A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Enzastaurin Plus R-CHOP Versus R-CHOP in Treatment-Naive Subjects With High-Risk Diffuse Large B-Cell Lymphoma Who Possess the Novel Genomic Biomarker DGM1™
Phase: PHASE3
Conditions: Diffuse Large B-Cell Lymphoma
Sponsor: Denovo Biopharma LLC

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CLINICAL PROTOCOL 
Title: 
A Randomized Phase 3 Study to Evaluate the Efficacy and 
Safety of Enzastaurin Plus R-CHOP Versus R-CHOP in 
Treatment-Naïve Subjects with High-Risk Diffuse Large B-Cell 
Lymphoma Who Possess the Novel Genomic Biomarker 
DGM1 (ENGINE Study)
 
Protocol Number: 
DB102-02 
IND Number: 
IND 133358 
Study Sponsor: 
Denovo Biopharma LLC 
10240 Science Center Drive, Suite 120 
San Diego, California 92121-6331 
Phone: +1.858.410.0262 
Facsimile: +1.858.799.1021 
 
 
Medical Monitor: 
Guy Gammon, MBBS MRCP 
ggammon@denovobiopharma.com 
Phone: +1. 310.710.8665 
 
 
Version:
Version 6.0 
US: Replaces Version 5.1 dated 27 February 2020 
China: Replaces Version 5.0 dated 18 December 2019 
 
Date: 
8 July 2021 
 
The information contained in this protocol is confidential and is intended for the use of clinical 
investigators. It is the property of Denovo Biopharma LLC and should not be copied by or 
distributed to persons not involved in the clinical investigation of enzastaurin, unless such 
persons are bound by a confidentiality agreement with Denovo Biopharma LLC. 
 

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SPONSOR APPROVAL 
 
 
The protocol has been approved by Denovo Biopharma LLC 
 
Responsible Medical Officer: Guy Gammon, MBBS MRCP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Company/Sponsor Signatory 
 
Date 
 
 

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PROTOCOL SYNOPSIS
TITLE 
A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of 
Enzastaurin Plus R-CHOP Versus R-CHOP in Treatment-Naïve Subjects 
with High-Risk Diffuse Large B-Cell Lymphoma Who Possess the Novel 
Genomic Biomarker DGM1 (ENGINE Study) 
SPONSOR 
Denovo Biopharma LLC 
RATIONALE 
Non-
th most common cancer in the 
United States with 72,580 new cases predicted to occur in 2016 (SEER 
database). Approximately 20,150 people were predicted to die from this 
disease in 2016. Of these, slightly more than half, approximately 11,450 
will be male, and 8,690 will be female. There are over a half million 
people with NHL living in this country. Diffuse Large B-Cell Lymphoma 
(DLBCL) is the most common of the NHLs, accounting for between 
30%-40% of all cases. The incidence of DLBCL generally increases with 
age and roughly half of all patients are over the age of 60 at the time of 
diagnosis (Lymphoma Research Foundation, 2018).
DLBCL is classified as an aggressive lymphoma meaning that its clinical 
course can progress rapidly to death. Nevertheless, patients with DLBCL 
can be cured with the appropriate treatment. The current standard of care 
treatment for DLBCL consists of rituximab added to the anthracycline-
containing combination chemotherapy regimen of cyclophosphamide, 
doxorubicin, vincristine and prednisone (NCCN Treatment Guidelines). 
This regimen is referred to as R-CHOP immunochemotherapy. For 
DLBCL as a whole, R-CHOP immunochemotherapy has resulted in cure 
rates of approximately 60%. However, for individual patients 5-year 
survival rates can range from 90% for low-risk DLBCL patients to less 
than 50% for high-risk DLBCL patients (Sehn et al., 2015, Zhou et al., 
2014). 
Most important, for those subjects refractory to R-CHOP therapy less 
than 10% achieve a durable remission with secondary therapy (Sehn et 
al., 2015). Thus, while R-CHOP remains the standard treatment for high-
risk, advanced stage DLBCL, approximately 30-40% patients fail front-
line therapy with most not achieving complete response or with early 
relapse. An essential step to move forward and improve the outcomes of 
these patients is to increase the rate of complete response to front-line R-
CHOP therapy (Chiapella et al., 2016). 
For this reason, there has been a great deal of effort placed on attempting 
to define disease characteristics that predispose patients to a poorer 
prognosis with R-CHOP therapy. Molecular and gene expression 
profiling of tumors and a variety of clinical prognostic indices have been 
used to identify patients at higher risk of failing R-CHOP 
immunochemotherapy. While this work has identified subgroups of 
patients who do not respond well to R-CHOP, to date these efforts have 
not resulted in substantial gains in response to front-line therapy. 
Denovo Biopharma (Denovo) has pioneered an alternative approach to 
this challenging problem. Denovo has developed a model that employs 
sophisticated pharmacogenomic testing to detect somatic biomarkers that 
identify those subjects who responded to a particular study treatment with 

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the aim of re-studying the drug of interest, in this case enzastaurin, in an 
enriched population. 
Applying this technology to archived DNA samples from completed 
studies of enzastaurin in subjects with DLBCL, Denovo has identified a 
somatic biomarker that reliably identified subjects for whom the study 
treatment significantly prolonged survival. Enzastaurin is an oral 
serine/threonine kinase inhibitor, that targets the protein kinase C (PKC), 
and phosphoinositide 3-kinase (PI3K) and AKT pathways to inhibit 
tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-
induced angiogenesis. 
The purpose of the current study is to prospectively assess the effect on 
overall survival (OS) of adding enzastaurin to R-CHOP 
immunochemotherapy in the front-line treatment of subjects with high-
risk DLBCL (IPI  3). The detailed rationale for this study is provided in 
greater depth in Section 1.5. 
STUDY DESIGN
This randomized, double-blind, placebo-controlled Phase 3 study intends 
to enroll approximately 235 treatment-naïve subjects with high-risk 
DLBCL. These subjects will be randomized 1:1 to R-CHOP plus 
enzastaurin or R-CHOP plus placebo. All subjects will receive up to 6 
cycles (1 cycle = 21 days) of treatment during combination phase. PET-
CT will be used for staging and to assess radiographic response at the end 
combination phase tumor response assessment. Subjects randomized to 
the enzastaurin arm who have a complete response (CR) or partial 
response (PR) (at 
(Cheson 2014) will have the opportunity to continue in the single-agent 
phase of the study and receive single-agent enzastaurin for up to 2 
additional years. 
PRIMARY OBJECTIVE
The primary objective of this study is to compare the effect of R-CHOP 
plus enzastaurin followed by enzastaurin or standard of care (SOC) 
versus R-CHOP followed by SOC on OS in treatment-naïve subjects with 
high-risk DLBCL who possess the DGM1 biomarker. 
SECONDARY 
OBJECTIVES 
To determine the effect on OS of adding enzastaurin to R-CHOP in 
treatment naïve subjects with high-risk DLBCL regardless of DGM1 
biomarker status. 
 
To evaluate Event-free Survival (EFS), including EFS rate at 12 
months (EFS12) and EFS rate at 24 months (EFS24), for all subjects, 
and for subjects who are DGM1 biomarker positive. 
 
To compare the combination phase investigator assessed CR rate and 
objective response rate (ORR) in subjects with high-risk DLBCL 
who are DGM1 biomarker positive administered R-CHOP plus 
enzastaurin versus R-CHOP. 
 
To further evaluate the safety profile of enzastaurin when 
administered in conjunction with R-CHOP.  
EXPLORATORY 
OBJECTIVES 
 
To determine enzastaurin and enzastaurin metabolite(s) 
concentrations for incorporation into a subsequent population 
pharmacokinetics (PK) analysis. 

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To determine if the presence of other somatic or tumor biomarkers 
predicts improved efficacy in subjects taking enzastaurin. 
 
To determine if chromaturia (orange/red discoloration of the urine) 
predicts improved efficacy in subjects taking enzastaurin. 
 
To obtain samples urine for potential future analysis of enzastaurin 
metabolites. 
 
To explore any relationship between subsequent DLBCL therapy(ies) 
and OS. 
 
To assess regional similarities of primary and secondary efficacy 
measures between China and US. 
NUMBER OF 
PATIENTS 
Approximately 235 subjects randomized 1:1 to receive R-CHOP plus 
enzastaurin or R-CHOP plus placebo. 
KEY ELIGIBILITY 
CRITERIA 
Inclusion Criteria  
All inclusion criteria must be met for the subject to be considered for the 
study. 
1. Male or female at least 18 years of age and able to provide 
informed consent. 
2. Histologically confirmed diagnosis of CD20 positive 
DLBCL based on the WHO classification (2016); the 
diagnosis must be confirmed at the enrolling site. 
Note: Subjects with high-grade B-cell lymphoma with MYC 
and BCL2 and/or BCL6 rearrangements, or high-grade B-
cell lymphoma, NOS are eligible.  
3. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0, 1 or 2. 
4. International Prognostic Index (IPI) score of at least 3.
5. Estimated life expectancy of at least 12 weeks. 
6. Adequate organ function as follows (within 14 days prior to 
randomization):  
a. Hepatic: total bilirubin  1.5 times upper limit of 
normal (ULN) (  5 times ULN in the case of Gilberts 
Syndrome, liver or pancreatic involvement by 
lymphoma); alanine transaminase (ALT) and 
aspartate transaminase (AST)  2.5 times ULN 
(  5 times ULN if liver involvement) 
b. Renal: creatinine clearance of  40 mL/min by 
Cockcroft- Gault equation 
c. Bone marrow: platelets  75 x 109/L, absolute 
neutrophil count (ANC)  1.5 x 109/L, hemoglobin 
 8 g/dL. (Platelets  50 x 109/L, ANC  1.0 x 109/L, 
hemoglobin  7.0 g/dL permitted if documented bone 
marrow involvement) 
7. Male or female with reproductive potential, must be willing 
to use an approved contraceptive method (for example, 
intrauterine device (IUD), birth control pills, or barrier 

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device) during and for 3 months after discontinuation of 
study treatment. Women of childbearing potential must have 
a negative serum pregnancy test within 7 days prior to 
randomization. 
a. Men are considered of reproductive potential unless 
they have undergone a vasectomy and confirmed 
sterile by a post-vasectomy semen analysis.  
b. Women are considered of reproductive potential 
unless they have undergone hysterectomy and/or 
surgical sterilization (at least 6 weeks following a 
bilateral oophorectomy, bilateral tubal ligation, or 
bilateral tubal occlusive procedure that has been 
achieved postmenopausal status (defined as cessation 
of regular menses for greater than 12 consecutive 
months in women at least 45 years of age). 
8. Left ventricular ejection fraction  50% by echocardiography 
or nuclear medicine multi-gated scan. 
9. Must be able to swallow tablets. 
10. Must be able to comply with study protocol procedures. 
11. Willing to consent to have blood stored for possible future 
biomarker and disease analysis. 
12. Must have available and willing to submit pre-systemic 
treatment DLBCL tumor biopsy tissue/slides for central 
pathology review. 
Exclusion Criteria 
None of the exclusion criteria is met in order for the subject to be 
considered for the study. 
1. Received treatment with an investigational drug within the 
last 30 days. 
2. Receiving or has received radiation or any other systemic 
anticancer treatment for lymphoma (Up to 10 days of 
corticosteroids prior to randomization are permitted but 
should be administered after eligibility IPI determination and 
imaging scans). 
3. History of indolent lymphoma or follicular Grade 3b 
lymphoma. 
4. Primary mediastinal (thymic) large B-cell lymphoma. 
5. B-cell lymphoma, unclassifiable, with features intermediate 
between DLBCL and classical Hodgkin lymphoma. 
6. Burkitt lymphoma. 
7. Pregnancy or breastfeeding. 
8. Known central nervous system (CNS) involvement. 
9. Any significant concomitant disorder based on the discretion 
of the investigator, including but not limited to active 

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bacterial, fungal, or viral infection, incompatible with 
participation in the study. 
10. A second primary malignancy (except adequately treated 
non-melanoma skin cancer); subjects who have had another 
malignancy in the past, but have been disease-free for more 
than 5 years, and subjects who have had a localized 
malignancy treated with curative intent and disease free for 
more than 2 years are eligible. 
11. Use of a strong inducer or moderate or strong inhibitor of 
CYP3A4 (See Appendix A. 
Examples of Inhibitors and 
Inducers of CYP 3A4) within 7 days prior to start of study 
therapy or expected requirement for use on study therapy. 
12. Personal or immediate family history of long QT syndrome, 
QTc interval > 450 msec (males) or > 470 msec (females) at 
screening (recommended that QTc be calculated using 
Fridericia correction formula, QTcF: see Section 6.2.1), or a 
history of unexplained syncope. 
13. Use of any medication that can prolong the QT/QTc interval 
(See Appendix C. 
Drugs That Can Prolong the QT 
Interval) within 7 days prior to start of study therapy or 
expected requirement for use on study therapy.
14. History of severe allergic or anaphylactic reaction to 
monoclonal antibody therapy. 
15. Confirmed diagnosis of progressive multifocal 
leukoencephalopathy. 
16. Ongoing grade 2 or higher peripheral neuropathy. 
17. Have any of the following cardiac disorders: uncontrolled 
hypertension, unstable angina, myocardial infarction within 
8 weeks of randomization, New York Heart Association 
(NYHA) Grade 2 or higher congestive heart failure, 
ventricular arrhythmia requiring medication within 1 year of 
randomization, Fontaine Classification stage III or higher 
peripheral arterial disease. 
18. Received a live vaccine within 28 days of randomization. 
19. HIV positive. 
20. Evidence of chronic hepatitis C infection as indicated by 
antibody to HCV with positive HCV-RNA.
21. Evidence of chronic hepatitis B infection as indicated by either: 
a) HBsAg+ or  
b) HBcAb+ with HBV-DNA+ (any detectable amount is 
considered positive) 

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TEST PRODUCT, 
DOSE, AND ROUTE OF 
ADMINISTRATION
Kinenza® (enzastaurin) 125 mg; matching placebo. 
Combination Phase (6 x 21-day cycles with R-CHOP) 
Subjects will receive a loading dose of 1125 mg (3 tablets TID) followed 
by 500 mg (4 tablets QD) of study drug (enzastaurin/placebo) daily. All 
four tablets will be taken together within 30 minutes after a meal and at 
approximately the same time daily to maintain steady-state 
concentrations. The tablets must not be crushed or broken for 
administration. 
Sigle-Agent Phase 
Following completion of up to 6 cycles of R-CHOP, subjects in the 
continue to take single-agent study drug (enzastaurin 500 mg) daily for 
up to 2 additional years.  
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Following screening (within 28 days), subjects will receive up to 6 cycles 
of R-CHOP immunochemotherapy (21-day cycles) plus study drug, 
during the combination phase. Note: for the R-CHOP regimen, subjects 
will receive a rituximab product, which may include Rituxan/MabThera 
or an FDA-approved rituximab biosimilar. However, for a given subject, 
Rituxan/MabThera or an FDA- approved rituximab biosimilar cannot be 
used interchangeably during the study; each subject must use the same 
rituximab product exclusively throughout the study treatment course. 
Following completion of the combination phase of the study, each 
the enzastaurin arm who have a CR or PR 
will be offered single-agent study drug for up to 2 additional years. All 
other subjects, including all subjects randomized to the placebo arm, will 
receive no further treatment on study, will receive standard of care based 
on their response assessment, and will go into the follow up phase and be 
evaluated for survival every 3 months until completion of the study or up 
to 5 years, whichever occurs first. The study is expected to take 
approximately 3.5 years to complete. 
EFFICACY 
EVALUATIONS 
The determination of response and progression will be based on 
standardized criteria: Lugano Classification (Cheson 2014). PET-CT 
should be performed during screening and at the end of the combination 
phase. A CT will be performed for an interim assessment which occurs 
after the completion of R-CHOP administration in Cycle 3 (PET-CT is 
ce or local SOC, see Appendix D 
for details). The end of combination phase restaging tumor assessment 
(PET-CT) will be performed at least 4 weeks but preferably at 6 to 
8 weeks after the completion of the last cycle of R-CHOP; weeks 
calculated from the last administration of rituximab product. Subjects will 
be seen or contacted at regular intervals in the single-agent and follow-up 
phases of the study to determine survival status. 
SAFETY 
EVALUATIONS 
Vital signs, physical exams, adverse events, ECGs, safety labs. 

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DATA MONITORING 
COMMITTEE 
An independent Data Monitoring Committee (DMC) will meet during the 
study to review safety data and monitor study progress. 
STATISTICAL PLAN 
 
Study sample size was estimated for the primary efficacy objective. 
The primary outcome of this study is OS, with the primary analysis to be 
conducted in DGM1 biomarker positive subjects. 
Study subjects will be randomized 1:1 to R-CHOP + enzastaurin or 
R-CHOP + placebo. This will be an event driven study. 66 events are 
required to provide approximately 90% power to detect a HR of 0.45 for 
OS in subjects who are positive for the DGM1 biomarker, when using a 
stratified log-rank statistic having one-sided alpha of 0.0235 (Section 
7.4). Statistical significance will be achieved with an estimated HR 
 0.613. 
Assuming control arm subjects have one-year survival of approximately 
60% to 70% and median survival of approximately 24 to 30 months, the 
trial will have an approximate sample size of 200 DGM1 biomarker 
positive subjects. If the enrollment period is 12-18 additional months, 
approximately 12 to 24 additional months will be required for 66 events 
to occur. If approximately 15% of trial subjects will be DGM1 biomarker 
negative, the trial would enroll approximately 235 subjects, with 200 
being biomarker positive and 35 being biomarker negative. 
 
