considered to have 
occurred after the start of treatment. For vital signs (excluding weight and height) and ECG 
measures, baseline results will be identified for the set. Baseline will be determined separately for 
each laboratory analyte. 
7.3. 
Multicentre Studies 
The centre effect will not be considered for this study.  
7.4. 
Multiple Comparisons/Multiplicity 
NA for this study. 
7.5. 
Common Conventions  
• 1 pound = 0.454 kg 
• 1 inch = 2.54 cm 
• 1 year = 365.25 days.  Year is calculated as (days / 365.25) and will be rounded up to 
1 significant digit for purposes of presentation 
• 1 month = 30.4375 days.  Month is calculated as (Days / 30.4375) and will be 
rounded up to 1 significant digit for purposes of presentation 
• Body mass index (BMI) calculated as [weight (kg)/height (m)2]  
• BMI calculated as [weight (lb) / height (in)2] × 703 


 
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• Post baseline duration in days = end date – start date + 1 (divide by 7 to convert to 
weeks, divide by 30.4375 to convert to months, and divide by 365.25 to convert to 
years; round result to 1 decimal place). 
• Listings typically will be sorted by study phase, dose level, study treatment, subject 
identification number (concatenated site and subject number), visit, date, and time, if 
collected. 
• Any date in the listings will use the date9. format, for example, 07MAY2002.  
7.6. 
Missing Data 
Unless noted otherwise, missing data will not be imputed.  
7.7. 
Statistical Analysis Software  
All statistical analyses for this study will be performed using SAS® version 9.4 or higher (SAS® 
Institute Inc., Cary NC).   
8. 
STATISTICAL ANALYSIS 
Phase 1a: 
Data for the first three dose levels of phase 1a will be listed. 
Phase 1b: 
NA 
8.1. 
Disposition of Subjects 
Phase 1a: 
A subject listing indicating analysis population will be presented for the safety population. 
Subject disposition, including primary reasons for treatment and study withdrawal and vital status, 
will be listed based on the safety population. 
Phase 1b: 
NA 
8.2. 
Demographics and Baseline Disease Characteristics 
The subject listings for demographic and baseline characteristics will be provided for all the related 
data. 
• Age  
• Sex (male, female) 
• Race (American Indian or Alaska Native, Asian, Black of African American, Native 
Hawaiian or Other Pacific Islander, White, Other, Not Reported) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not Reported) 


 
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• Body mass index 
• Performance status – will be presented using the Eastern Cooperative Oncology 
Group (ECOG) scale.  
• Primary cancer diagnosis (standardized term) 
• Tumor stage at initial diagnosis (DLBCL) (Stage 0, I, II, III, IV, Not applicable, 
Unknown) 
• Tumor stage at study entry (DLBCL) (Stage 0, I, II, III, IV, Not applicable, 
Unknown) 
• Time to initial diagnosis  
• Myeloma diagnosis and subtype at study entry (IgG, IgA, IgE, IgD, IgM, Light chain 
myeloma, and Non-secretory) 
• ISS stage initial diagnosis (MM) (I, II, II, and Unknown) 
• ISS stage study entry (MM) (I, II, II, and Unknown) 
• Is there a history of CNS involvement? (MM) (Yes, No) 
8.2.1 Prior Anti-cancer Therapies 
Patient level listing for prior cancer related therapy will be provided. 
8.2.2 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
V24.0) coding dictionary in use at the time of the analysis and presented by system organ class 
(SOC) and preferred term (PT). Medical history will be listed by the MedDRA high-level group 
term (HLGT) and PT. 
8.3. 
Efficacy Analyses 
NA 
8.3.1 Analysis of Primary Efficacy Endpoint  
NA 
8.3.2 Analysis of Secondary Efficacy Endpoints  
NA 
8.4. 
Safety Analyses 
8.4.1 General Considerations 
Safety of EZM0414 including DLT for the Phase 1a dose escalation part and all safety events data 
in phase 1a (dose escalation part)  


