Study to Assess Enzastaurin + R-CHOP in Subjects With DLBCL With the Genomic Biomarker DGM1™

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the Non-Hodgkin's Lymphomas,
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.

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 patients to less than 50% for high-risk patients.

Most important, for those subjects refractory to R-CHOP therapy less than 10% achieve a
durable remission with secondary therapy. 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 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.

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 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.

Enzastaurin, an acyclic bisindolylmaleimide, is a potent and selective inhibitor of PKC-beta.
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-beta) at ser9, induces cell death (apoptosis), and suppresses
proliferation in cultured cell lines from human colon cancers, glioblastoma and lymphomas.
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.

Inclusion Criteria

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. Subjects
with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements and
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):

1. Hepatic: total bilirubin ≤1.5 times upper limit of normal (ULN); alanine
transaminase (ALT) and aspartate transaminase (AST) ≤1.5 times ULN (<5 times ULN
if liver involvement)

2. Renal: creatinine clearance of >50 mL/min by Cockcroft- Gault equation

3. Bone marrow: platelets ≥75 x 109/L, absolute neutrophil count (ANC) ≥1.5 x 109/L,
hemoglobin ≥10 g/dL. (Platelets ≥50 x 109/L, ANC ≥1.0 x 109/L, hemoglobin ≥8 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.

1. Men are considered of reproductive potential unless they have undergone a
vasectomy and confirmed sterile by a post-vasectomy semen analysis.

2. 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 accordance with the device's label) 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.

12. Must have available and willing to submit pre-systemic treatment DLBCL tumor biopsy
tissue/slides for central pathology review.

Exclusion Criteria

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 7 days of corticosteroids are permitted but must 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 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 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 Day1, NYHA Grade 2 or higher
congestive heart failure, ventricular arrhythmia requiring medication within 1 year of
Day 1, NYHA Grade 2 or higher peripheral vascular disease.

18. Received a live vaccine within 28 days of study Day 1.

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:

1. HBsAg+ or

2. HBcAb+ with HBV-DNA+ (any detectable amount is considered positive)