 

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TABLE OF CONTENTS 
SPONSOR APPROVAL .................................................................................................................2 
PROTOCOL SYNOPSIS.................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................14 
1 INTRODUCTION ...................................................................................................................16 
1.1 
Diffuse Large B-Cell Lymphoma ................................................................................16 
1.2 
Enzastaurin ...................................................................................................................17 
1.3 
Summary of Relevant Prior Animal and Human Studies ............................................17 
1.3.1
Absorption, Metabolism and Drug Interactions.....................................................17
1.3.2 Preclinical and Clinical Toxicity ...........................................................................18 
1.3.3 Pharmacokinetics in Humans.................................................................................19 
1.3.4 Previous Human Studies of Patients With NHL ....................................................20 
1.4 
Discovery and Validation of DGM1 Biomarker ..........................................................23 
1.5 
Study Rationale ............................................................................................................26 
2 OBJECTIVES ..........................................................................................................................27 
2.1 
Primary Objective ........................................................................................................27 
2.2 
Secondary Objectives...................................................................................................27 
2.3 
Exploratory Objectives ................................................................................................27 
3 INVESTIGATIONAL PLAN ..................................................................................................28 
3.1 
Discussion of Study Design .........................................................................................30 
4 STUDY POPULATION ..........................................................................................................31 
4.1 
Inclusion Criteria .........................................................................................................31 
4.2 
Exclusion Criteria ........................................................................................................32 
4.3 
Rationale for Key Exclusion Criteria ...........................................................................33 
4.4 
Withdrawal of Subjects ................................................................................................33 
4.4.1 Discontinuation of Study Treatment ......................................................................33 
4.4.2 Withdrawal from Follow-Up .................................................................................34 
4.5 
Termination of the Study .............................................................................................34 
5 TREATMENT .........................................................................................................................35 
5.1 
Treatments Administered .............................................................................................35 
5.1.1 Pre-randomization Treatment ................................................................................35 
5.1.2 Combination ...........................................................................................................35 
5.1.3 Single-Agent ..........................................................................................................36 
5.2 
Materials and Supplies .................................................................................................37 
5.2.1 Enzastaurin (Kinenza®)/Placebo ...........................................................................37 
5.2.2 Rituximab Product .................................................................................................37 
5.2.3 Cyclophosphamide .................................................................................................38 
5.2.4 Doxorubicin ...........................................................................................................38 

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5.2.5
Vincristine..............................................................................................................38
5.2.6 Prednisone ..............................................................................................................39 
5.3 
Method of Assignment to Treatment ...........................................................................39 
5.4 
Rationale for Selection of Doses in the Study .............................................................39 
5.5 
Dose Modifications ......................................................................................................39 
5.5.1 Enzastaurin .............................................................................................................39 
5.5.2 R-CHOP .................................................................................................................40 
5.6 
Blinding........................................................................................................................41 
5.7 
Concomitant Therapy...................................................................................................41 
5.7.1 Effect of Concomitant Medications on Enzastaurin Concentrations .....................42 
5.7.2 Effect of Enzastaurin on Concomitant Medications ..............................................43 
5.7.3
Colony-Stimulating Factors...................................................................................43
5.7.4 QT Interval Prolonging Medications .....................................................................43 
5.7.5 Central Nervous System (CNS) Prophylaxis .........................................................43 
5.8 
Treatment Compliance .................................................................................................44 
6 EFFICACY, SAFETY EVALUATIONS, AND SAMPLE COLLECTION AND TESTING 
(STANDARD LABORATORY TESTING AND APPROPRIATENESS OF 
MEASUREMENTS)................................................................................................................45 
6.1 
Efficacy Measures ........................................................................................................45 
6.1.1 Tumor Assessments and Schedule .........................................................................45 
6.1.2 Primary Efficacy Measure .....................................................................................45 
6.1.3 Secondary Efficacy Measures ................................................................................45 
6.1.4 Exploratory Efficacy Measures..............................................................................45 
6.2 
Subject Evaluations ......................................................................................................46 
6.2.1 Pretreatment Evaluations .......................................................................................46 
6.2.2 Evaluations on Study .............................................................................................46 
6.2.3 Visit Windows .......................................................................................................48 
6.2.4 Post-treatment Evaluations/Follow up ...................................................................48 
6.2.5 Post-treatment Visit Windows ...............................................................................48 
6.3 
Safety Evaluations .......................................................................................................49 
6.3.1 Definitions..............................................................................................................49 
6.3.2 Adverse Event Reporting Period ...........................................................................50 
6.3.3 Recording Adverse Events.....................................................................................51 
6.3.4 Reporting Serious Adverse Events ........................................................................51 
6.3.5 Events That Will Not Be Reported Individually....................................................52 
6.3.6 Reporting of Study Endpoints................................................................................52 
7 STATISTICAL METHODS ....................................................................................................53 
7.1 
General Considerations ................................................................................................53 
7.2 
Disposition of Subjects ................................................................................................53 

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7.3
Subject Characteristics.................................................................................................53
7.4 
Sample Size and Efficacy Analyses .............................................................................53 
7.5 
Safety Analysis ............................................................................................................55 
7.5.1 Adverse Events and Serious Adverse Events ........................................................56 
7.5.2 Laboratory Tests ....................................................................................................56 
7.5.3 QTc ........................................................................................................................56 
7.6 
The Data Monitoring Committee .................................................................................56 
8 ETHICAL AND REGULATORY CONSIDERATIONS .......................................................57 
8.1 
Protocol and Regulatory Compliance ..........................................................................57 
8.2 
Protocol Amendments ..................................................................................................57 
8.3 
Regulatory Binder ........................................................................................................57 
8.4
Informed Consent.........................................................................................................57
8.5 
Institutional Review Boards and Independent Ethics Committees ..............................58 
8.6 
IRB/IEC Communications ...........................................................................................58 
8.7 
Curriculum Vitae and Medical Licenses......................................................................58 
8.8 
Subject Confidentiality ................................................................................................58 
8.9 
Financial Disclosure.....................................................................................................59 
9 QUALITY ASSURANCE .......................................................................................................60 
9.1 
Routine Clinical Site Monitoring .................................................................................60 
9.2 
Site Audits ....................................................................................................................60 
10 DATA MANAGEMENT AND RECORD KEEPING............................................................61 
10.1 
Case Report Forms (CRF) ...........................................................................................61 
10.2 
Record Retention .........................................................................................................61 
11 USE OR PUBLICATION OF STUDY-RELATED INFORMATION ...................................62 
12 INVESTIGATOR PROTOCOL SIGNATURE PAGE ...........................................................63 
13 SCHEDULE OF EVENTS ......................................................................................................64 
14 REFERENCES ........................................................................................................................67 
APPENDIX A. 
EXAMPLES OF INHIBITORS AND INDUCERS OF CYP 3A4 ...........69 
APPENDIX B. 
INTERNATIONAL PROGNOSTIC INDEX............................................70 
APPENDIX C. 
DRUGS THAT CAN PROLONG THE QT INTERVAL .........................71 
APPENDIX D. 
TUMOR ASSESSMENT...........................................................................73 
APPENDIX E. 
FONTAINE CLASSIFICATION ..............................................................79 
 

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LIST OF TABLES 
Table 1.
Summary of Prior Studies of Enzastaurin Performed in Subjects with NHL ...................21
Table 2. 
Summary of Combination Dosing Regimens .................................................................... 35 
Table 3. 
R-CHOP Regimen ............................................................................................................. 36 
Table 4. 
Summary of Post-Combination Treatments ...................................................................... 37 
Table 5. 
Adverse Events/Serious Adverse Events Reporting Guide ............................................... 51 
Table 6. 
Schedule of Events ............................................................................................................ 64 
Table 7. 
Variables ............................................................................................................................ 70 
Table 8.
Definition of Risk Groups .................................................................................................70
 
LIST OF FIGURES 
Figure 1. 
Progression Free Survival R-CHOP/Enzastaurin vs R-CHOP .......................................... 24 
Figure 2. 
Overall Survival R-CHOP/Enzastaurin vs R-CHOP ......................................................... 24 
Figure 3. 
Overall Survival R-CHOP/Enzastaurin Arm Based on Presence or Absence of DGM1 
Biomarker .......................................................................................................................... 25 
Figure 4. 
Overall Survival for DGM1 Positive, High-
 3) Subjects 
R-CHOP/Enzastaurin vs R-CHOP .................................................................................... 25 
Figure 5. 
Overall Survival by Presence or Absence of DGM1 Biomarker R-CHOP Arm............... 26 
Figure 6. 
Study Schema .................................................................................................................... 29 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
amino alanine transferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC
complete blood count
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form
CRu 
unconfirmed complete response 
CT 
computed tomography 
CTCAE 
Common Toxicity Criteria Adverse Events 
DGM1 
Denovo Genomic Marker 1 
DLBCL 
diffuse large B-cell lymphoma 
DMC 
data monitoring committee
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event free survival 
EIAEDs 
enzyme-inducing anti-epileptic drugs 
GCP 
Good Clinical Practice 
GSK3  
glycogen synthase kinase 3 beta 
HBV 
hepatitis B virus
HCV 
hepatitis C virus
HIPAA 
Health Insurance Portability and Accountability Act 
HIV  
human immunodeficiency virus 
HR 
hazard ratio 
ICD 
informed consent document 
ICH 
International Conference on Harmonization 
ID 
identification 
IEC 
Independent Ethics Committee 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board
IUD 
intrauterine device 
IV 
intravenous 
LDH 
lactate dehydrogenase 
mOS 
median overall survival 
MRI 
magnetic resonance imaging 

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MTD
maximum tolerated dose
MUGA 
multiple gated acquisition 
NCI 
National Cancer Institute 
NHL 
Non-
 
NOS 
not otherwise specified 
NYHA
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease (disease progression) 
PET 
positron emission tomography 
PFS 
progression free survival 
P-gp 
p-glycoprotein  
PI
Principal Investigator
PI3K 
phosphoinositide 3-kinase 
PK 
pharmacokinetics 
PKC 
protein kinase C
po 
per os (oral administration) 
PR 
partial response 
PT 
Preferred Term 
QD 
once daily 
R-CHOP 
rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine, 
and prednisone 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SEC 
US Securities and Exchange Commission 
SNP 
single-nucleotide polymorphism 
SOC 
standard of care 
SOE 
Schedule of Events 
TEAE 
treatment-emergent adverse event 
TID 
three times daily 
ULN
upper limit of normal
VEGF
vascular endothelial growth factor 
WHO 
World Health Organization 
 
 

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1
INTRODUCTION
1.1 
DIFFUSE LARGE B-CELL LYMPHOMA 
Non-
th most common cancer in the United States with 
72,580 new cases predicted to occur in 2016 (SEER database). Approximately 20,150 people 
were predicted to die from this disease in 2016. Of these, slightly more than half, approximately 
11,450 will be male, and 8,690 will be female. There are over a half million people with NHL 
living in this country. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the 
NHLs, accounting for between 30% 40% of all cases. The incidence of DLBCL generally 
increases with age and roughly half of all patients are over the age of 60 at the time of diagnosis 
(Lymphoma Research Foundation, 2018). 
DLBCL is classified as an aggressive lymphoma meaning that its clinical course can progress 
rapidly to death. Nevertheless, patients with DLBCL can be cured with the appropriate treatment. 
The current standard of care treatment for DLBCL consists of rituximab added to the 
anthracycline-containing combination chemotherapy regimen of cyclophosphamide, 
doxorubicin, vincristine and prednisone (NCCN Treatment Guidelines). This regimen is referred 
to as R-CHOP immunochemotherapy. For DLBCL as a whole, R-CHOP immunochemotherapy 
has resulted in cure rates of approximately 60%. However, for individual patients 5-year survival 
rates can range from 90% for low-risk DLBCL patients to less than 50% for high-risk DLBCL 
patients (Sehn et al., 2015; Zhou et al., 2014). 
Most important, for those subjects refractory to R-CHOP therapy less than 10% achieve a 
durable remission with secondary therapy (Sehn et al., 2015). Thus, while R-CHOP remains the 
standard treatment for high-risk, advanced-stage DLBCL, approximately 30 40% of patients fail 
front-line therapy with most not achieving Complete Response (CR) or with early relapse. An 
essential step to move forward and improve the outcomes of these patients is to increase the rate 
of complete response to front-line R-CHOP therapy (Chiapella et al., 2016).
For this reason, there has been a great deal of effort placed on attempting to define disease 
characteristics that predispose patients to a poorer prognosis with R-CHOP therapy. Molecular 
and gene expression profiling of tumors and a variety of clinical prognostic indices have been 
used to identify patients at higher risk of failing R-CHOP immunochemotherapy. While this 
work has identified subgroups of patients who do not respond well to R-CHOP, to date these 
efforts have not resulted in substantial gains in response to front-line therapy. 
Denovo Biopharma (Denovo) has pioneered an alternative approach to this challenging problem. 
Denovo has developed a model that employs sophisticated pharmacogenomic testing to detect 
somatic biomarkers that identify those subjects who responded to a particular study treatment 
with the aim of re-studying the drug of interest, in this case enzastaurin, in an enriched 
population. 
Applying this technology to archived DNA samples from completed studies of enzastaurin in 
subjects with DLBCL, Denovo has identified a somatic biomarker that reliably identified 
subjects for whom the study treatment significantly prolonged survival. Enzastaurin is an oral 
serine/threonine kinase inhibitor, that targets the PKC, and phosphoinositide 3-kinase (PI3K) and 

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AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress 
tumor-induced angiogenesis. 
The purpose of the current study is to prospectively assess the effect on survival of adding 
enzastaurin to R-CHOP immunochemotherapy in the front-line treatment of an enriched 
population of subjects with DLBCL. The detailed rationale for this study is provided in greater 
depth below. 
1.2 
ENZASTAURIN 
Enzastaurin, an acyclic bisindolylmaleimide, is a potent and selective inhibitor of PKC- . At 
plasma concentrations achieved clinically, enzastaurin and its metabolites suppress signaling not 
only through PKC, but also through the PI3K/AKT pathway; these pathways promote tumor-
induced angiogenesis, as well as tumor cell survival and proliferation. Accordingly, inhibition of 
signaling pathways by enzastaurin suppresses the phosphorylation of glycogen synthase kinase 3 
beta (GSK3 ) at ser9, induces cell death (apoptosis), and suppresses proliferation in cultured cell 
lines from human colon cancers (Gokmen-Polar et al., 2001), glioblastoma (da Rocha et al., 
2002), and lymphomas (Shipp et al., 2002). Oral dosing with enzastaurin to achieve exposure 
levels similar to that in human clinical studies suppresses vascular endothelial growth factor 
(VEGF)-induced angiogenesis and the growth of human colon cancer and glioblastoma 
xenografts. These studies have demonstrated that enzastaurin can suppress tumor growth through 
multiple mechanisms: the direct effect of inducing tumor cell death, suppressing tumor cell 
proliferation, and the indirect effect of suppressing tumor-induced angiogenesis. 
Enzastaurin was developed by Eli Lilly and Company (Lilly). Lilly performed 51 clinical studies 
and 15 clinical pharmacology studies of enzastaurin: 39 single-agent studies (enzastaurin alone, 
or enzastaurin with drugs other than anti-cancer agents) and 27 combination studies (enzastaurin 
+ another anti-cancer agent). As of September 2013, a total of 4,387 cancer patients and healthy 
subjects were enrolled in Lilly-sponsored clinical trials, of whom approximately 3,337 subjects 
received enzastaurin. Of the approximately 3,337 subjects who received enzastaurin, 3,149 were 
cancer patients and 188 were healthy subjects in 9 completed clinical pharmacology studies. In 
2014, Denovo completed the transfer of ownership of enzastaurin to enable its further clinical 
development. Denovo has identified a unique subset of patients with DLBCL who responded 
favorably to enzastaurin in a prior trial of similar design to this current study. 
1.3 
SUMMARY OF RELEVANT PRIOR ANIMAL AND HUMAN STUDIES 
1.3.1 
Absorption, Metabolism and Drug Interactions 
Food significantly increases exposures to enzastaurin and its metabolites in both healthy subjects 
and cancer patients. Patients are required to take enzastaurin in the fed state in order to maximize 
drug absorption. 
Enzastaurin is primarily metabolized in the liver, with minimal renal elimination. However, 
when enzastaurin was given to cancer patients with mild, moderate, or severe hepatic 
impairment, exposures tended to be lower than exposures observed in patients with normal 
hepatic function in previous studies, and decreased with increasing severity of hepatic 
dysfunction. It is currently not recommended to administer enzastaurin to patients with moderate 
or severe hepatic impairment. 

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The human cytochrome P450 (CYP) 3A enzyme appears to be responsible for the observed 
routes of enzastaurin metabolism: 
 Plasma exposures of enzastaurin were reduced significantly in patients receiving CYP3A 
enzyme-inducing anti-epileptic drugs (EIAEDs) compared to patients not receiving EIAEDs. 
Concomitant medications that are potent inducers of CYP3A are expected to significantly 
decrease enzastaurin exposures. 
 Potent CYP3A inhibitors (eg, ketoconazole) resulted in significantly higher exposures to 
enzastaurin in healthy subjects. Concomitant medications that are potent inhibitors of 
CYP3A are expected to significantly increase enzastaurin exposures. 
 In the presence of the weak CYP3A inhibitor cimetidine, the area under the curve (AUC) and 
maximum plasma concentration (Cmax) of enzastaurin increased approximately 20%, but 
there was no appreciable effect of cimetidine on the AUC or Cmax of the metabolite 
LSN326020. Concomitant medications that are weak CYP3A inhibitors are not expected to 
cause clinically significant changes in enzastaurin exposures. 
 Enzastaurin is a moderate inhibitor of CYP3A in cancer patients and may increase exposures 
to orally administered drugs that are CYP3A substrates. 
 In vitro studies suggest that enzastaurin and its major metabolite are inhibitors of CYP2C8, 
CYP2C9, and CYP2C19. If this inhibition occurs in vivo, exposures to drugs that are 
substrates of these enzymes may be increased. A warfarin interaction study in cancer patients 
indicates that enzastaurin is a weak inhibitor of CYP2C9 (area under the plasma 
concentration time curve from time zero to infinity ratio [AUC0- ] of 1.28). 
 In vitro data indicate that enzastaurin may be a P-glycoprotein (P-gp) inhibitor. However, in 
a drug interaction study with intravenous (IV) digoxin (a P-gp substrate), 500-mg daily doses 
of enzastaurin did not affect the exposures of digoxin in cancer patients; these results suggest 
that enzastaurin has no effect on P-gp activity in vivo. 
 The administration of a proton pump inhibitor had no significant effect on the exposure to 
enzastaurin when enzastaurin was administered in the fed state. 
 In mice, enzastaurin has been observed to produce an increase in hexobarbital-induced sleep, 
which suggests that enzastaurin may enhance the effect of anesthetic agents. 
 
1.3.2 
Preclinical and Clinical Toxicity 
1.3.2.1 
Liver 
Liver tumors were noted in a 2-year rat carcinogenicity study; the relevance of this finding to 
humans is unknown. 
Transient, mild increases in aspartate aminotransferase (AST) and alanine aminotransaminase 
(ALT) levels were observed in enzastaurin clinical trials. 

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1.3.2.2
Cataracts
Cataracts occurred in dogs in a 6-month study at approximately 3- to 5-fold the maximum human 
plasma exposures seen in cancer patients given 525 mg enzastaurin. 
1.3.2.3 
Retinal Findings 
High doses of enzastaurin (1500 mg/kg) given to transgenic (Tg.rasH2) mice every day for 
6 months caused hypertrophy of the retinal pigmented epithelium (RPE). These changes were not 
seen in mice given lower doses of enzastaurin for 6 months or in a 1-month study in mice given 
higher doses of enzastaurin. The relevance of this finding to humans is not clear. Some cases of 
blurred vision and also some rare but serious cases of retinal detachment/tear, blurred vision, and 
visual impairment have been reported in clinical trials. 
1.3.2.4 
Thrombocytopenia 
Enzastaurin-related thrombocytopenia has been reported and is usually mild and reversible.
1.3.2.5 
Hemorrhage 
Hemorrhage, possibly related to enzastaurin, was observed, including reports of possibly related 
fatal cerebral hemorrhage in patients with glioblastoma multiforme. 
1.3.2.6 
QTc Prolongation 
Nonclinical data suggest a potential for QT/QT interval corrected for heart rate (QTc) 
prolongation for both enzastaurin and its active metabolite, LSN326020. QTc prolongation has 
also been observed at steady state, following the administration of enzastaurin 500-mg daily 
doses to cancer patients, and a concentration-QT effect has been observed with higher doses. The 
protocol requires careful and frequent ECG monitoring. 
1.3.2.7 
Pregnant or Lactating Women 
Enzastaurin has not been evaluated in pregnant or lactating women, as these subjects have been 
excluded from enzastaurin clinical studies. Therefore, women of childbearing potential must 
have a negative serum pregnancy test prior to taking enzastaurin. 
1.3.2.8 
Adverse Events 
The most frequent ( 5%) AEs seen in single-agent Phase 1b and 2 enzastaurin studies in cancer 
subjects that were considered by the investigator to be possibly related to enzastaurin were 
fatigue (15.6%), chromaturia (12.3%), diarrhea (9.4%), nausea (9.3%), platelets decreased 
(7.4%), and transaminase elevated (6.4%). The most frequent adverse drug reactions reported in 
subjects receiving enzastaurin in the DLBCL Phase 3 maintenance study (PRELUDE; H6Q-MC-
JCBJ) were diarrhea (20.1%), chromaturia (19.5%), limb edema (15.8%), and prolonged QTc 
interval (11.63%). In general, the events reported for subjects in combination studies occurred at 
frequencies that were not higher than those described for the anti-cancer agents used.  
1.3.3 
Pharmacokinetics in Humans 
Pharmacokinetics (PK) of enzastaurin was evaluated in a Phase 1, non-randomized, open-label, 
dose-
escalating oral doses of enzastaurin from 
20 mg to 700 mg administered to 47 subjects with advanced or metastatic cancer. The data 

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showed that the maximum drug concentration in plasma (Cmax) of enzastaurin was reached 
within 4 hours of dosing. The half-life of enzastaurin ranged from 12.3 to 26.7 hours and 
accumulated 1.5- to 3.0-fold upon daily dosing. There was temporal linearity since plasma 
concentrations from Day 1 dosing predicted Day 28 concentrations reasonably well. Dose 
escalation proceeded with only three dose-limiting toxicities (DLTs) of prolongation of QTc by 
>50 msec over baseline. One of these occurred at the 700-mg dose and two others at the 525-mg 
dose. Laboratory and non-laboratory National Cancer Institute (NCI) Common Toxicity Criteria 
(CTC; NCI 1998, CTC Version 2) Grade 3 or 4 toxicities were not observed at any dose level. 
The maximum tolerated dose (MTD) was not identified to be in the dose range 20 to 700 mg. No 
increase in mean plasma exposures was seen at 700 mg compared to 525 mg. The most 
commonly reported toxicities were fatigue and reddish discoloration of urine and feces 
(enzastaurin is red in color). Overall, enzastaurin was well tolerated in this study. 
In Study H6Q-MC-JCAJ (JCAJ), a Phase 2 trial of enzastaurin as single-agent therapy in 
subjects with recurrent high-grade glioma, subjects on enzyme-inducing anti-epileptic drugs 
(EIAEDs) such as phenytoin and carbamazepine had significantly decreased enzastaurin 
exposures. 
The pharmacokinetics of enzastaurin was evaluated in 25 native Chinese cancer patients who 
each received a fixed dose of 500 mg of enzastaurin. Twenty-one subjects were available for the 
PK analysis. The Tmax was found to be approximately four hours and the half-life of enzastaurin 
was found to be approximately 14 hours. The mean AUC at steady state was 29,100 nmol.h/L for 
enzastaurin and 21,800 nmol.h/L for the active metabolite LSN326020. These results compare 
favorably with those from studies in other cancer patients in which the mean AUCss for 
enzastaurin ranged from 23,600 to 44,100 nmol.h/L and for LSN326020 from 15,000 to 23,000 
nmo.h/L. Enzastaurin appeared to be safe and well tolerated in this population (Li, X et al., 
2016). 
Previous human studies have shown that 14 days of daily oral dosing is needed to achieve steady 
state exposures of enzastaurin. 
1.3.4 
Previous Human Studies of Patients With NHL 
The Lilly 
 Brochure lists seven studies in 899 subjects in which enzastaurin was 
administered to patients with NHL. Of these, four studies administered enzastaurin to 
approximately 673 subjects with DLBCL. These seven studies are summarized in 
Table 1 below. 