 
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DLT evaluation will be performed based on the DLT Population (Section 6.1) and the other safety 
listings will be provided on the Safety Population. 
Data from the phase 1a will be presented. 
8.4.2 Study Drug Exposure 
Study drug exposure and compliance in the phase 1b will be listed for the Safety population.   
Compliance will be calculated as: [(total number of dose of drug administered during treatment 
period)/ (total number of dose planned to administer during treatment period)] *100% 
8.4.3 Adverse Events 
Listings will be provided for all reported treatment-emergent adverse events (TEAEs), defined as 
AEs that started or worsened in severity on or after the date of the first dose of study drug through 
30 after the end of treatment, or prior to initiation of another investigational agent or cytotoxic 
chemotherapy.  Missing or partially missing start and end dates for AEs and SAEs will not be 
imputed.  For cases in which it is not possible to ascertain treatment-emergence, the event will be 
classified as treatment-emergent. 
The reported AE term will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.0.  The severity of each AE will be graded by the Investigator based on 
version 5.0 of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE).  If a severity grading scale does not exist for an AE, the Investigator will classify 
the severity as mild, moderate, severe, life-threatening/debilitating, or fatal based on the criteria 
described in the study protocol.  The causal relationship between the occurrence of an AE and 
study drug will be judged by the Investigator as “probable”, “possible”, “unlikely”, or “unrelated”. 
The following listings will be presented for part 1a: 
• All TEAEs 
• Treatment-emergent serious adverse events (SAEs)  
• TEAEs leading to discontinuation of study drug  
8.4.4 Laboratory Values 
Laboratory assessments and specific clinical laboratory tests are described in detail in 
Section 13.1.8 of Protocol. Blood samples for the following clinical laboratory tests were 
collected: 
• Hematology: Hemoglobin, hematocrit, WBC, differential blood count with ANC, 
platelet count, RBC. 
• Serum chemistries:  alkaline phosphatase, ALT, AST, total bilirubin, blood urea 
nitrogen, creatinine, bicarbonate, albumin, calcium, magnesium, glucose, phosphorus, 
total protein, and triglycerides. 
• Coagulation: partial thromboplastin, partial thromboplastin time (PTT), aPTT, and 
international normalized ratio (INR). 
• Urinalysis: glucose, blood, protein, and pH. 


 
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• Viral serology: HBV, HCV, HIV, and human T-cell lymphotropic virus 1 (HTLV-1). 
The following listings for hematology, chemistry and coagulation, and urinalysis will be provided: 
• Subject listings of all lab values 
• Subject listings for Grade 3 and 4 lab values 
• Subject listings for laboratory results < 0.25 x LLN or > 2.5 x ULN 
8.4.5 Vital Signs 
Subject listing of heart rate, temperature, systolic blood pressure, and diastolic blood pressure will 
be provided: 
8.4.6 Electrocardiograms (ECGs) 
NA 
8.4.7 ECOG 
NA 
8.4.8 Physical Examination 
NA 
8.4.9 Prior and Concomitant Medications and Procedures 
The following definition will be used to define prior and concomitant medications: 
• Prior medications will include medications which stopped prior to the first dose of 
study drug. 
• Concomitant medications are defined as medications that were started prior to first 
dose of study drug or at any time after the start of first dose of study drug and stopped 
prior to the discontinuation of study drug.  
The reported medication term will be coded using the World Health Organization (WHO) Drug 
Dictionary in effect at the time of the analysis.  The number and percentage of participants taking 
concomitant medications will be summarized by dose level/Cohorts and generic name, sorted in 
decreasing order of frequency.  All reported prior and concomitant medications will be listed by 
subject. 
8.4.10 Subsequent Anticancer Therapy 
NA 


 
Statistical Analysis Plan 
 
V 1.0, 23 July 2024 
Epizyme, Inc. 
Confidential 
Page 18 of 18 
9. 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS 
9.1. 
Analysis of Pharmacokinetics  
Plasma concentrations will be listed based on the PK population. 
9.2. 
Analysis of Pharmacodynamics 
No pharmacodynamic analysis will be conducted in this study.  
10. 
REFERENCES 
1. Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. Journal of the 
Royal Statistical Society: Series C (Applied Statistics). 2015; 64(3):507-523. 
2. Yuan Y, Hess KR, Hilsenbeck SG, et al. Bayesian Optimal Interval Design: A Simple and 
Well-Performing Design for Phase I Oncology Trials. Clinical Cancer Research: an official 
Journal of the American Association for Cancer Research. 2016; 22(17):4291-4301. 
3. Zhou H, Lee JJ, Yuan Y. BOP2: Bayesian optimal design for phase II clinical trials with simple 
and complex endpoints. Statistics in Medicine. 2017; 36(21):3302-3314.