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Table 1. 
Summary of Prior Studies of Enzastaurin Performed in Subjects with NHL 
Study ID/ 
Title 
Enza 
Dose 
Objective 
Key I/E 
Criteria 
# of 
Subjects 
Results 
H6Q-MC-JCAI 
A Multicenter, 
nonrandomized, open-label, 
single arm, Phase 2 study of 
enzastaurin in patients with 
relapsed/refractory DLBCL 
500 mg/day 
6 x 28-day cycles 
Primary 
endpoint: 
clinical 
response 
rate 
Relapse following < 4 
prior treatment 
regimens at least one of 
which must have been 
CHOP 
N = 55 
(42 evaluable) 
Clinical RR: 21.8% 
ORR: 4% 
H6Q-MC-JCAO  
A Multicenter, 
nonrandomized, open-label, 
single arm, Phase 2 study of 
enzastaurin in patients with 
relapsed mantle cell 
lymphoma 
500 mg/day 
6 x 28-day cycles 
FFP for 
 
PFS 
Relapse following < 5 
prior treatment 
regimens 
N = 59 
FFP rate for  3 cycles: 35.6% 
A subset of subjects had extended stable 
disease with 6 free from progression for 
> 6 months and 3 remaining on study for at 
least 15 months. No objective complete or 
PR were observed in this study. Median 
PFS: 1.97 months 
H6Q-MC-S011 
A Phase 2 Study of 
Enzastaurin in Patients with 
Follicular Lymphoma 
1125 mg loading 
dose D1 followed 
by 500 mg/d 
ORR; 
PFS 
Gr 1 or 2 follicular 
lymphoma; Stage III or 
IV disease; no more 
than one prior treatment 
regimen
N = 66 
(53 evaluable) 
ORR = 26.4% (3.8% CR). Median PFS = 
551 days 
H6Q-M-S013 
An Open-Label, Single-
Arm, Phase 2 study of 
Rituximab, Gemcitabine 
and Oxaliplatin plus Oral 
Enzastaurin as Treatment 
for Patients with Relapsed 
DLBCL 
1125 mg loading 
dose D1 followed 
by 500 mg/d 
PFS rate 
at 12 
months 
DLBCL  60 y.o. or if 
< 60 not eligible for 
ASCT 
N = 68 treated 
PFS rate at 12 months = 16.4% 

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Study ID/ 
Title 
Enza 
Dose 
Objective 
Key I/E 
Criteria 
# of 
Subjects 
Results 
H6Q-MC-S028 
An Open-Label, 
Randomized, Phase 2 Study 
of R-CHOP Plus 
Enzastaurin versus R-CHOP 
in the First-Line Treatment 
of Patients with 
Intermediate and High-Risk 
Diffuse Large B-Cell 
Lymphoma 
6 x 21-day cycles 
of R-CHOP plus 
enzastaurin or 
R-CHOP 
enzastaurin dose: 
1125 mg loading 
dose followed by 
500 mg/day. 
Maintenance 
enzastaurin 
500 mg/d for up 
to 3 years 
PFS, RR, 
OS 
Chemo naïve adults 
with histologically 
confirmed DLBCL
N = 101 
(100 evaluable); 
57 enzastaurin, 
43 placebo 
Median PFS: for R-CHOP/enzastaurin 
36.2 months (95% CI: 20.2, NE; range 
1-55 months); R-CHOP 23 months (95% 
CI: 9, NE; range 1-46.2 months; HR, 0.73; 
p = 0.151) 
High risk (IPI score > 2) 
R-CHOP/enzastaurin PFS when compared 
to R-CHOP: HR, 0.5; p = 0.037). 
Safety profile similar to control with slight 
increase in febrile neutropenia in 
enzastaurin arm. 
PK demonstrated no relevant drug-drug 
interactions between enzastaurin and 
CHOP components 
H6Q-MC-S057 
A Multicenter, Open-Label, 
Noncomparative Study of 
Enzastaurin in Patients with 
Non-
Lymphomas 
1125 mg loading 
dose D1 followed 
by 250 mg BID 
ORR 
Relapsed subjects with 
TCL, or IBCL, or 
ABCL 
N = 57 
ORR: CTCL = 18.2%; SLL=14.3% and 
follicular grade 1 & 2 = 12.5%; Follicular 
grade 3a & 3b = 20.0% and history of 
IBCL = 10.0%. All responses were PR, 
except 1 CTCL patient had a CRu. 
H6Q-MC-JCBJ 
A Phase 3 Study to 
Investigate the Prevention 
of Relapse in Lymphoma 
Using Daily Enzastaurin 
(PRELUDE) 
500 mg/d for up 
to 3 years 
DFS 
DLBCL, CR or CRu 
R-CHOP, stage 3 or 4 
disease or bulky stage 2 
disease 
N = 758 
randomized; 
742 treated; 
Enzastaurin 493; 
placebo 249 
Investigator-assessed DFS HR 0.92 
(p = 0.54) 
Safety profile: 
TEAEs 93.1% enzastaurin vs 92.4% 
placebo; 
Gr 3/4 QTc prolongation: 3.4% 
enzastaurin vs 2.4% placebo; all but one = 
Gr 3 
Abbreviations: ABCL, aggressive B-cell lymphoma; ASCT, autologous stem cell transplant; BID, twice daily; CR, complete response; CRu, unconfirmed 
complete response; CTCL, cutaneous T-cell lymphoma; DFS, disease free survival; DLBCL, diffuse large B-cell lymphoma; FFP, freedom from progression; 
Gr, grade; HR, hazard ration; IBCL, indolent B-cell lymphoma; IPI, International Prognostic Index; NE, non-estimable; ORR, objective response rate; OS, 
overall survival; PK, pharmacokinetic; PFS, progression free survival; PR, partial response; RR, response rate; SLL, small lymphocytic lymphoma; TCL, T-cell 
lymphoma; TEAE, treatment-emergent adverse event 
 
 

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1.4
DISCOVERY AND VALIDATION OF DGM1 BIOMARKER
As noted in the introduction, Denovo has pioneered an alternative approach to improving the 
response of patients with DLBCL to first line therapy with R-CHOP. Denovo has developed a 
model that employs sophisticated pharmacogenomic testing to detect somatic biomarkers that 
identify those subjects who responded to a particular study treatment with the aim of re-studying 
the drug of interest, in this case enzastaurin, in an enriched population. 
The first such test of this model was applied to the Prelude trial. This was a multinational, 
randomized, double-blind, placebo-controlled study of high-risk DLBCL (IPI  3) patients with a 
histologic diagnosis of diffuse large B-cell lymphoma (DLBCL) and a CR or CRu, or a negative 
FDG-PET scan after 6 8 cycles of R-CHOP. Patients were randomly assigned in a 2:1 ratio to 
receive either enzastaurin 500 mg daily or an identical placebo as maintenance therapy, for a 
planned treatment duration of 3 years. The primary endpoint was DFS, defined as lack of disease 
progression or death. Data were analyzed three years after the last enrolled subject initiated 
treatment. 
The study enrolled 758 subjects (enzastaurin, n = 504; placebo, n = 254). Median age at 
enrollment was 64 years (range 21 89); at diagnosis, 65% of patients had stage IV disease, 48% 
had B symptoms, and 25% had a mass >10 cm; baseline disease and patient characteristics were 
well balanced between treatment arms. Fifty-seven percent had a negative PET scan following 
completion of R-CHOP. Median follow-up time for all patients was 48 months (range 0.03 80). 
At the time of analysis, 209 events had occurred. The DFS HR for enzastaurin vs placebo was 
0.92 (95% CI: 0.69, 1.22; 2-sided log-rank p = 0.54). DFS at 24 and 48 months were 79% and 
70% for the enzastaurin arm, and 75% and 71% for placebo, respectively. OS at 24 and 48 
months was 87% and 81% for enzastaurin, and 89% and 82% for placebo; HR for enzastaurin vs 
placebo was 1.04 (95% CI: 0.74, 1.47; 2-sided log-rank p = 0.81) (Crump et al., 2013). 
DNA samples extracted from blood of patients enrolled in the Prelude trial were genotyped using 
whole genome single nucleotide polymorphism (SNP) arrays. Approximately 5 million SNPs 
were analyzed. It was found that a specific configuration for two SNPs located on chromosome 
8, Reference SNP ID 309605 (rs309605) and Reference SNP ID 309604 (rs309604), was 
strongly associated with survival in the enzastaurin arm. The p-value for this association was 5.8 
x 10-9 (Note, given the multiple comparisons performed in exploratory pharmacogenomic 
research, a p-value smaller than 5x10-8 is usually considered the threshold for genome-wide 
significance.). This biomarker is now referred to as the Denovo Genomic Marker 1 (DGM1). 
To confirm these findings from the Prelude trial, an analysis of the DGM1 biomarker was 
performed using archived DNA samples extracted from blood specimens from the P2 study of 
enzastaurin added to R-CHOP therapy in the front-line treatment of patients with intermediate or 
high-risk DLBCL. In this study, 101 subjects were randomized 3:2 to receive R-CHOP plus 
enzastaurin or R-CHOP as first line therapy for intermediate or high-risk DLBCL (enzastaurin-
58 subjects, control-43 subjects). Following the initial treatment period, subjects in the 
enzastaurin group received maintenance enzastaurin for up to 3 years or until disease 
progression. The median PFS for patients in the enzastaurin arm was 36.2 months vs 22.6 
months for in the control arm (HR = 0.73; p = 0.151). After adjusting for imbalances in baseline 
IPI score (  2 vs > 2) and Eastern Cooperative Oncology Group (ECOG) PS (0 vs 1 or 2), the 

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HR was 0.59 (95% CI: 0.32, 1.09; one sided p-0.048) (Hainsworth et al., 2016). In a post-hoc 
subgroup analysis, subjects with an IPI score > 2 had a median PFS that was not evaluable in the 
enzastaurin arm compared to 8.9 months in the control arm (HR = 0.50). The 2-year OS was 
75% and 69% in favor of enzastaurin in the overall population and 71% and 55% in favor of 
enzastaurin in the subset of subjects with an IPI score > 2. Conversely, in the post-hoc subgroup 
analysis, subjects with intermediate risk (IPI score 2) had an estimated increase in mortality from 
the addition of enzastaurin; approximately 90% of patients with IPI score 2 in the enzastaurin 
arm were DGM1 positive. 
The Kaplan-Meier curves for PFS (Figure 1) and OS (Figure 2) are shown below. 
Figure 1. 
Progression Free Survival R-CHOP/Enzastaurin vs R-CHOP 
 
 
The mOS was not reached in either group. The HR for survival was 0.81 (0.39 1.67), p = 0.33. 
Figure 2. 
Overall Survival R-CHOP/Enzastaurin vs R-CHOP 
 
0
10
20
30
40
50
60
0
10
20
30
40
50
60
70
80
90
100
Months
R-CHOP/Enza (N=55)
R-CHOP (N=42)

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Analyzing these data based on the presence or absence of the DGM1 biomarker yields the 
following results (Figure 3). In the R-CHOP/enzastaurin arm, mOS for those with the DGM1 
biomarker was not reached and for those lacking the biomarker was 22.5 months. The HR was 
0.1 (0.02 0.49) 
 
Figure 3. 
Overall Survival R-CHOP/Enzastaurin Arm Based on Presence or Absence 
of DGM1 Biomarker 
 
As discussed earlier, a subgroup analysis showed that addition of enzastaurin to R-CHOP had 
more favorable efficacy in high-risk DLBCL subjects and this efficacy is also observed in 
subjects who possess the DGM1 biomarker (Figure 4). The mOS for DGM1 positive, high-risk 
DLBCL (IPI  3) subjects in the R-CHOP/enzastaurin arm was not reached compared to 32.3 
months for DGM1 positive, high-risk DLBCL subjects in the R-CHOP arm. The HR was 0.28 
(0.1, 0.81). 
Figure 4. 
Overall Survival for DGM1 Positive, High-Risk DLBCL (IPI  3) Subjects 
R-CHOP/Enzastaurin vs R-CHOP 
 
The question arises as to whether the DGM1 biomarker is a predictive or prognostic biomarker. 
This question can best be answered by performing the same biomarker analysis on subjects in the 
0
10
20
30
40
50
60
0
10
20
30
40
50
60
70
80
90
100
Months
R-CHOP/Enza (N=29)
R-CHOP (N=22)

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R-CHOP control arm. When survival in the control arm (R-CHOP only) was analyzed, no 
improvement in survival was observed for subjects who possessed the 
 biomarker. The 
HR for survival in those subjects with the DGM1 biomarker was 1.02 (0.23 4.63) compared to 
those subjects who lacked the biomarker. These data are shown in Figure 5. These data 
demonstrate that in subjects with DLBCL, the DGM1 biomarker is a predictor of improved 
survival in the presence of enzastaurin, but does not confer a better prognosis for subjects who 
carry this biomarker. 
Figure 5. 
Overall Survival by Presence or Absence of DGM1 Biomarker R-CHOP 
Arm 
 
1.5 
STUDY RATIONALE 
The purpose of this study is to prospectively confirm the biomarker analysis results of the Phase 
2 (study H6Q-MC-S028) study of enzastaurin in subjects with newly diagnosed high-risk 
DLBCL. The primary objective will be to analyze the effect on OS of adding enzastaurin to R-
CHOP therapy in high-risk DLBCL (IPI  3) subjects who possess the DGM1 biomarker. This 
study aims to determine whether there is markedly improved survival in this enriched population 
compared to the current standard of care, R-CHOP alone. This study will be conducted in the 
United States, China and possibly other countries with an appropriate incidence of biomarker 
positive patients. The range of biomarker-positive subjects is approximately 68% for subjects of 
African ancestry living in the Southwest United States, approximately 90% for subjects of 
European ancestry, to approximately 95% of subjects living in Beijing, China. (International 
Genome Sample Resource-1000 Genomes Project). 
0
10
20
30
40
50
60
0
10
20
30
40
50
60
70
80
90
100
M onths
DGM1+ (N=33)
DGM1- (N=6)

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2
OBJECTIVES
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to compare the effect of R-CHOP plus enzastaurin 
followed by enzastaurin or standard of care (SOC) versus R-CHOP followed by SOC on OS in 
treatment naïve subjects with high-risk DLBCL who possess the DGM1 biomarker. 
2.2 
SECONDARY OBJECTIVES 
 To determine the effect on OS of adding enzastaurin to R-CHOP in treatment-naïve 
subjects with high-risk DLBCL regardless of DGM1 biomarker status  
 To evaluate Event-free Survival (EFS), including EFS12 and EFS24, for all subjects, and 
for subjects who are DGM1 biomarker positive. 
 To compare the combination phase investigator assessed CR rate and objective response 
rate (ORR) in subjects with high-risk DLBCL who are DGM1 biomarker positive 
administered R-CHOP plus enzastaurin versus R-CHOP. 
 To further evaluate the safety profile of enzastaurin when administered in conjunction 
with R-CHOP. 
2.3 
EXPLORATORY OBJECTIVES 
 
To determine enzastaurin and enzastaurin metabolite(s) concentrations for incorporation 
into a subsequent population pharmacokinetics (PK) analysis. 
 
To determine if the presence of other somatic or tumor biomarkers predicts improved 
efficacy in subjects taking enzastaurin. 
 
To determine if chromaturia (orange/red discoloration of the urine) predicts improved 
efficacy in subjects taking enzastaurin. 
 
To obtain samples urine for potential future analysis of enzastaurin metabolites. 
 
To explore any relationship between subsequent DLBCL therapy(ies) and OS. 
 
To assess regional similarities of primary and secondary efficacy measures between 
China and US. 

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3
INVESTIGATIONAL PLAN
This is a multinational, multicenter, randomized, placebo-controlled Phase 3 study of enzastaurin 
added to R-CHOP in the treatment of treatment naïve subjects with high-risk DLBCL. The trial 
will enroll approximately 235 subjects with treatment-naïve DLBCL. For purposes of ensuring 
diagnostic consistency across participating centers and regions, and as a measure of quality 
assurance, the diagnosis of DLBCL will be reviewed and confirmed by an expert pathologist 
prior to final study analysis. Within 8 weeks of diagnosis or confirmation of diagnosis by the 
enrolling institution, subjects who meet all the inclusion and none of the exclusion criteria will 
be randomized 1:1 to receive R-CHOP plus enzastaurin or R-CHOP plus placebo for up to six, 
21-day cycles (combination phase). R-CHOP will be administered in standard doses. Enzastaurin 
or placebo will be administered as an 1,125 mg loading dose (3 tablets TID within 30 minutes 
after a meal) on the first day after completion of R-CHOP administration in Cycle 1 and then 500 
mg/day (4 tablets once daily within 30 minutes after a meal) thereafter. High-risk DLBCL 
subjects will be defined as those with an IPI score of at least 3. 
After completion of the combination phase of treatment, subjects will be reassessed using PET-
CT and subsequently 
randomized to the enzastaurin arm who have a CR or PR 
by the 
Lugano Classification (Cheson 2014) will be offered single-agent enzastaurin at 500 mg/day (4 
tablets once daily) continuously for up to 2 additional years. All other subjects on the enzastaurin 
arm and subjects randomized to the placebo arm will receive no further study treatment and 
transition into the follow up phase of the study; these subjects will receive standard of care based 
on their response assessment. 
During follow up, all subjects will be followed for survival every 3 months until completion of 
the study, or 5 years, whichever comes first. The study is expected to take approximately 3.5 
years to complete. The study schema is shown below in Figure 6. 

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Figure 6.
Study Schema
 
Histologically confirmed DLBCL 
Consent 
Complete screening procedures 
All I/E criteria met 
Randomize
Within 8 weeks of Dx** 
                             R-CHOP + enzastaurin                    R-CHOP + placebo 
6 cycles                     
 
                                      Unblind                                              Unblind
                                                   
 
                                        CR, PR*  | (SD, PD)                            SOC 
                                            
 
                          Single-agent enzastaurin                                          
                    500 mg/d up to 2 additional years                                            
                        F/U until completion of trial                 F/U until completion of trial 
 
* Subjects with PR may receive single agent enzastaurin 
; all other subjects randomized to the 
enzastaurin arm will receive stand of care (SOC). 
**Within 8 weeks of diagnosis or confirmation of diagnosis by the enrolling institution 

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3.1
DISCUSSION OF STUDY DESIGN
This study is designed to confirm the biomarker analysis results of the Phase 2 (H6Q-MC-S028) 
study that suggested improved efficacy by adding enzastaurin to standard R-CHOP therapy in 
subjects with high-risk DLBCL who possess the DGM1 biomarker. Consequently, most of the 
features of that trial have been maintained in the current protocol. In order to minimize the 
potential for bias, the study will utilize a blinded, placebo-controlled design during the 
combination phase. In order to ensure that subjects are able to make an informed decision on 
their care, the treatment assignment of all subjects will be unblinded following completion of the 
combination phase and subsequent tumor assessment. 
While a number of prognostic indices have been developed for patients with DLBCL, the Phase 
index will be used in the current study. This index defines 5 variables: age (> 60), tumor stage 
(III or IV), number of extranodal sites (> 1), ECOG performance status (> 1) and serum lactate 
dehydrogenase (LDH) (> 1 times upper limit of normal). One point is assigned for each variable 
and subjects with 3 points are classified as high-intermediate risk, and subjects with 4 or 5 points 
are classified as high-risk DLBCL. Subjects must have at least 3 points in order to be eligible for 
this study (See Appendix B. International Prognostic Index). 
Because of the small number of biomarker negative subjects exposed to enzastaurin in Phase 2, 
biomarker negative subjects, as well as biomarker positive subjects, will be enrolled in this 
study. 

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4
STUDY POPULATION
Unless otherwise noted below, all eligibility criteria must be assessed within 28 days prior to 
randomization; tests performed as standard of care qualify for eligibility assessment if performed 
within this timeframe. Eligibility labs may be re-performed to meet eligibility if it is within the 
specified timeframe prior to randomization. IPI score (including LDH), and imaging scans 
should be performed before corticosteroids. 
4.1 
INCLUSION CRITERIA 
All inclusion criteria must be met for the subject to be considered for the study. 
1. Male or female at least 18 years of age and able to provide informed consent.
2. Histologically confirmed diagnosis of CD20 positive DLBCL based on the WHO 
classification (2016); the diagnosis must be confirmed at the enrolling site.  
Note: Subjects with high-grade B-cell lymphoma with MYC and BCL2 and/or 
BCL6 rearrangements, or high-grade B-cell lymphoma, NOS are eligible. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 
4. International Prognostic Index (IPI) score of at least 3. 
5. Estimated life expectancy of at least 12 weeks. 
6. Adequate organ function as follows (within 14 days prior to randomization): 
a. Hepatic: total bilirubin  1.5 times upper limit of normal (ULN) (  5 times 
ULN in the case of Gilberts Syndrome, liver or pancreatic involvement by 
lymphoma); alanine transaminase (ALT) and aspartate transaminase (AST) 
 2.5 times ULN (  5 times ULN if liver involvement) 
b. Renal: creatinine clearance of  40 mL/min by Cockcroft- Gault equation 
c. Bone marrow: platelets  75 x 109/L, absolute neutrophil count (ANC)  1.5 
x 109/L, hemoglobin  8 g/dL. (Platelets  50 x 109/L, ANC  1.0 x 109/L, 
hemoglobin  7.0 g/dL permitted if documented bone marrow involvement) 
7. Male or female with reproductive potential, must be willing to use an approved 
contraceptive method (for example, intrauterine device (IUD), birth control pills, or 
barrier device) during and for 3 months after discontinuation of study treatment. 
Women of childbearing potential must have a negative serum pregnancy test within 
7 days prior to randomization. 
a. Men are considered of reproductive potential unless they have undergone a 
vasectomy and confirmed sterile by a post-vasectomy semen analysis. 
b. Women are considered of reproductive potential unless they have undergone 
hysterectomy and/or surgical sterilization (at least 6 weeks following a 
bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive 
procedure that has been confirmed in 
) or 
achieved postmenopausal status (defined as cessation of regular menses for 
greater than 12 consecutive months in women at least 45 years of age). 
8. Left ventricular ejection fraction  50% by echocardiography or nuclear medicine 
multi-gated scan. 
9. Must be able to swallow tablets. 
10. Must be able to comply with study protocol procedures. 
11. Willing to consent to have blood stored for possible future biomarker and disease 
analysis. 

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12. Must have available and willing to submit pre-systemic treatment DLBCL tumor
biopsy tissue/slides for central pathology review.
4.2 
EXCLUSION CRITERIA 
None of the exclusion criteria is met in order for the subject to be considered for the study. 
1. Received treatment with an investigational drug within the last 30 days.
2. Receiving or has received radiation or any other systemic anticancer treatment for
lymphoma (Up to 10 days of corticosteroids is permitted but should be
administered after eligibility IPI determination and imaging scans).
3. History of indolent lymphoma or follicular Grade 3b lymphoma.
4. Primary mediastinal (thymic) large B-cell lymphoma.
5. B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
classical Hodgkin lymphoma.
6. Burkitt lymphoma.
7. Pregnancy or breastfeeding.
8. Known central nervous system (CNS) involvement.
9. Any significant concomitant disorder based on the discretion of the investigator,
including but not limited to active bacterial, fungal, or viral infection, incompatible
with participation in the study.
10. A second primary malignancy (except adequately treated non-melanoma skin
cancer); subjects who have had another malignancy in the past, but have been
disease-free for more than 5 years, and subjects who have had a localized
malignancy treated with curative intent and disease free for more than 2 years are
eligible.
11. Use of a strong inducer or moderate or strong inhibitor of CYP3A4 (See
Appendix A. Examples of Inhibitors and Inducers of CYP 3A4) within 7 days prior to
start of study therapy or expected requirement for use on study therapy.
12. Personal or immediate family history of long QT syndrome, QTc interval > 450
msec (males) or > 470 msec (females) at screening (recommended that QTc be
calculated using Fridericia correction formula, QTcF: see Section 6.2.1), or a
history of unexplained syncope.
13. Use of any medication that can prolong the QT/QTc interval (See Appendix C.
Drugs That Can Prolong the QT Interval) within 7 days prior to start of study therapy 
or expected requirement for use on study therapy. 
14. History of severe allergic or anaphylactic reaction to monoclonal antibody therapy.
15. Confirmed diagnosis of progressive multifocal leukoencephalopathy.
16. Ongoing grade 2 or higher peripheral neuropathy.
17. Have any of the following cardiac disorders: uncontrolled hypertension, unstable
angina, myocardial infarction within 8 weeks of randomization, New York Heart
Association (NYHA) Grade 2 or higher congestive heart failure, ventricular
arrhythmia requiring medication within 1 year of randomization, Fontaine
Classification stage III or higher peripheral arterial disease.
18. Received a live vaccine within 28 days of randomization.
19. HIV positive.

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20. Evidence of chronic hepatitis C infection as indicated by antibody to HCV with 
positive HCV-RNA. 
21. Evidence of chronic hepatitis B infection as indicated by either: 
a) HBsAg+ or  
b) HBcAb+ with HBV-DNA+ (any detectable amount is considered positive) 
4.3 
RATIONALE FOR KEY EXCLUSION CRITERIA 
This study is designed to confirm the biomarker analysis results of the Phase 2 (H6Q-MC-S028) 
study that demonstrated improved efficacy by adding enzastaurin to standard R-CHOP therapy in 
subjects with high-risk DLBCL who possess the DGM1 biomarker. Consequently, most of the 
features of that trial have been maintained in the current protocol. Because the number of DGM1 
biomarker negative subjects treated in that study was too small to definitively assess their 
response to enzastaurin, both biomarker positive and negative subjects will be enrolled in the 
current study. 
Because enzastaurin can prolong the QT interval, patients with a personal or immediate family 
history of long QT syndrome QTc interval > 450 msec (males) or 470 msec (females) at 
screening, a history of ventricular arrhythmias requiring medication within 1 year of 
randomization or a history of unexplained syncope, are excluded from participating in the 
study. 
Because of the risk of cardiac dysfunction in subjects receiving anthracycline-based 
chemotherapy, the protocol excludes subjects with clinical or laboratory evidence of left 
ventricular dysfunction. An increase in the frequency of left ventricular cardiac function 
assessment is recommended in subjects who have received doxorubicin in the past, 
particularly as the cumulative dose exceeds 300 mg/m2. 
Although subjects with chronic hepatitis B infections may be treated with R-CHOP in 
conjunction with antiviral medication, the lack of PK or safety data with such combinations 
has prompted the exclusion of patients with chronic hepatitis B and C infections from this 
study. 
4.4 
WITHDRAWAL OF SUBJECTS 
4.4.1 
Discontinuation of Study Treatment 
Subjects must discontinue study treatment for any of the following reasons: 
1. The subject withdraws consent or requests to discontinue treatment on study. 
2. The subject refuses to comply with the requirements for study evaluations/visits. 
3. The subject develops 
condition or circumstances that prevents further administration of study treatment or 
would place the subject at unacceptable risk, as determined by the Investigator in 
consultation with the Medical Monitor.  
4. 
 
5. Progressive disease that requires institution of a non-study therapy. 

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6. The subject becomes pregnant. Pregnant subjects should be followed for the duration of
the pregnancy and the outcome of the pregnancy should be documented.
7. The subject cannot tolerate the study treatment despite dose delay and modification and
appropriate supportive care.
8. Subject develops QTc prolongation >500 msec with life-threatening signs and symptoms
(eg, arrhythmia, chronic heart failure, hypotension, shock, syncope) or torsade de pointes
(CTCAE Grade 4).
9. Discontinuation of the study by the Sponsor, relevant regulatory agencies, or Institutional
Review Board (IRB)/Independent Ethics Committee (IEC).
10. The subject dies.
All randomized subjects who discontinue from the study treatment should undergo the applicable 
End of Treatment (EOT) procedures and, unless consent is withdrawn, followed for survival as 
indicated in the Schedule of Events (SOE) in Table 6. 
4.4.2 
Withdrawal from Follow-Up 
Subjects may withdraw or may be withdrawn from study follow-up, for any of the following 
reasons: 
1. The subject withdraws consent or requests to be withdrawn from the study.
2. The subject dies.
3. The study concludes.
4.5 
TERMINATION OF THE STUDY 
The Sponsor retains the right to terminate the study at any time. 

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5
TREATMENT
5.1 
TREATMENTS ADMINISTERED 
Subjects will be randomly assigned to receive one of the following: R-CHOP plus enzastaurin 
(Arm A) or R-CHOP plus placebo (Arm B). There are two treatment periods: combination and 
single agent. Study treatment should be initiated within 3 days of randomization. For the R-
CHOP regimen, subjects will receive a rituximab product, which may include Rituxan/MabThera 
or an FDA-approved rituximab biosimilar. However, for a given subject, Rituxan/MabThera or 
an FDA-approved rituximab biosimilar cannot be used interchangeably during the study; each 
subject must use the same rituximab product exclusively throughout the study treatment course. 
5.1.1 
Pre-randomization Treatment 
Subjects may receive up to 10 days of treatment with corticosteroids prior to randomization. 
Such pre-randomization treatment should not 
imaging 
scans, and IPI determination (including LDH) have been completed. Eligibility CBC must be 
assessed before or > 14 days after transfusion. 
5.1.2 
Combination 
During the combination phase of the study, all subjects will receive R-CHOP in standard doses 
for up to six, 21-day cycles. Subjects in the enzastaurin arm (Arm A) will receive a 1125 mg 
loading dose on the first day following completion of R-CHO administration in Cycle 1 followed 
by 500 mg daily. Subjects in the placebo arm (Arm B) will take an identical number of tablets. 
These treatments are summarized in Table 2 and Table 3. 
Table 2. 
Summary of Combination Dosing Regimens 
Arm A 
Arm B 
R-CHOP* 
Up to six 21-day cycles 
Up to six 21-day cycles 
Enzastaurina 
Day 2b: 1125 mg (3 tablets 
TID); 
Subsequent doses: 500 mg (4 
tablets) QD 
 
Matching Placeboa
 
Day 2b: 3 tablets TID; 
Subsequent doses: 4 tablets QD 
*See details in Table 3 below. 
a 
Taken within 30 minutes after a meal 
b 
If R-CHO given over 2 days, the loading dose will be given on Day 3. 
 

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Table 3.
R-CHOP Regimen
Drug 
Dose/Mode 
Day of Cycle 
Rituximab*** 
375 mg/m2 IV* 
Day 1** 
Cyclophosphamide 
750 mg/m2 IV 
Day 1 
Doxorubicin 
50 mg/m2 IV 
Day 1 
Vincristine 
1.4 mg/m2 i.v. (2 mg max) 
Day 1 
Prednisone 
100 mg po 
Days 1 5 
Abbreviations: IV, intravenous; po, per os (oral administration) 
*Premedicate with acetaminophen and antihistamine. First infusion: start at 50 mg/hr and increase by no more 
than 50 mg/hr every 30 minutes until a maximum of 400 mg/hr. Subsequent infusions: start at 100 mg/hr and 
increase by no more than 100 mg/hr every 30 minutes until a maximum of 400 mg/hr. If the subject did not 
experience a Gr 3 or 4 infusion reaction during Cycle 1, a 90-minute infusion can be administered with a 
glucocorticoid-containing chemotherapy regimen for subsequent infusions. Please consult full rituximab 
prescribing information for details. 
given on Day 2. Prednisone would then be given Days 2 6 and enzastaurin loading dose would be given on Day 
3. Although it is preferred that the entire R-CHOP regimen is administered on Day 1 in subsequent cycles, 
investigators may administer R-CHOP over two days in the same manner as Cycle 1 in subsequent cycles. 
Flexibility with R-CHOP schedule is allowed per local institutional practice. 
*** A rituximab product (Rituxan/MabThera or an FDA-approved rituximab biosimilar) may be used. However, 
for a given subject, Rituxan/MabThera or an FDA-approved rituximab biosimilar cannot be used interchangeably 
during the study; each subject must use the same rituximab product exclusively throughout the study treatment 
course. 
The investigator or his/her designee is responsible for explaining the correct use of the 
investigational agent(s) to subjects, verifying that instructions are followed properly, maintaining 
accurate records of study drug dispensing and collection, and returning all unused medication to 
Denovo or its designee at the end of the study, unless it is th
of unused investigational product (IP) on site. 
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug. 
At the completion of the combination phase, a restaging tumor assessment will be performed at 
least 4 weeks but preferably at 6 to 8 weeks after the last combination cycle of R-CHOP; weeks 
calculated from the last administration of rituximab product. Enzastaurin/placebo will continue 
to be taken daily until unblinding determines transition to either the follow up phase or single-
agent phase (see Section 5.1.3). Unblinding to treatment assignment will occur after the post-
combination phase tumor response assessment is determined and documented. 
5.1.3 
Single-Agent 
Following completion of 6 cycles of combination therapy and restaging via PET-CT, the 
treatment assignment for each subject will be unblinded. Subjects in the enzastaurin arm who 
have achieved a CR 
 will have the opportunity to continue in 
the single-agent phase of the study. These subjects will receive single agent enzastaurin at 500 
mg/day for up to 2 additional years. Subjects who discontinue R-CHOP plus enzastaurin therapy 
before 6 cycles but otherwise meet these response criteria will also be allowed to continue to 
single-agent enzastaurin 
; these subjects must also undergo 
end of combination phase tumor assessment (at least 4 weeks but preferably 6 to 8 weeks after 

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the last combination cycle of R-CHOP) with response documented before unblinding. All other 
subjects will receive no further study treatment and will transition into the follow up phase; these 
subjects will receive standard of care based on their response assessment. The post-combination 
treatments are summarized in Table 4. 
Table 4. 
Summary of Post-Combination Treatments 
Arm A 
Arm B 
CR, PR*
500 mg (4 tablets) QD with 
food for up to 2 additional 
years
Standard of Care
SD, PD 
Standard of Care 
Standard of Care
Abbreviations: CR, complete response; PD, disease progression; PR, partial response; QD, once daily; 
SD, stable disease 
*
 
5.2 
MATERIALS AND SUPPLIES 
5.2.1 
Enzastaurin (Kinenza®)/Placebo 
Enzastaurin will be supplied by Denovo as enzastaurin monohydrochloride tablets containing 
125 mg of active drug. The tablets must not be crushed or broken for administration.
The drug will be supplied in bottles containing 96 tablets. A separate bottle containing 9 tablets 
will be supplied for the loading dose. 
Room temperature storage condition is recommended for the tablet drug product. The pharmacist 
or designee will dispense the correct number of tablets for each dosing cycle. 
If a patient vomits within 30 minutes of taking a dose of enzastaurin, the enzastaurin dose should 
be repeated one time only, that same day, if nausea/vomiting is tolerable (at the discretion of the 
investigator). 
Enzastaurin should be taken at approximately the same time every day, within approximately 30 
minutes after a meal, preferably breakfast or lunch. 
Matching placebo will be supplied for the combination phase of the study and should be taken in 
the same fashion as enzastaurin. 
5.2.2 
Rituximab Product 
Rituximab product, which may include Rituxan/MabTheraor an FDA-approved rituximab 
biosimilar, will be supplied locally and should be prepared according to the package insert or 
local institutional practice.  
Premedication consisting of acetaminophen and diphenhydramine may attenuate infusion 
reactions and should be given approximately 30 60 minutes before each infusion. A 
glucocorticoid may also be administered prior to rituximab product infusion if that is the local 
standard of care. 

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On Day 1 of each 21-day cycle, rituximab product is given as a slow intravenous infusion at a 
dose of 375 mg/m2. Rituximab product should never be administered as an intravenous 
push or bolus, as severe infusion reactions may occur. These reactions typically occur during 
the first infusion with a time to onset of 30 120 minutes. 
First Infusions 
The subject must be afebrile at the time of the first infusion. Rituximab product should not be 
mixed or diluted with other drugs. The initial infusion rate should be 50 mg/hr. If the subject 
tolerates this infusion, the rate can be escalated in 50 mg/hr increments every 30 minutes to a 
maximum of 400 mg/hr. If an infusion reaction develops, the infusion should temporarily be 
resumed at one-half the previous rate. 
For Cycle 1, at the 
rituximab product may be given alone on Day 1 with 
other components of CHOP given on Day 2. Prednisone would then be given Days 2 6 and 
enzastaurin loading dose or placebo would be given on Day 3. Additionally, investigator may 
choose to administer rituximab product over 2 days at the beginning of each cycle per local 
practice. Although it is preferred that the entire R-CHOP regimen is administered on Day 1 in 
subsequent cycles, investigators may administer R-CHOP over two days in the same manner as 
Cycle 1 in subsequent cycles. 
Subsequent Infusions
If the subject tolerated the first infusion well, subsequent infusions of rituximab product can be 
administered at an initial rate of 100 mg/hr and increased in 100 mg/hr increments at 30-minute 
intervals to a maximum of 400 mg/hr. If the subject did not tolerate the first infusion well, 
subsequent infusions should follow the guideline for first infusion above. If the subject did not 
experience a Grade 3 or 4 infusion reaction during Cycle 1, a 90-minute infusion can be 
administered with a glucocorticoid-containing chemotherapy regimen for subsequent infusions. 
Please consult full rituximab prescribing information for details. 
5.2.3 
Cyclophosphamide 
Cyclophosphamide will be supplied locally and should be prepared according to the package 
insert or local institutional practice. Cyclophosphamide 750 mg/m2 will be given intravenously 
on Day 1 of each 21-day cycle. If the investigator elects to give R-CHOP over 2 days, 
cyclophosphamide will be given on Day 2. 
5.2.4 
Doxorubicin
Doxorubicin will be supplied locally and should be prepared according to the package insert or 
local institutional practice. Doxorubicin 50 mg/m2 will be given intravenously on Day 1 of each 
21-day cycle. If the investigator elects to give R-CHOP over 2 days, doxorubicin will be given 
on Day 2. 
5.2.5 
Vincristine 
Vincristine will be supplied locally and should be prepared according to the package insert or 
local institutional practice. Vincristine 1.4 mg/m2 (2 mg max) will be given by intravenous push 

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on Day 1 of each 21-day cycle. If the investigator elects to give R-CHOP over 2 days, vincristine 
will be given on Day 2. 
5.2.6 
Prednisone 
Prednisone will be supplied locally. Prednisone 100 mg will be given orally from Day 1 through 
Day 5 of each 21-day cycle. If the investigator elects to give R-CHOP over 2 days, prednisone 
will be given on Day 2 through Day 6. 
5.3 
METHOD OF ASSIGNMENT TO TREATMENT 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized through a web-based (IWRS) or voice-activated (IVRS) randomization system. 
Randomization will be stratified by IPI score: 3 vs 4, 5, and by region. 
5.4 
RATIONALE FOR SELECTION OF DOSES IN THE STUDY 
As discussed previously, the purpose of this study is to confirm the results of the Phase 2 study, 
H6Q-MC-S028. The dose of enzastaurin used in the Phase 2 study was 500 mg/day following an 
1125 mg loading dose. This dose has been administered to over 600 subjects with DLBCL. In the 
completed Phase 2 study, when combined with R-CHOP, this dose was found to have a safety 
profile similar to that of the R-CHOP control arm. 
R-CHOP is still considered the standard of care for subjects with DLBCL and will be 
administered in the recommended doses.
5.5 
DOSE MODIFICATIONS 
5.5.1 
Enzastaurin 
5.5.1.1 
During Combination Therapy 
Subjects should be supported by initiation of colony stimulating factors and/or platelet 
transfusions. If a subject experiences any of the following events that are considered related to 
the study drug, enzastaurin/placebo will be held until the event resolves (all CTCAE grades are 
based on CTCAE v4.03): 
 Febrile neutropenia, defined as ANC < 1.0 x 109/L with a single temperature of 
> 101°F/38.3°C or sustained temperature of  100.4°F/38°C for more than one hour 
 CTCAE Grade 4 anemia, neutropenia or thrombocytopenia that continues after delaying 
R-CHOP therapy or Grade 3 thrombocytopenia with clinically significant bleeding that 
continues after delaying R-CHOP therapy 
 CTCAE Grade 3 or 4 transaminase elevations 
 CTCAE Grade 3 or 4 nonhematologic toxicity (excluding alopecia) considered clinically 
relevant. Study drug should be held for Grade 3 or 4 nausea or vomiting that lasts for 
more than 3 days despite supportive management. (Note: subjects with QTc >500 msec 
should have ECGs performed in triplicate, approximately five minutes apart. If 2 of the 3 
ECGs demonstrate QTc > 500 msec [Grade 3 QTc prolongation], study drug should be 
held, and a repeat ECG should be performed within 7 days after study drug is held.)

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If the event resolves to  
(or if the QTc corrects to 
 450 msec [males] or  470 msec [females]), enzastaurin/placebo should be restarted at a 
reduced dose of 250 mg (2 tablets) per day. If, after restarting therapy, the subject does not have 
recurrence of the event after 14 days, the dose of enzastaurin/placebo may be re-escalated to 500 
mg (4 tablets) at the discretion of the investigator. If the event has not resolved to Grade 1 or to 
baseline (or QTc to  450 msec [males] or  470 msec [females]) within 42 days 
or the same event reoccurs during therapy at the 250 mg/day dose, enzastaurin/placebo will be 
discontinued.  
Except for subjects who had enzastaurin discontinued for QTc prolongation, subjects who had 
enzastaurin discontinued during the combination phase (in the enzastaurin arm) and experienced 
a CR or PR at end of combination treatment, may receive single agent enzastaurin during the 
single-agent phase at the discretion of the investigator. 
5.5.1.2 
During Single-Agent Therapy 
If a subject experiences any of the following events that are considered related to enzastaurin, the 
drug will be held until the event resolves (all CTCAE grades are based on CTCAE v4.03): 
 ANC < 0.5 x 109/L for longer than 7 days, or ANC < 1.0 x 109/L with a single 
temperature of > 101°F/38.3°C (or sustained temperature of  100.4°F/38°C for more 
than one hour) or platelet count < 25 x 109/L 
 CTCAE Grade 3 or 4 transaminase elevations 
 Other CTCAE Grade 3 or 4 nonhematologic toxicity considered clinically relevant (Note: 
subjects with QTc > 500 msec should have ECGs performed in triplicate, approximately 
five minutes apart. If 2 of the 3 ECGs demonstrate QTc > 500 msec [Grade 3 QTc 
prolongation], study drug should be held, and a repeat ECG should be performed within 7 
days after study drug is held.) 
 
If the event resolves to  
(or if the QTc corrects to 
 450 msec [males] or  470 msec [females]), enzastaurin should be restarted at a reduced 
dose of 250 mg (2 tablets) per day. If, after restarting therapy, the subject does not have 
recurrence of the event after 14 days, the dose of enzastaurin may be re-escalated to 500 mg (4 
tablets) at the discretion of the investigator. If the event has not resolved to Grade 1 or to the 
(or QTc to  450 msec [males] or  470 msec [females]) within 42 days, or 
the same event reoccurs during therapy at the 250 mg/day dose, the subject will be discontinued 
from study treatment. 
5.5.2 
R-CHOP 
Dose reductions for R-CHOP chemotherapy will follow standard guidelines according to 
package insert or local institutional practice. Use of granulocyte-colony stimulating factors 
(eg, filgrastim or pegfilgrastim) as primary prophylaxis is encouraged. If subjects require delay 
of therapy due to neutropenia (based on parameters described below), or develop neutropenic 
fever, cytokines should be administered during subsequent courses. If delay in therapy due to 
neutropenia, or neutropenic fever occurs even when cytokines are used, the doses of 

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myelosuppressive agents (cyclophosphamide, doxorubicin) should be decreased to 75% for
subsequent courses. 
On the day of scheduled treatment: 
 ANC 1.2 x 109/L and platelets 75 x 109/L or ANC  1.0 x 109/L and platelets 
 50 x 109/L if documented bone marrow involvement, full dose. 
 ANC < 1.2 x 109/L or platelets < 75 x 109/L or ANC < 1.0 x 109/L and platelets < 50 
x 109/L if documented bone marrow involvement, delay dose at least 1 week
(maximum delay 21 days) until counts are above these levels. Recommend instituting 
granulocyte-colony stimulating factors if not already done so. 
For patients with symptomatic Grade 3 or any Grade 4 non-hematologic toxicity (except 
alopecia, nausea, and vomiting), treatment should be delayed until toxicity resolves to
Grade 1
or baseline, then continue with 75% doses of offending agents. 
Other toxicity delays of any of the individual chemotherapy regimen drugs (rituximab, 
cyclophosphamide, doxorubicin, vincristine and prednisone) are allowed. Other toxicity delays 
for R-CHOP as an unit are allowed to a maximum of two  14-day delays over all the 6 
treatment cycles. 
Even if R-CHOP is discontinued early, subjects who would otherwise qualify for single-agent 
treatment (Section 5.1.3) may move on to the single-agent phase of the study, at the discretion of 
the investigator. 
Rituximab product (Rituxan/MabThera or an FDA-approved rituximab biosimilar) will not be 
dose reduced, but infusion rates should be changed in accordance with the prescribing 
information listed in the package insert. Dose reductions for individual component of CHOP are 
allowed per local institutional practice or package insert. 
Dose modifications for changes in weight may be conducted per institutional practice. It is 
suggested that body weight change of more than 10% from weight used for previous dose 
calculation should lead to recalculation of BSA and dose adjustment if necessary.  
5.6 
BLINDING 
The combination period follows a double-blind, placebo-controlled design. Subjects will be 
randomized to receive enzastaurin or placebo tablets identical in appearance to the 
investigational product. Investigators, subjects and the Sponsor will be blinded to the treatment 
assignments. Treatment assignment will be unblinded after completion of the post-combination 
phase tumor assessment. 
5.7 
CONCOMITANT THERAPY
No other chemotherapy, immunotherapy, surgery for cancer, or experimental medications will be 
permitted while the patients are on study treatment. Radiation therapy is not permitted during the 
6 cycles Combination Phase. Consolidation radiotherapy is permitted after the completion of 
Combination Phase if it is site SOC, but it must be performed after the tumor assessment is 
complete. Any disease progression requiring other forms of specific antitumor therapy will be 

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cause for discontinuation from study treatment. Subjects discontinued from study treatment must 
continue to be followed for safety and efficacy assessments. 
Subjects are allowed to receive full supportive care therapies concomitantly during the study. At 
each visit, appropriate documentation of all forms of premedication, supportive care, and 
concomitant medications must be captured on the case report form (CRF). 
Concomitant medications and supportive care therapies must also be documented at the time of 
discontinuation.  
Premedication will be given per institutional guidelines. 
5.7.1 
Effect of Concomitant Medications on Enzastaurin Concentrations 
In vitro metabolism studies using human liver microsomes have demonstrated metabolism of 
enzastaurin is primarily by CYP3A. Concomitant medications that are potent inducers or 
inhibitors of isozyme CYP3A will therefore affect enzastaurin exposure. Concomitant drugs that 
are inducers of CYP3A could result in lower exposures of enzastaurin and its metabolites while 
concomitant drugs that are inhibitors of CYP3A may increase the exposure of enzastaurin and its 
metabolite(s) in patients. Potent inhibitors of CYP3A, such as ketoconazole, are expected to 
increase enzastaurin exposure. Based on these considerations, subjects who require therapy with 
a strong inducer or moderate or strong inhibitor of CYP3A4 should not be enrolled into the 
study. If medically justified, subjects may be enrolled if such inhibitors or inducers can be 
discontinued or alternative drugs that do not affect these enzymes can be substituted > 7 days 
before the first dose of the study drug. 
During study participation administration of enzastaurin with a strong inducer or moderate or 
strong inhibitor of CYP3A4 should be avoided, if possible. However, a subject who develops a 
condition that may require use of such drugs is not required to permanently discontinue 
enzastaurin if the subject is experiencing clinical benefit. If medically appropriate, investigators 
may wish to use a therapeutic alternative that would not be expected to affect these enzymes. For 
subjects who require temporary use of a strong inducer or moderate or strong inhibitor of 
CYP3A4, enzastaurin should be interrupted during use of the other medication and then resumed 
no early than 7 days after its completion. For subjects who require initiation of chronic therapy 
with a drug that potently affects these enzymes, investigators must consult with the Medical 
Monitor to consider the best course of action. 
A list of moderate and potent CYP3A inhibitors and potent inducers is found in Appendix A. 
In order to avoid potential drug-drug interaction it is recommended that subjects enrolled in this 
study not use traditional Chinese medications while participating in this study. 
Subjects on enzyme-inducing anti-epileptic drugs (EIAED) such as phenytoin, carbamazepine, 
and phenobarbital should be switched to non-EIAEDs such as levetiracetam, gabapentin, 
topiramate, tiagabine, zonisamide, or clonazepam at least two weeks prior to initiating study 
drug. 

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5.7.2
Effect of Enzastaurin on Concomitant Medications
Data indicate that enzastaurin may affect the metabolism of drugs that are metabolized by 
cytochrome P450 isozymes. A drug interaction study indicates that enzastaurin may increase the 
effect of warfarin. Subjects who must take warfarin while taking enzastaurin should be 
monitored carefully and the dose of warfarin adjusted to prevent toxicity. 
Pharmacokinetic evaluation in a subset of subjects in the completed Phase 2 study (H6Q-MC-
S028) indicated that addition of enzastaurin to R-CHOP did not affect exposure (AUC) to 
doxorubicin, cyclophosphamide, 4-ketocyclophosphamide or dechloroethyl-cyclophosphamide. 
5.7.3 
Colony-Stimulating Factors 
Use of colony-stimulating factors (eg, filgrastim or pegfilgrastim) as primary prophylaxis is 
encouraged and may be based on the recommendations of the American Society of Clinical 
 However, colony-
stimulating factors should not be instituted prior to C1D1 and are prohibited before screening 
labs are performed. 
5.7.4 
QT Interval Prolonging Medications 
Nonclinical data suggest a potential for QT/QT interval corrected for heart rate (QTc) 
prolongation for both enzastaurin and its active metabolite. QTc prolongation has also been 
observed at steady state, following the administration of enzastaurin 500-mg daily doses to 
cancer patients, and a concentration-QT effect has been observed with higher doses. 
Based on these considerations, subjects who require therapy with medications that prolong the 
QT interval should not be enrolled into the study. If medically justified, subjects may be enrolled 
if such medications can be discontinued or alternative drugs that do not prolong the QT interval 
can be substituted > 7 days before the first dose of the study drug. 
During study participation administration of enzastaurin with medications that can prolong the 
QT interval should be avoided. However, a subject who develops a condition that may require 
use of such drugs is not required to permanently discontinue enzastaurin if the subject is 
experiencing clinical benefit. If medically appropriate, investigators should use a therapeutic 
alternative that would not be expected to affect QT interval. For subjects who require temporary 
use of a medication that can prolong the QT interval, enzastaurin should be interrupted during 
use of the other medication and then resumed no early than 7 days after its completion. For 
subjects who require initiation of chronic therapy with a drug that potently affects the QT 
interval, investigators must consult with the Medical Monitor to consider the best course of 
action. 
A list of drugs that can prolong the QT interval is found in Appendix C. 
5.7.5 
Central Nervous System (CNS) Prophylaxis 
Subjects considered high-risk for CNS relapse (Schmitz et al. JCO 2016) may be administered 
during combination phase only 
intrathecal administration of CNS prophylaxis is permitted. During single agent phase, 
intravenous administration is permitted 
.  

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5.8
TREATMENT COMPLIANCE
Subject compliance with study drug must be stressed and assessed at each visit. Compliance will 
be assessed by direct questioning, review of study calendars and counting returned tablets. Each 
subject should be instructed to return all study drug packaging and unused material to the study 
site at each visit. The study site will keep a record of all drug dispensed to and returned by 
subjects throughout the study. Study site personnel will return all unused medication to Denovo 
investigational product on site.
Deviations from the prescribed dosage regimen should be recorded in the case report form 
(CRF). 
For subjects who are significantly noncompliant (< 80% or > 120% of expected study drug taken 
in a visit interval), investigative sites must counsel subjects on the importance of study drug 
compliance and drug accountability. Subjects who are consistently out of the compliance range 
may be discontinued. 
Treatment compliance information for enzastaurin will be collected through pill counts at each 
visit. The estimate of percent compliance will be determined by: 
 
The number of tablets taken will be determined by counting the number of tablets returned at 
each visit and subtracting that number from the number of pills dispensed. The number of pills 
expected to be taken will be determined by the assigned dose and taking into account any 
prescribed dose holds and reductions. 
No minimal level of compliance will be defined for patient inclusion in efficacy analyses. 
However, exploratory analysis of compliance may be undertaken by regressing percent 
compliance on selected efficacy endpoints. If significant results are indicated, further analysis 
may be performed to determine the level of compliance that best delineates each endpoint. 

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6
EFFICACY, SAFETY EVALUATIONS, AND SAMPLE COLLECTION 
AND TESTING (STANDARD LABORATORY TESTING AND 
APPROPRIATENESS OF MEASUREMENTS) 
Refer to the Schedule of Events (Section 13) for the timing of study procedures. 
6.1 
EFFICACY MEASURES
6.1.1 
Tumor Assessments and Schedule
sessed by the investigator using standardized criteria: Lugano 
Classification (Cheson 2014). The scans will be submitted to a central imaging vendor for 
potential central review as needed.  
See Appendix D for detailed guidance on tumor assessments including method of assessment, 
timing of assessments, and definitions of tumor response and progression. 
6.1.2 
Primary Efficacy Measure 
The primary efficacy endpoint for this trial is OS in subjects who are DGM1 biomarker positive. 
OS is defined as the elapsed time from the date of randomization to the date of death from any 
cause. For patients not known to have died as of the data cut-off date, OS will be censored at the 
last contact date or last date known to be alive, whichever is later. 
6.1.3 
Secondary Efficacy Measures 
 OS in all subjects regardless of DGM1 biomarker status. OS is defined as the time 
between randomization and death due to any cause.  
 EFS including EFS12 and EFS24, for all the subjects, and for the subjects who are 
DGM1 biomarker positive.  
 EFS is defined as the time from randomization until occurrence of one of the 
following events, whichever occurs first:  
 Disease progression 
 Relapse from CR 
 Initiation of subsequent systemic anti-lymphoma therapy 
 Death due to any cause 
 EFS 12 is defined as the event-free status at 12 months (%) from randomization.  
 EFS 24 is defined as the event-free status at 24 months (%) from randomization. 
 CR as defined in Appendix D in subjects who are DGM1 biomarker positive 
 ORR (CR and PR as defined in Appendix D) in subjects who are DGM1 biomarker 
positive  
6.1.4 
Exploratory Efficacy Measures 
 Chromaturia (orange/red discoloration of urine)  
 Germline polymorphisms and tumor gene mutations 
 Post-study treatments, lack of post-study treatment 
 Subgroup analyses of primary and secondary efficacy measures in China region and US 
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6.2
SUBJECT EVALUATIONS
6.2.1 
Pretreatment Evaluations 
Unless otherwise noted below, all pretreatment evaluations must be performed within 28 days 
prior to randomization; tests performed as standard of care qualify for eligibility assessment if 
performed within this timeframe. Eligibility labs may be re-performed to meet eligibility if it is 
within the specified timeframe prior to randomization. IPI score (including LDH), and imaging 
scans should be performed before administration of corticosteroids. Subjects must sign an 
approved informed consent document (ICD) prior to undergoing any study specific evaluations. 
A complete history, physical (including height and weight) and ECOG performance 
status. 
A unilateral bone marrow biopsy (BMB) should be performed if clinically indicated (eg, 
to evaluate indeterminant PET-CT findings, cytopenia, or presence of discordant 
lymphoma). 
Pretreatment laboratory tests include: CBC (Hgb, WBC with differential, platelets), 
chemistry panel (serum creatinine, creatinine clearance, total bilirubin, direct bilirubin, 
AST/ALT, LDH, alkaline phosphatase (ALP), BUN or Urea, glucose, potassium, sodium, 
calcium), HIV, hepatitis B and C, and serum pregnancy test (within 7 days prior to 
randomization for women with reproductive potential). Organ function assessment 
(hepatic, renal, and bone marrow) as indicated in the eligibility criteria must be 
performed within 14 days prior to randomization. 
Biomarker: Blood test for DGM1. Blood will be stored for immuno-typing (includes 
potential additional biomarker analysis and lymphoma subtyping). The Sponsor and 
clinical study site will be blinded to DGM1 results during the study. 
ECG with QT corrected by Fri
formula (QTcF = QT/RR0.33) is recommended. 
Echocardiogram or nuclear medicine test of ventricular function (MUGA) 
Documentation of tumor histology and CD20 expression: The subject will be enrolled 
based on confirmation of the histologic diagnosis at the enrolling site. Following 
enrollment in the study, tumor histology will be confirmed by a central pathology review 
that will be used for the final study analysis. DLBCL subtype assessment (eg, cell of 
origin, tumor mutations) may also be performed by central pathology review. Tissue 
slides/samples must be submitted for review once the subject is enrolled. Instructions for 
submission of tissue slides/samples will be detailed in a separate manual. 
Radiology Imaging: See Appendix D and SOE (Table 6). A PET-CT performed as part 
of standard of care qualifies for the screening requirement as long as it was performed 
within 28 days of randomization. 
6.2.2 
Evaluations on Study 
Please see the SOE (Table 6) for the timing of procedures. 
CBC: CBC will be performed at all study visits until the subject completes/discontinues 
study treatment and enters the follow-up phase. The SOE (Table 6)  shows the timing of 
CBCs

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Chemistries: Chemistries will be performed at all study visits until the subject 
completes/discontinues study treatment and enters the follow-up phase. The SOE 
(Table 6)  shows the timing of chemistry testing. 
Serum Pregnancy: Performed at all scheduled study visits starting with Cycle 2; must be 
negative to continue study treatment. 
Urinalysis: Urinalysis will be performed using ambient urine sample by the central 
laboratory. Subjects that do not continue into the single-agent phase will have urinalysis 
on C1D1 and EOT. Subjects that continue to the single-agent phase will have urinalysis 
on C1D1 and V9. 
Urine color assessment: Urine color assessment using ambient urine sample by the 
central laboratory will occur on C1D1, C1D8, and C2D1 for all subjects. Subjects that do 
not continue into the single-agent phase will also have urine color assessment at EOT. 
Subjects that continue to the single-agent phase will also have urine color assessment at 
V9. The Sponsor and clinical site will be blinded to the results of the urine color 
assessment during the study. 
Urine metabolites: Frozen urine samples collected will be retained for possible future 
analysis of enzastaurin metabolites. If such analyses are conducted, the results will be 
reported separately by the Sponsor. 
Brief Physical Exam: vital signs, heart, lungs, abdomen and lymph node exam.
Radiology Imaging: See Appendix D and SOE (Table 6). 
Bone Marrow Biopsy: required at end of treatment in those patients who have otherwise 
achieved a CR and had a positive BMB at screening/baseline.
ECG: ECGs will be performed at C1D2 or C1D3 (to coincide with the first dose of 
enzastaurin/placebo), C2D1, C4D1, C6D1, V9, V12-17 and EOT. The ECGs on 
C1D2/C1D3, C2D1, and C4D1 will be performed prior to taking enzastaurin/placebo and 
approximately 4-6 hours after the subject has taken his/her study medication. ECGs on 
C6D1, V9, V12-17 and EOT will be performed before study treatment if applicable. If 
R-CHOP is expected to be delayed greater than 7 days but enzastaurin/placebo is being 
taken, ECG should be performed as an unscheduled visit at the temporal timepoint and 
repeated on the appropriate Cycle/Day when cycles are restarted (ie, R-CHOP is
administered). The QT interval corrected by Fri
ula is recommended and all 
ECG equipment must have been recently calibrated and well maintained. 
Population PK: Two blood samples per subject will be collected on C2D1 and C4D1 for 
population pharmacokinetic analysis. The sample on C2D1 should be collected prior to 
administration of enzastaurin (pre-dose); the C4D1 blood sample should be collected 
between 3-6 hours after the enzastaurin dose. The time of the dose administration and 
blood sampling will be recorded on a laboratory requisition. 
Approximately 2 mL of blood will be collected with K2EDTA for each sample (See SOE 
(Table 6). 
Samples will be analyzed for enzastaurin at a laboratory approved by the Sponsor using a 
validated liquid chromatography tandem mass spectrometry (LC/TS/MS) method. It is 
intended that the blood samples collected from patients receiving placebo (R-CHOP 

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alone) will not be analyzed. If a patient discontinues before study completion, an effort 
should be made to obtain a blood sample at the time of discontinuation.
Adverse Events: Assessment of adverse events will be performed at every visit using 
CTCAE Version 4.03. A copy of the CTCAE can be downloaded from the CTEP 
homepage (http://ctep.info.nih.gov).
Concomitant Medications: Concomitant medications with doses and start and stop dates 
must be recorded. 
Unblinding: Unblinding should occur no later than 2 days after the end of combination 
phase tumor response is determined. The initial single-agent visit, V9, should occur as 
soon as possible but no later than 3 days after unblinding. 
Survival: All subjects will be followed for survival. 
6.2.3 
Visit Windows 
6.2.3.1 
During Combination Therapy 
During the combination phase of this study each cycle begins with the administration of R-
CHOP. CBC, chemistry, urine tests, and pregnancy tests can be performed one to two days prior 
to the administration of R-
assessments to be performed as indicated on the SOE (Table 6). Unless R-CHOP requires delay 
due to tolerability/AE, every effort should be made to administer R-CHOP to maintain the 21-
day cycles (-1/+3 days).  
6.2.3.2 
During Single-Agent Therapy 
During the single-agent phase of the study the visit window is +/- 5 days. 
6.2.4 
Post-treatment Evaluations/Follow up 
EOT Testing: Subjects will have (EOT evaluation as outlined in the SOE (Table 6). EOT 
date should be the last dosing date of any component of enzastaurin/placebo + R-CHOP, 
or the date of treatment discontinuation decision is made, whichever comes later. All 
EOT testing/visit in the SOE (Table 6) should be based on this date. The window of +/-7 
days is allowed. 
OS: All subjects will be followed for survival every 3 months until completion of the 
study, or 5 years, whichever comes first. If the subject is unable to travel, evaluation of 
survival can be accomplished by telephone contact, if necessary. At the end of the study 
all subjects will be contacted one final time to ascertain survival status. 
Post-treatment Therapy: Every effort should be made to collect data regarding 
subsequent DLBCL treatments received, if any, after study treatment is discontinued. 
6.2.5 
Post-treatment Visit Windows 
Following completion of the treatment portion of the study, the visit window will be ± 14 days. 

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6.3
SAFETY EVALUATIONS
6.3.1 
Definitions 
6.3.1.1 
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug 
whether or not considered to have been caused by the drug. An AE may be any unfavorable and 
unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug and does not imply any judgment about causality (21 CFR 312.32a). 
Examples include: reactions or side effects, a pre-existing condition that worsens in severity or 
frequency, a concurrent illness, an injury, or a clinically significant laboratory abnormality. 
6.3.1.2 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is an AE that meets at least one of the following criteria: 
 
Is fatal 
 
Is life-threatening (A life-threatening AE is an AE that places the subject at immediate 
risk of death from the reaction as it occurred. It does not include a reaction that, had it 
occurred in a more severe form, might have caused death.) 
 
Requires inpatient hospitalization or prolongs an existing hospitalization, excluding 
emergency room visits. (See Section 6.3.5 for other excluded events) 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect in the offspring of an exposed 
subject.(Note: pregnancy in a study subject should be reported promptly to the sponsor on 
the appropriate form, and depending on the regulations for each region, may also need to 
be reported promptly to the regulatory authorities.) 
 
Other important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result in subject 
hospitalization, or the development of drug dependency or drug abuse. 
The onset date of an SAE is defined as the date on which it met the criteria for an SAE; eg, the 
date of admission to a hospital. The end date is the date on which it no longer met the criteria for 
an SAE, eg, the date that the subject was discharged from a hospital. 
6.3.1.3 
Relationship to Investigational Product 
In this study, some subjects will be receiving both R-CHOP and enzastaurin; enzastaurin is 
considered the investigational product and the investigator should assess each AE for its possible 
relationship to enzastaurin, not the other medications in this treatment regimen. The relationship 
of an adverse event to the investigational product should be classified by the investigator using 
the following guidelines: 

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Definite: Experience follows a reasonable temporal association and could not have been 
explained by the subjects underlying condition or is confirmed with a positive re-challenge. 
Probable: Experience follows a reasonable temporal association, is confirmed by improvement 
clinical state. 
Possible: Experience follows a reasonable temporal association, but may have been produced by 
 
Unlikely: Experience does not follow a clear temporal association, and is probably produced by 
 
Unrelated: No relationship between the experience and administration of the investigational 
product. 
For this study, AEs that are considered by the investigator to have a Possible, Probable, or 
related  to the 
investigational product. 
6.3.1.4 
Severity of Adverse Events 
The severity of an AE should be defined according to the National Cancer Institute (NCI) 
Common Toxicity Criteria Adverse Events (CTCAE) Version 4.03. AEs that are not listed in the 
NCI Common Toxicity Criteria should be evaluated using the following guidelines: 
1 = Mild AE: Awareness of symptom, but easily tolerated; usually transient requiring no 
special treatment; does not interfere with usual status or activities 
2 = Moderate AE: May be ameliorated by simple therapeutic measures; may interfere 
with usual activities 
3 = Severe AE: Incapacitating, inability to perform usual activities 
4 = Life threatening or disabling AE 
5 = Fatal AE 
6.3.2 
Adverse Event Reporting Period 
AEs will be recorded from the time of the first administration of study treatment until 7 days 
after the last administration of study treatment (ie, any components of R-CHOP and 
enzastaurin/placebo). 
All SAEs will be recorded from the time of randomization until 30 days after the last 
administration of study treatment. SAEs determined to be related to study drug will be collected 
beyond 30 days.  
Table 5 outlines the AE and SAE reporting. 

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Table 5.
Adverse Events/Serious Adverse Events Reporting Guide
Time 
After Informed 
Consent  
Before Study 
Treatment* 
Randomization
First Dose of 
Study 
Treatment 
7-Days Post 
Last Dose of 
Study 
Treatment 
30-Days Post 
Last Dose of 
Study 
Treatment 
Long-Term 
Follow-up
Events 
to 
Report
Any clinically 
significantly 
medical 
conditions will 
be documented 
as medical 
history 
All SAEs 
All AE/SAEs
All 
new/ongoing 
AE/SAEs 
All 
new/ongoing 
SAEs 
SAEs 
related to 
study drug
Abbreviations: AE, adverse event; SAE, serious adverse event  
*Study treatment: any components of R-CHOP and enzastaurin/placebo; Study drug: enzastaurin/placebo. 
6.3.3 
Recording Adverse Events 
AEs should only be recorded by an investigator or by a healthcare provider qualified by training 
and experience. Subjects should be asked in an open-ended manner about the occurrence of AEs. 
All AEs, regardless of whether or not ascribed to the investigational product, should be recorded 
in the CRF.
It is generally not necessary to record both a diagnosis and its associated symptoms and 
 
If an AE necessitates a procedure, the description of the event (eg, appendicitis) rather than the 
procedure (appendectomy) should be listed as the AE. 
Any ongoing AE should be followed during study visits until resolution (with or without 
sequelae, or death, or ICF withdrawal, or last evaluation) to be recorded upon the subject 
discontinuation from the study. 
6.3.4 
Reporting Serious Adverse Events 
The investigator should notify the Sponsor, or Designee, of any event that meets one of the 
criteria for an SAE within 24 hours of learning of the event. This can be done by completing 
SAE entry through eCRF in the EDC.  
In the event of EDC outage, this SAE notification should be made by email to 
GlobalSAEInbox@covance.com (FAX numbers are available in case email is not functioning). 
Following receipt of this notification, the Sponsor, with input from the investigator, will 
complete the final SAE Report. 
Each SAE should be followed until resolution, or until such time as the investigator determines 
its cause or determines that it has become stable. This includes all the SAEs that have not 
 Information pertaining 
to follow-up of SAEs should be reported to the Sponsor within 24 hours of its availability. 

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It is the i
Board (IRB) or Independent Ethics Committee (IEC) according to the requirements of the 
IRB/IEC. 
6.3.5 
Events That Will Not Be Reported Individually 
As per 21 CFR 312.32 this section identifies events that the Sponsor does not plan to report 
individually. Infusion reactions are known adverse reactions with a rituximab product 
(Rituxan/MabThera or an FDA-approved rituximab biosimilar) and will be documented as an AE 
only, but will not be reported individually as an SAE. 
Hospitalization strictly for administration of R-CHOP will not be reported as SAEs. 
Hospitalization for elective procedures for treatment of pre-existing conditions (eg, hip 
replacement for pre-existing osteoarthritis) will not be reported as SAEs unless the condition has 
worsened since beginning the study drug. Hospitalizations for administrative reasons, such as 
insurance reimbursement, will not be reported as SAEs.  
Disease progression itself is not an SAE. Hospitalization due to signs and/or symptoms meeting 
serious criteria should be reported as SAEs with the event terms other than progression disease 
(PD) even though the PD is identified later. Hospitalization strictly for administration of 2nd line 
treatment should not be reported as a SAE, regardless of PD or not. 
6.3.6 
Reporting of Study Endpoints 
As per 21 CFR 312.32, the Sponsor does not plan to report death from progression of DLBCL, 
which is a study endpoint, as an SAE. 

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7
STATISTICAL METHODS
7.1 
GENERAL CONSIDERATIONS 
Efficacy and safety analyses will be conducted on the full analysis set. For efficacy, analysis will 
be conducted on an intent-to-treat basis. A per protocol analysis may also be performed. Safety 
analyses will include data from all patients receiving at least one dose of the investigational 
product according to the treatment the patients actually received. 
Details of the statistical analyses planned can be found in the separate statistical analysis plan. 
General plans are summarized below. 
7.2 
DISPOSITION OF SUBJECTS 
A detailed description of subject disposition will be provided. It will include: 
 
Total number of subjects randomized 
 
Total number of subjects treated 
 
Summary of reasons for subjects randomized but not treated 
 
Summary of data on subject discontinuation 
 
Account of all identified important protocol deviations 
7.3 
SUBJECT CHARACTERISTICS
Subject characteristics will include a summary of the following: 
 
Subjects demographics 
 
Baseline disease characteristics
 
Preexisting conditions 
 
Concomitant drugs 
 
Subsequent DLBCL therapy(ies) 
7.4 
SAMPLE SIZE AND EFFICACY ANALYSES 
Study sample size was estimated for the primary efficacy objective.  
The primary outcome of this study is overall survival (OS), with the primary analysis to be 
conducted in DGM1 biomarker positive subjects. Study subjects will be randomized 1:1 to R-
CHOP plus enzastaurin or R-CHOP plus placebo. The family-wise type-I error rate will be 
-sided) of 2.5% by applying an alpha allocation plan for the analyses of 
OS in both the DGM1 biomarker-positive subgroup and the entire ITT population. Since the 
primary objective of the study is to compare the effect of R-CHOP plus enzastaurin versus R-
CHOP on OS in DLBCL subjects who are DGM1 positive, the OS superiority test will be 
conducted at 1-sided significance level of 2.35% in the DGM1 positive subgroup. The alpha 
level allocated to the OS analysis in the entire population will be derived based on the actual 
number of OS events observed in the DGM1 positive subgroup and in the entire population at 
final analysis using the approach presented by (Spiessens B & Debois M, 2010). At the final 

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analysis, if the ratio of observed OS events in the DGM1 positive subgroup over the entire 
population is, as anticipated, 85%, (ie, 66/78 OS events), then statistical significance will be 
achieved in the OS analysis in the entire population at an alpha level (1-sided) of approximately 
1%. 
This will be an event driven study. In the trial 66 events are required to provide approximately 
90% power to detect a HR of 0.45 for OS in subjects who are positive for the DGM1 biomarker, 
when using a stratified log-rank statistic having one-sided alpha of 0.0235. Statistical 
significance will be achieved with an estimated HR  0.613. The target HR of 0.45 is a very 
strong positive effect on OS, which was supported by the biom
study (HR (95% CI): 0.28 (0.1, 0.81) in the same target population, see Section 1.1). 
Assuming control arm patients have one-year survival of approximately 60% to 70% and median 
survival of approximately 24 to 30 months, the trial will have an approximate sample size of 200 
DGM1 biomarker positive subjects. If the enrollment period is 12-18 months, approximately 12 
to 24 additional months will be required for 66 events to occur. Recognizing that the number of 
66 events is fixed while the sample size is an approximation, the sample size will be re-assessed 
as the enrollment target of 200 DGM1 biomarker positive subjects is approached.  
It is expected that approximately 15% of trial subjects will be DGM1 biomarker negative. Since 
the trial sponsor and investigators will not have access to data on DGM1 biomarker status, the 
enrollment required to achieve, in the 
projected timeframe, the targeted 66 events in the DGM1 biomarker positive subjects. If, for 
example, the DGM1 biomarker negative rate is approximately 15%, the trial would enroll 
approximately 235 subjects, with 200 being biomarker positive and 35 being biomarker negative. 
The final analysis will be performed when 
 at least 66 OS events occur from all subjects who are DGM1 biomarker positive 
(DGM1+), AND 
 either 22 OS events (ie
are reached from US DGM1+ subjects, or 18 months after last subject was 
randomized, whichever comes first. This requirement is to ensure a meaningful 
subgroup analysis of OS in each geographic region. 
If the addition of enzastaurin provides a statistically significance improvement in OS in the 
primary analysis in the DGM1
 biomarker positive subjects and the entire population, then this 
conclusion of benefit would be extended to the DGM1 biomarker negative subjects if, in that 
subgroup, the estimated HR  0.641, (Rothmann, 2012), which is the estimated effect that would 
-sided) of 2.5% in the entire population with an 
estimated 78 OS events. The details regarding multiplicity adjustment in all scenarios related to 
the OS analysis are provided in the statistical analysis plan. 
In a supportive analysis of OS data, a Cox proportional hazards model stratified by the factors 
used to stratify randomization may be used to adjust for major prognostic factors not used to 
stratify the randomization.
Adjustments will also be made to address the multiplicity of comparisons of R-CHOP plus 
enzastaurin versus R-CHOP plus placebo with respect to other secondary efficacy measures in 

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Section 6.1.3. If significance for the OS analysis is achieved in the DGM1 biomarker-positive 
subgroup and/or in the entire population, then the procedure will proceed to test three secondary 
measures in a pre-specified hierarchical manner using the specific method described below at the 
alpha level that is passed through the significance level for testing OS. During the testing, if any 
endpoint fails at the  level, then the subsequent endpoint(s) will be evaluating in a descriptive 
manner by presenting point estimates of effect and corresponding confidence intervals but 
without formal inference including p-values. 
1. The analysis of EFS will be performed by using the same statistical methods for the 
primary endpoint analysis. EFS rate at 12 months and EFS rate at 24 months, will be 
estimated using survival rate estimated at the timepoint by Kaplan-Meier method. The 
derivation of standard error, 95% CI of EFS rate and between group comparison will 
be performed using Greenwood method.
2. The CR in DGM1 biomarker positive subjects, will be analyzed using Cochran-
Mantel-Haenszel (CMH) method stratified by randomization factors.
3. ORR (CR+PR) in DGM1 biomarker positive subjects, will be analyzed using CMH 
method stratified by randomization factors.  
With the sample size derived to properly power the testing for the primary efficacy measure 
(OS), there will be approximately 89% power to detect a treatment difference of 20% in CR rate 
(secondary measure) at completion of the combination phase in DGM1 biomarker positive 
subjects, assuming a control arm CR rate at 18%. 
Approximately 100 EFS events from DGM1 biomarker-positive patients are expected when the 
targeted 66 OS events from DGM1 biomarker-positive patients are reached. A total of 100 EFS 
events would provide 80% and 90% statistical power to detect a treatment effect on EFS when 
the true HR would be 0.57 and 0.52, respectively, based on a log-rank test at 1-sided alpha level 
of 0.025. 
7.5 
SAFETY ANALYSIS 
All subjects who receive at least one dose of investigational product will be included in the 
safety analysis. The analysis will include: 
 Summary of extent of exposure 
 Summary of the number of blood transfusions required 
 Summary of adverse events, serious adverse events and subjects discontinuing for 
adverse events rates 
 Summary of laboratory findings and change from baseline 
 Summary of vital signs findings and change from baseline 
 Summary of QTc data and change from baseline according to ICH E14  
 Summary of other relevant safety observations  
 Listings of laboratory and non-laboratory adverse events by maximum CTCAE v4.03 
grade and relationship to study treatment 

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7.5.1
Adverse Events and Serious Adverse Events
AEs and SAEs will be listed and summarized by subject ID number. Additionally, AEs leading 
to discontinuations will be listed separately. All verbatim terms will be mapped to a System 
Organ Class and Preferred Term using MedDRA. The number and percentage of subjects 
experiencing one or more AEs will be summarized by PT, maximum grade reported, and 
relationship to study treatment. A narrative description will be included for SAEs and AEs 
leading to discontinuation of the study treatment. 
7.5.2 
Laboratory Tests 
Laboratory tests will be listed by subject ID number and visit number. Laboratory tests will be 
graded and summarized using CTCAE v4.03. Laboratory data will be summarized using 
descriptive statistics, by use of shift tables and with listings of clinically significant 
abnormalities. In these listings, any abnormally high or low values will be flagged according to 
the laboratory reference range. 
7.5.3 
QTc 
The QT interval will be corrected using Fri
QTcF intervals will be summarized 
categorically by ICH grade and by maximum observed values and change from baseline. 
7.6 
THE DATA MONITORING COMMITTEE  
An independent Data Monitoring Committee (DMC) will be formed having 3 to 5 members of 
physicians and statistician(s). The mission of the DMC will be to safeguard the interests of study 
participants and to enhance the integrity and credibility of the trial. The DMC will periodically 
review safety and efficacy data and data regarding quality of trial conduct. The DMC will 
provide recommendation to the Sponsor regarding appropriate actions on the conduct of study. 

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8
ETHICAL AND REGULATORY CONSIDERATIONS
8.1 
PROTOCOL AND REGULATORY COMPLIANCE 
The investigator must conduct the study according to this protocol. 
In the United States, the study must be conducted by all investigators in compliance with Good 
Clinical Practices (GCP) as defined in the U.S. FDA Code of Federal Regulations 21 CFR 312 
(Investigational New Drug Application), 21 CFR 50 (Protection of Human Subjects), 21 CFR 54 
(Financial Disclosure by Clinical Investigators), 21 CFR 56 (Institutional Review Boards) and 
ICH guidelines (Guideline to Good Clinical Practice). Investigators conducting this study in 
other countries must comply with the Declaration of Helsinki, ICH-GCP guidelines and all other 
applicable country-specific regulations.
8.2 
PROTOCOL AMENDMENTS 
Any changes to this protocol will be initiated by the Sponsor as a protocol amendment. The 
investigator must submit the amendment to the IRB/IEC, with a revised ICD if applicable. The 
investigator must receive written approval from the IRB/IEC before the amendment may take 
effect. 
8.3 
REGULATORY BINDER 
To be in compliance with GCPs, the investigator must maintain accurate, complete, and 
organized documentation supporting the conduct of the study. This documentation includes, but 
is not limited to, the following: study personnel qualifications and training, IRB/IEC approvals 
and communications, communications with the Sponsor, Site Signature & Responsibility Log, 
laboratory accreditations and reference ranges, Form FDA 1572s, and ICD (copies of IRB/IEC-
approved versions, signed/dated originals, or copies for all enrolled subjects). 
8.4 
INFORMED CONSENT 
Prior to the performance of any protocol-specific procedures, informed consent must be obtained 
and documented by the use of a written ICD approved by the Sponsor and the IRB/IEC. The ICD 
by the person conducting the informed consent discussion. The ICD must fulfill the requirements 
as contained in the U.S. Code of Federal Regulations (21 CFR 50.25), the ICH guidelines 
(Section 4.8), and the Declaration of Helsinki. In addition to these requirements, the ICD must 
contain wording whereby the subject permits the review of his/her relevant medical records by 
representatives of Denovo and by representatives of the U.S. Food and Drug Administration 
(FDA) or other applicable national or local regulatory or health authorities. The ICD must be 
written in a language understandable to the subject or to the representative. 
A signed and dated copy of the ICD must be given to the person signing the document. The 
original must be retained by the investigator with the study documentation and be available for 
inspection by persons conducting an audit of the study (eg, regulatory authorities, Denovo 
representatives).
The Sponsor will provide the study sites with a template ICD. Modifications to this template may 
be made by study site personnel to be in compliance with national, regional (eg, state) or local 

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laws and/or institutional requirements. All versions of the ICD should be reviewed and approved 
by Denovo prior to the submission of the ICD for IRB/IEC approval. 
8.5 
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS 
COMMITTEES 
The protocol, ICD, subject recruitment procedures (eg, advertisements), information about 
payments and compensation available to subjects, and any amendments must be approved by a 
properly constituted IRB or IEC in compliance with current regulations of the U.S. FDA, ICH 
guidelines, and any country-specific regulations. Specifically, the study must not be initiated 
until the investigator has provided Denovo with documentation of IRB/IEC approval of the 
protocol, the ICD, and all recruiting materials. In addition, prior to their implementation or use, 
there must be documented IRB/IEC approval for the following: protocol amendments, revised 
ICDs, subject recruitment materials (eg, advertisements), and study-related supplements that are 
provided to study subjects. 
8.6 
IRB/IEC COMMUNICATIONS 
The investigator must make timely and accurate reports to the IRB/IEC on the progress of the 
study, as well as satisfying any other local IRB/IEC regulations regarding reporting, including 
reporting on safety aspects of the study (eg, SAEs, safety letters). During the conduct of the 
study, the frequency of IRB/IEC reporting should be based on 
. 
Furthermore, at the completion or early termination of the study, a final report must be made to 
the IRB/IEC by the investigator within the applicable IRB/IEC timeframes. 
It is the inv
available for review by Denovo representatives as part of the study monitoring process. Copies 
of all correspondence between the investigator and the IRB/IEC (including all attachments to any 
correspondence) must be provided for the Denovo internal file. 
8.7 
CURRICULUM VITAE AND MEDICAL LICENSES 
The Principal Investigator is responsible for ensuring that the study is being conducted by 
qualified personnel. Documentation of these qualifications must be maintained within the 
Regulatory Binder, and includes the following: 
Curriculum Vitae (CV): CVs for the Principal Investigator and all sub-investigators listed on the 
Form FDA 1572 must be signed and dated. These CVs must show affiliation with the institution 
conducting the study and be current within two years of the personnel initiating their 
participation in the study. 
Medical Licenses: Medical licenses (physicians, physician assistants, nurses) listed on the Form 
FDA 1572 must be kept current, and copies must be maintained in the Regulatory binder during 
 
8.8 
SUBJECT CONFIDENTIALITY 
The i
medical 
information obtained for the purposes of this study is confidential, and disclosure to third parties, 
other than those noted below, is prohibited. Subjects should not be identified by name, social 
security number or medical record number on any documents or materials (samples, slides) sent 

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to Denovo or its representatives (eg, data management organization) or during verbal 
communications. Subjects should be identified only by their initials and protocol-assigned 
subject ID number. 
For clinical sites in the US, study personnel should follow the requirements of the Health 
Insurance Portability and Accountability Act (HIPAA). 
All clinical information is confidential, but data generated for this study must be available for 
inspection on request to representatives of the U.S. FDA, other national or local regulatory or 
health authorities, Denovo representatives, and the associated IRB/IEC. 
All records must be kept in a secured area. 
8.9 
FINANCIAL DISCLOSURE 
Documentation of each i
nancial interest in Denovo Biopharma 
LLC is required by the U.S. Code of Federal Regulations (21 CFR 54). A financial disclosure 
form provided by the Sponsor must be completed, signed, and dated by the Principal Investigator 
and each sub-investigator listed on the Form FDA 1572. This form must be executed prior to the 
investigator must inform the Sponsor of any change in his/her financial interest in the Sponsor 
for up to one year after the end of the study. 
The U.S. Securities and Exchange Commission (SEC) prohibits any person who has material, 
non-public information concerning Denovo or a possible transaction involving Denovo from 
purchasing or selling securities in reliance upon such information or from communicating such 
information to any other person or entity under circumstances in which it is reasonably 
foreseeable that such person or entity is likely to purchase or sell such securities in reliance upon 
such information. 

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9
QUALITY ASSURANCE
9.1 
ROUTINE CLINICAL SITE MONITORING 
Denovo CRAs or designees will make a pre-study site visit (if deemed necessary) to determine 
the qualifications of the investigator, inspect the clinical facilities, and fully inform the 
investigator of his/her responsibilities and the procedures for assuring adequate and correct 
documentation. During the course of the study, a Denovo CRA or representative will make 
routine contacts (eg, telephone communications or site visits) at appropriate intervals to review 
Binder, the investigational product handling and accountability procedures, and data recording 
practices; and to ensure that the study is being conducted in compliance with applicable 
requirements. CRF entries will be verified against source documentation. 
The investigator and the site personnel are expected to cooperate with Denovo CRAs or 
representative and to provide, upon request, all relevant study documentation that is requested at 
each site visit. 
9.2 
SITE AUDITS 
The investigator must permit inspection of the study files (eg, source documentation such as 
) by a 
Sponsor representative and by authorized representatives of the U.S. FDA or other applicable 
regulatory agencies. If the site is informed of an inspection by any regulatory authority, the 
investigator should notify Denovo immediately. 

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10
DATA MANAGEMENT AND RECORD KEEPING
10.1 
CASE REPORT FORMS (CRF) 
A validated, secure electronic CRF (eCRF) will be used for this study. eCRFs should be 
completed in a timely manner and must be available for review during routine monitoring visits. 
All references to specific subjects must be made by subject ID number, not by name. Subject 
confidentiality should be maintained by obscuring all names, social security numbers or subject 
record numbers (using a black marker) in any reports or records sent to the Sponsor or its 
representatives. The Principal Investigator, or designee, is responsible for reviewing each page of 
the eCRF and for signing the appropriate forms. By signing the eCRF, the investigator attests to 
the accuracy and completeness of the information contained in the eCRFs. 
10.2 
RECORD RETENTION 
Records that individually or collectively permit the evaluation of the conduct of the study and the 
representatives and by U.S. and non-U.S. regulatory authorities. The investigator must retain 
these records minimally for a period of two years following the date of the last marketing 
application and until there are no pending or contemplated marketing applications, or for at least 
two years following the formal discontinuation of clinical development of the investigational 
product. However, these documents should be retained for a longer period if required by 
applicable regulatory requirements. The Sponsor will inform the investigator in writing when the 
study-related records are no longer needed. The investigator must notify the Sponsor in writing 
at least 30 days prior to the intended date of disposal of any study records related to this protocol. 
If the investigator leaves the institution where the study was conducted, the investigator must 
inform the Sponsor in writing where the records associated with this protocol are archived and 
who is responsible for their security. 

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11
USE OR PUBLICATION OF STUDY-RELATED INFORMATION
All information obtained as a result of this study should be regarded as confidential. 
Information regarding use or publication of study-related information will be provided to the 
investigator in a separate Clinical Trial Agreement. 
 
 

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12
INVESTIGATOR PROTOCOL SIGNATURE PAGE
I understand that all information supplied to me by Denovo Biopharma LLC is confidential. 
I understand that this protocol and all amendments must be submitted to the appropriate 
IRB/IEC. 
I have read protocol DB102-02 and its appendices and agree to adhere to all requirements in the 
conduct of the study. 
In signing below, I agree:
 
To assume responsibility for the proper conduct of the study at my site 
 
To conduct the study in compliance with this protocol, any future amendments, and 
with any other study procedures provided by Denovo Biopharma LLC. 
 
That I am aware of, and will comply with Good Clinical Practices (GCP) and all 
applicable regulatory requirements 
 
To ensure that all persons assisting me with the study are adequately informed about 
the study and of their study-related duties as delegated by me 
 
Not to implement any changes to the protocol without written agreement from 
Denovo Biopharma LLC and prior review and written approval from the Ethics 
Committee/Institutional Review Board (EC/IRB) except where necessary to eliminate 
an immediate hazard to study subjects 
 
I acknowledge that failure to adhere to these stipulations may constitute a breach of 
governmental regulations, may invalidate the data and may result in termination of the study at 
my site. 
 
 
 
 
 
 
 
Date
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institution Name 
 
 
 
 
 

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13 
SCHEDULE OF EVENTS 
Table 6. 
Schedule of Events 
 
SCR/ 
Rand. 
Combination Phase 
(1 Cycle = 21 days, visit -1/+3d) 
Single-agent Phase2 
(visit± 5d) 
EOT3 
Follow up4  
(visit ±14d) 
Cycle 
C1 
C2 
C3 
C4 
C5 
C6 
V81 
S1 
S2 
Q3 mos until 
EOS 
Visit 
1 
2 
3 
4 
5 
6 
7 
9 11 
12 17 
Assessments / Days  
-28-0 
D1 
D2/3 
D8 
D1 
D1 
D1 
D1 
D1 
Q6 weeks
Q12 weeks 
Procedures: 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IPI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Paraffin/Slides 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam
X
X
 
 
 
 
 
 
 
 
X
 
Brief physical exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
Height/Weight6  
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
ECOG PS 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Echo or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG7 
X 
 
X8 
 
X 
 
X 
 
X 
 
X9 
X 
X 
 
AEs 
 
X 
X 
X10 
Con meds 
 
X 
X 
 
Randomization11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblinding 
 
 
 
 
 
 
 
 
 
X12 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Subsequent DLBCL 
therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
Diagnostic/Tumor Assessment Tests: 
PET-CT 
X 
 
 
 
 
 
 
 
 
 X14 
X15 
X15 
CT 
 
 
 
 
 
X16 
 
 
 
 
X15 
X15 

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SCR/ 
Rand. 
Combination Phase 
(1 Cycle = 21 days, visit -1/+3d) 
Single-agent Phase2 
(visit± 5d) 
EOT3 
Follow up4  
(visit ±14d) 
Cycle 
C1 
C2 
C3 
C4 
C5 
C6 
V81 
S1 
S2 
Q3 mos until 
EOS
Visit 
1 
2 
3 
4 
5 
6 
7 
9 11 
12 17 
Assessments / Days  
-28-0 
D1 
D2/3 
D8 
D1 
D1 
D1 
D1 
D1 
Q6 weeks
Q12 weeks 
BMB17 
X 
 
 
X 
Laboratory Tests: 
CBC18 
X
X
X
X
X
X
X
X
X
X
X
X
 
Chem18 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis19 
 
X 
 
 
 
 
 
 
 
 
X9 
 
X20 
 
Urine color19 
 
X 
 
X 
X 
 
 
 
 
 
X9 
 
X20 
 
Pregnancy, serum21 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK22 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Biomarker: 
DGM1 & 
Immuno-typing23 
 
X 
 
 
 
 
 
 
 
 
X9 
 
X20 
 
Study Drugs: 
R-CHOP24 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Enzastaurin/placebo25 
 
 
X
X
X
X
X
X
X
X
X
X
 
 
1. 
Perform on all subjects after completion of last R-CHOP cycle; all assessments except PET-CT, BMB and unblinding to be performed 22 days (-1/+3 days) from last 
administration of rituximab product. PET-CT, BMB and unblinding occurs as described below (please see footnote #12 and #14).
2. 
Enzastaurin arm only for those patients with CR (PR at 
. The initial 
single-agent visit, V9, should occur as soon as possible but no later than 3 days after unblinding. Note: the interval between V11 and V12 is 12 weeks
3. 
Performed for subjects who discontinue or complete study therapy (-/+ 7 days visit window). If the previous laboratory tests and ECG were performed after last dose of 
study treatment and this was 1 week prior to EOT visit, the laboratory tests and ECG do not need to be repeated. Urinalysis and urine color to be collected if not 
collected at V9 during the single agent phase. 
4.
Subjects contacted in person or by telephone.
5. 
Submit after randomization, preferably before the end of Cycle 1.  
6. 
Height will only be performed at V1. 
7. 
At Visit 1 (C1D2 or C1D3, on whichever day enzastaurin/placebo loading dose is given), C2D1, and C4D1 perform ECG prior to and approximately 4-6 hours after 
enzastaurin/placebo dose. ECG on C6D1, V9, V12-17 and EOT is performed prior to any study treatment if applicable. During treatment, hold enzastaurin if QTc > 500 

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msec; perform triplicate ECGs approximately five minutes apart; see Section 5.5.1 for further guidance. If R-CHOP is expected to be delayed greater than 7 days but 
enzastaurin/placebo is being taken, ECG should be performed as an unscheduled visit at the temporal timepoint and repeated on the appropriate Cycle/Day when cycles 
are restarted (ie, R-CHOP administered). 
8. 
Perform ECG prior to and approximately 4-6 hours after enzastaurin/placebo first dose on C1D2 or C1D3, whichever day the enzastaurin/placebo loading dose is taken. 
9.
V9 only.
10. Collect AE/SAEs as described in Section 6.3.2  
11. Subjects who meet eligibility criteria should be randomized within 8 weeks of diagnosis or confirmation of diagnosis by the enrolling institution and within the 28-day 
screening window, Study treatment should be started within 3 days of randomization. 
12. Unblinding to treatment arm should occur no later than 2 days after, but not before, the end of combination phase tumor response is determined. Subjects in enzastaurin 
-agent Phase and continue taking enzastaurin. All other subjects, including those in the 
placebo arm, will discontinue study treatment and enter Follow up after all applicable EOT assessments are performed. 
13. Every effort should be made to collect subsequent DLBCL therapies. 
14. Perform at least 4 weeks but preferably 6 to 8 weeks after completion of R-CHOP; weeks calculated from last administration of rituximab product. (See Appendix D) 
15. Preform as medically/clinically indicated by standard of care. 
16. Perform after R-CHOP administration at the end of Cycle 3 (See Appendix D for further guidance). PET-CT without contrast is acceptable per local SOC. 
17. A bone marrow biopsy (BMB) is not required at screening/baseline unless clinically indicated (eg, to evaluate indeterminant PET-CT findings, cytopenia, or presence of 
discordant lymphoma). BMB is required at end of combination treatment in those patients who have otherwise achieved a CR and had a positive BMB at 
screening/baseline. 
18. For Screening, within 14 days of randomization on study: may be performed 1-2 days prior to R-CHOP administration during combination phase if that is the enrolling 
t of the investigator patient safety is not compromised, C1D1 CBC and chemistry not 
required if Screening CBC and chemistry performed up to 3 days prior to C1D1. 
19. Urinalysis and urine color will be performed using ambient urine sample by the central lab; Sponsor and clinical sites will be blinded to the results of urine color. 
20. Only for subjects who do not enter into single-agent phase. 
21. For Screening, must be negative within 7 days prior to randomization in women with reproductive potential. Subsequent pregnancy tests may be performed 1-2 days 
prior to R-
 
22. PK samples to be collected: C2D1 pre-dose and C4D1 3-6 hours post enzastaurin/placebo dose. 
23. Whole blood sample collected for DGM1 testing and stored for immuno-typing (includes potential additional biomarker analysis and lymphoma subtyping). DGM1 
biomarker testing will be performed by the central lab and both the Sponsor and clinical sites will be blinded to the results. Samples will be collected at C1D1 for all 
subjects and at V9 for those subjects who entered single-agent phase and at EOT for all other subjects.  
24. R-CHO administered on Day 1 and prednisone (P) given Days 1-5. A
cretion, rituximab product may be given alone on Day 1 with other components 
of CHOP given on Day 2. Prednisone would then be given Days 2-6.  
25. Loading dose given on C1D2 unless R-CHOP is split over two days, then given on C1D3. Loading dose = 3 tabs TID approximately 30 minutes after a meal. Dose on all 
following days: 4 tablets QD taken together daily approximately 30 minutes after a meal. If necessary (eg, because of pause in R-CHOP dosing), study drug can be 
dispensed at an unscheduled visit.
 

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14
REFERENCES
Cheson BD et al., Report of an international workshop to standardize response criteria for non-
Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999; 
Apr;17(4):1244. 
Cheson, BD et al. Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014; 32:3059-
68. 
Chiapella, A, et al. State-of-the-art Therapy for Advanced-stage Diffuse Large B-cell 
Lymphoma. Hematol Oncol Clin North Am. 2016; 30:1147-1162. 
Crump M, et al. A Phase III Study of Enzastaurin in Patients with High-Risk Diffuse Large B 
Cell Lymphoma Following Response to Primary Treatment: The Prelude Trial. Blood. 2013; 
122:371.
da Rocha AB, Mans DR, Regner A, Schwartsmann G. Targeting protein kinase C: new 
therapeutic opportunities against high-grade malignant gliomas? Oncologist. 2002; 7(1):17-33. 
Fontaine R, Kim M, Kieny R. Surgical treatment of peripheral circulation disorders [in 
German] Helv Chir Acta. 1954; 21(5 6):499 533. 
Gokmen-Polar Y, et al. Elevated protein kinase C betaII is an early promotive event in colon 
carcinogenesis. Cancer Res. 2001; 61(4):1375-1381. 
Hainsworth, JD, et al. A randomized, phase 2 study of R-CHOP plus enzastaurin vs R-CHOP in 
patients with intermediate- or high-risk diffuse large B-cell lymphoma. Leuk Lymphoma 2016; 
57(1):216-8. 
Li, X et al. A pharmacokinetic and safety study of a fixed oral dose of enzastaurin HCl in native 
Chinese patients with refractory solid tumors or lymphoma. Oncotarget. 2016; Apr 
5;7(14):18585-18593. 
Lymphoma Research Foundation. Diffuse Large B-Cell Lymphoma [Fact sheet]. 2018; 
Retrieved from https://lymphoma.org/wp-
content/uploads/2018/05/LRF_FACTSHEET_DIFFUSE_LRG_BCELL_LYMPHOMA_DLBC
L.pdf 
O'Brien, P. C. and Fleming, T. R., "A Multiple Testing Procedure for Clinical Trials," 
Biometrics. 1979; 35:549-556. 
Rothmann, et al. Testing in a Prespecified Subgroup and the Intent-to-Treat Population; Drug 
Information Journal. 2012; 46(2):175-179. 
Schmitz, N, et al. CNS international prognostic index: a risk model for CNS relapse in patients 
with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016; 34:3150-56. 
Sehn, L and Gascoyne, R. Diffuse large B-cell lymphoma: optimizing outcome in the context of 
clinical and biologic heterogeneity. Blood. 2015; 125:22-32. 
Shipp MA, et al. Diffuse large B-cell lymphoma outcome prediction by gene expression 
profiling and supervised machine learning. Nat Med. 2002; 8(1):68-74. 

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Spiessens B, Debois M. Adjusted significance levels for subgroup analyses in clinical trials. 
Contemp Clin Trials 2010;31(6):647-656. 
Zhou, Z, et al. An enhanced International Prognostic Index (NCCN-IPI_ for patients with diffuse 
large B-cell lymphoma treated in the rituximab era. Blood. 2014; 123:837-42. 
 

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APPENDIX A.
EXAMPLES OF INHIBITORS AND INDUCERS OF CYP 3A4
Strong Inhibitors (Generic Name) 
Inducers (Generic name) 
Boceprevir 
Avasimibe 
Clarithromycin 
Bosentan 
Cobicistat 
Carbamazepine 
Conivaptan 
Efavirenz 
Danoprevir (and ritonavir) 
Etravirine 
Diltiazem  
Modafinil 
Elvitegravir (and ritonavir) 
Nafcillin 
Grapefruit and juice 
Phenytoin 
Idelalisib
Rifampin
Indinavir (and ritonaivir) 
 
Itraconazole 
 
Ketoconazole 
 
Lopinavir (and ritonavir) 
 
Mibefradil
 
Nefazodone 
 
Nelfinavir 
 
Posaconazole 
 
Ritonavir 
 
Saquinavir (and ritonaivir) 
 
Telaprevir 
 
Telithromycin 
 
Tipranavir (and ritonavir) 
 
Troleandomycin 
 
Voriconazole 
 
 
 
Moderate Inhibitors (Generic Name) 
 
Aprepitant
 
Cimetidine 
 
Ciprofloxacin 
 
Clotrimazole 
 
Crizotinib 
 
Cyclosprine 
 
Dronedarone 
 
Erythromycin 
 
Fluconazole 
 
Fluvoxamine 
 
Imatinib 
 
Tofisopam 
 
Verapamil 
 
Reference: Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers (9/26/2016): 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664.htm#4 (accessed 27 August 2019). 
 

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APPENDIX B.
INTERNATIONAL PROGNOSTIC INDEX
This tumor scoring system divides the population into risk groups (Table 8) by assigning one 
point for the presence of each of 5 variables (Table 7). For this study subjects must have a score 
of at least 3 in order to participate. 
Table 7. 
Variables 
Variable
Criteria 
Points 
Age 
> 60 
1 
Tumor Stage
III or IV
1
Number extranodal sites 
> 1 
1 
ECOG performance status 
> 1 
1 
Serum LDH 
> 1 times normal 
1 
 
Table 8. 
Definition of Risk Groups 
Risk Group 
Score (number risk factors)
Low 
0 1 
Low-Intermediate 
2 
High-Intermediate 
3 
High 
4 5 
Source: [Anonymous]. 1993. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-
Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329(14):987-94. 

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APPENDIX C.
DRUGS THAT CAN PROLONG THE QT INTERVAL
Generic Name 
Brand Names (Partial List) 
Drug Class 
Propofol 
Diprivan, Propoven 
Anesthetic, general
 
Sevoflurane
Ultane, Sojourn 
Aclarubicin (Only on Non-US 
Market) 
Aclacin, Aclacinomycine, Aclacinon, 
Aclaplastin, Jaclacin 
Anti-cancer 
Arsenic trioxide
Trisenox 
Oxaliplatin 
Eloxatin 
Vandetanib 
Caprelsa 
Amiodarone 
Cordarone, Pacerone, Nexterone 
Antiarrhythmic 
 
Disopyramide
Norpace 
Dofetilide 
Tikosyn 
Dronedarone 
Multaq 
Flecainide 
Tambocor, Almarytm, Apocard, Ecrinal, 
Flécaine 
Hydroquinidine,Dihydroquinidine 
(Only on Non-US Market) 
Serecor 
Ibutilide 
Corvert 
Procainamide 
Pronestyl, Procan 
Quinidine 
Quinaglute, Duraquin, Quinact, Quinidex, Cin-
Quin, Quinora 
Sotalol 
Betapace, Sotalex, Sotacor 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Clarithromycin 
Biaxin, Prevpac 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, Ery-Tab, 
Eryc Ranbaxy, Erypar, Eryped, Erythrocin 
Stearate Filmtab, Erythrocot, E-Base, 
Erythroped, Ilosone, MY-E, Pediamycin, 
Abboticin, Abboticin-ES, Erycin, PCE 
Dispertab, Stiemycine, Acnasol, Tiloryth 
Levofloxacin 
Levaquin, Tavanic 
Moxifloxacin 
Avelox, Avalox, Avelon 
Roxithromycin (Only on Non-US 
Market) 
Rulide, Xthrocin, Roxl-150, Roxo, Surlid, 
Rulide, Biaxsig, Roxar, Roximycinv, 
Roxomycin, Rulid, Tirabicin, Coroxin 
Citalopram 
Celexa, Cipramil 
Antidepressant, 
SSRI 
Escitalopram 
Cipralex, Lexapro, Nexito, Anxiset-E (India), 
Exodus (Brazil), Esto (Israel), Seroplex, Elicea, 
Lexamil, Lexam, Entact (Greece), Losita 
(Bangladesh), Reposil (Chile), Animaxen 
(Colombia), Esitalo (Australia), Lexamil 
(South Africa) 
Domperidone (Only on Non-US 
Market) 
Motilium, Motillium, Motinorm Costi, Nomit 
Antiemetic 
Ondansetron
Zofran, Anset, Ondemet, Zuplenz, Emetron, 
Ondavell, Emeset, Ondisolv, Setronax 
Fluconazole 
Diflucan, Trican 
Antifungal 

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Generic Name 
Brand Names (Partial List) 
Drug Class 
Pentamidine 
Pentam 
Chloroquine 
Aralen 
Antimalarial 
Halofantrine (Only on Non-US 
Market) 
Halfan 
Haloperidol 
Haldol (US & UK), Aloperidin, Bioperidolo, 
Brotopon, Dozic, Duraperidol (Germany), 
Einalon S, Eukystol, Halosten, Keselan, Linton, 
Peluces, Serenace, Serenase, Sigaperidol 
Antipsychotic 
Levomepromazine 
(methotrimeprazine) (Only on 
Non-US Market) 
Nosinan, Nozinan, Levoprome
Levosulpiride (Only on Non-US 
Market)
Lesuride, Levazeo, Enliva (with rabeprazole) 
Pimozide 
Orap 
Thioridazine
Mellaril, Novoridazine, Thioril 
Chlorpromazine 
Thorazine, Largactil, Megaphen 
Antipsychotic / 
Antiemetic 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 
Sulpiride (Only on Non-US 
Market) 
Dogmatil, Dolmatil, Eglonyl, Espiride, Modal, 
Sulpor 
Antipsychotic, 
atypical 
Sultopride (Only on Non-US 
Market) 
Barnetil, Barnotil, Topral 
Donepezil 
Aricept 
Cholinesterase 
inhibitor 
Cocaine 
Cocaine 
Local anesthetic 
Terodiline (Only on Non-US 
Market) 
Micturin, Mictrol (not bethanechol) 
Muscle relaxant 
Methadone 
Dolophine, Symoron, Amidone, Methadose, 
Physeptone, Heptadon 
Opiate 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 
3 inhibitor 
Cilostazol 
Pletal 
Ibogaine (Only on Non-US 
Market) 
None 
Psychedelic 
Terlipressin (Only on Non-US 
Market) 
Teripress, Glypressin, Terlipin, Remestyp, 
Tresil, Teriss and others 
Vasoconstrictor 
Papaverine HCl (Intra-coronary)
none
Vasodilator, 
Coronary 
Note: Drugs removed from market not listed. 
Reference: https://crediblemeds.org (last revision date: June 25, 2019); accessed 20 August 2019 
 
 

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APPENDIX D.
TUMOR ASSESSMENT
 
Tumor Assessment Criteria 
The determination of response and progression will be based on standardized criteria: Lugano 
Classification (Cheson 2014). 
Method of Assessment 
Imaging-based evaluation will be used in this study as the primary basis of DLBCL response 
assessment. The recommended and preferred method for radiographic tumor assessment for this 
study is fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography 
(CT) scan (PET-CT). If PET-CT is unavailable, a contrast-enhanced CT may be substituted; 
contrast material may be omitted in subjects for whom use of a contrast agent becomes medically 
contraindicated. MRI scanning is not advised b
subjects for whom this is a necessary alternative to CT scanning. 
Hybrid PET-CT scanners may be used to acquire the required CT images only if CT produced by 
the scanner is of diagnostic quality and includes intravenous contrast (unless medically 
contraindicated). Non-diagnostic CT images acquired for attenuation purposes during the PET-
CT are not acceptable as the only CT scan for the timepoint. Diagnostic CT images with contrast 
(unless medically contraindicated) with a standalone CT scanner must be acquired if PET-CT is 
unable to acquire diagnostic CT images. 
If the diagnostic CT and PET are acquired on the same day, it is strongly recommended that the 
PET is performed prior to the CT with IV contrast. 
Recommended that PET images be converted to SUV maps to support comparison across 
timepoints and to standardize viewing conditions. 
For radiographic assessments, it is highly recommended that the same method of assessment and 
the same technique (eg, scan type, scanner, subject position, dose of contrast, injection/scan 
interval) be used to characterize each identified and reported lesion at baseline and during study 
treatment and follow-up. Whole-body PET-CT scanning should be extended from the base of the 
skull to mid-thigh. If CT is used, images of the neck, chest, abdomen, and pelvis should be 
performed with cuts of  0.5 mm in slice thickness contiguously. 
All relevant radiographic and clinical information required to make each tumor status assessment 
must be made available for source verification as requested by the study sponsor. 
The 5 Point Scale (5-PS) is used for PET interpretation (see table below). 
 

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5 Point Scale (5-PS)
Score 
Description 
1 
No uptake 
2 
Uptake  mediastinum 
3 
Uptake > mediastinum but  liver 
4 
Uptake moderately > liver 
5 
Uptake markedly higher than liver and/or new lesions 
X 
New areas of uptake unlikely to be related to lymphoma 
Adapted from Cheson 2014 
 
Timing of Disease Assessments 
During screening, imaging-based tumor assessments should be performed within the specified 
screening period. On-study tumor assessments should be performed as indicated in the SOE 
(Table 6) which includes an interim assessment and an end of combination treatment assessment. 
If PET-CT, rather than CT, performed at the interim assessment timepoint (after Cycle 3 R-
CHOP administration), it should be performed as long as possible after the administration of R-
CHOP but before the next cycle (eg, C3D20); interim assessment should not result in a change in 
therapy unless there is biopsy-proven evidence of refractory lymphoma or lymphoma 
progression. 
At the completion of the combination phase, a restaging tumor assessment (PET-CT) will be 
performed at least 4 weeks but preferably at 6 to 8 weeks after the completion of the last cycle of 
R-CHOP; weeks calculated from the last administration of rituximab product. 

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Definitions of Tumor Response and Progression 
(Adapted from Cheson 2014)
Complete Response 
COMPLETE 
RESPONSE  
(CR)
PET-CT Based Response 
CT Based Response 
Complete Metabolic Response (CMR)
Complete Response (CR) 
(all of the following) 
Lymph nodes and 
extralymphatic sites
Score, 1, 2, or 3 with or without residual 
mass on 5-PS* 
Target nodes/nodal masses must regress to 
 1.5 cm in LDi 
No extralymphatic sites of disease 
Non-measured lesions
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if indeterminate, 
IHC negative 
physiologic update or with activation within spleen or marrow (eg 
with chemotherapy or myeloid colony-stimulating factors) uptake may be greater than normal mediastinum and/or 
liver. In this circumstance, CMR may be inferred if uptake at sites of initial involvement is no greater than 
surrounding normal tissue even if the tissue has high physiologic uptake. 
LDi, longest transverse diameter of a lesion 
 
Partial Response 
PARTIAL 
RESPONSE 
(PR) 
PET-CT Based Response 
CT Based Response 
Partial Metabolic Response (PMR) 
Partial Response (PR) 
(all of the following) 
Lymph nodes and 
extralymphatic 
sites 
Score, 4 or 5 on 5-PS with reduced uptake 
compared with baseline and residual mass(es) of 
any size 
 
At interim these findings suggest responding 
disease 
 
At end of treatment these findings indicate 
residual disease 
 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
 
When a lesion is too small to measure on 
CT, assign 5 mm X 5 mm as the default 
value; when no longer visible, 0 mm X 
0 mm; for a node > 5 mm x 5 mm, but 
smaller than normal, use actual measurement 
for calculation 
Non-measured 
lesions
Not applicable 
Absent/normal, regressed, no increase 
Organ 
enlargement 
Not applicable
Spleen must have regressed by > 50% in 
length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the 
context of nodal response, consideration should 
be given to further evaluation with MRI or 
biopsy, or an interval scan 
Not applicable 
SPD, sum of the product of the perpendicular diameters for multiple lesions 
 

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Stable Disease
STABLE DISEASE 
(SD) 
PET-CT Based Response 
CT Based Response
No Metabolic Response (NMR) 
Stable Disease (SD) 
Target nodes/nodal 
masses, extranodal 
lesions 
Score, 4 or 5 on 5-PS with no significant 
change in FDG uptake from baseline at 
interim or end of treatment 
< 50% decrease in SPD of up to 6 
dominant, measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Non-measured 
lesions 
Not applicable 
No increase consistent with progression
Organ enlargement 
Not applicable 
No increase consistent with progression
New lesions
None 
None 
Bone marrow
No change from baseline
Not applicable
 
Progressive Disease 
PROGRESSIVE 
DISEASE 
(PD) 
PET-CT Based Response 
CT Based Response
Progressive Metabolic Disease (PMD) 
Progressive Disease (PD)
(at least one of the following) 
Individual target 
nodes/nodal masses, 
extranodal lesions 
 
Score, 4 or 5 on 5-PS with an increase in 
intensity of uptake from baseline and/or 
new FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment 
PPD progression 
An individual node/lesion must be 
abnormal with: 
 
LDi > 1.5cm and 
 
Increase by  50% from PPD 
nadir 
An increase in LDi or SDi from nadir 
 
0.5cm for lesions  2 cm 
 
1.0cm for lesions > 2cm 
 
In the setting of splenomegaly, the 
splenic length must increase by > 50% 
of the extent of its prior increase 
beyond baseline; if no prior 
splenomegaly, must increase by at least 
2cm from baseline 
New or recurrent splenomegaly 
Non-measured lesion
None 
New or clear progression of preexisting 
non-measured lesions 
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy 
or interval scan may be considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5cm in any axis 
A new extranodal site > 1.0cm in any 
axis; if < 1.0cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
PPD, cross product of the LDi and perpendicular diameter 
SDi, shortest axis perpendicular to the LDi

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Identification and Follow-up of Tumor Lesions and Organomegaly 
 
PET-CT Based Response Assessment 
All involved areas using 5-Point Scale should be assessed. 
A bone marrow biopsy (BMB) is not required at screening/baseline unless clinically indicated 
(eg, to evaluate indeterminant PET-CT findings, cytopenia, or presence of discordant 
lymphoma). BMB is required at end of treatment in those patients who have otherwise achieved 
a CR and had a positive BMB at screening/baseline. 
CT Based Response Assessment 
Target Lesions 
Up to 6 of the largest target nodes, nodal masses, or extranodal lesions that are clearly 
measurable in two diameters (longest diameter [LDi] and shortest diameter) should be selected 
as target lesions that will be used to quantitate the status of the disease during study treatment. 
Ideally, the target lesions should be in disparate regions of the body representative of the overall 
disease burden and include mediastinal, abdominal, and retroperitoneal areas of disease 
whenever these sites are involved. 
Extranodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI 
involvement, and cutaneous lesions. 
Target lesions will be measured and recorded at baseline and at the stipulated intervals during 
treatment. 
A measurable node: LDi > 1.5cm 
A measurable extranodal lesion: LDi > 1.0cm 
Non-Measured Lesions 
All other lesions, not selected as measured, dominant disease including nodal, extranodal and 
assessable disease but are still considered abnormal should be followed as non-measured (non-
target) disease (eg, cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial effusions, 
ascites). 
Spleen 
The spleen should be measured and recorded at baseline and at stipulated intervals during 
treatment. The spleen will be considered enlarged if > 13 cm in vertical (cranial to caudal) length 
by CT. 

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Bone Marrow
Bone marrow assessments will be based on morphologic evaluation of bone marrow biopsies; a 
2.5cm unilateral bone marrow biopsy is recommended along with immunohistochemistry and 
flow cytometry. 

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APPENDIX E.
FONTAINE CLASSIFICATION
Fontaine Classification 
Grade 
Symptoms 
Stage I 
Asymptomatic, incomplete blood vessel obstruction 
Stage II 
Mild claudication, pain in limb 
Stage IIA 
Claudication at a distance > 200 m 
Stage IIB 
Claudication at a distance < 200 m 
Stage III 
Rest pain, mostly in the feet 
Stage IV 
Necrosis and/or gangrene of the limb 
Fontaine R, Kim M, Kieny R. Surgical treatment of peripheral circulation disorders [in German] Helv 
Chir Acta. 1954;21(5 6):499 533