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

This randomized, placebo-controlled phase 3 study planned to enroll approximately 235 treatment-naïve subjects with high-risk Diffuse Large B-Cell Lymphoma (DLBCL). Subjects were randomized 1:1 to R-CHOP plus enzastaurin or R-CHOP (plus placebo during induction). All subjects received up to 6 cycles (3 weeks per cycle) of treatment. PET/ CT was used to assess radiographic response at the end of treatment. Each subject's treatment assignment was unblinded after combination phase tumor response assessment. Subjects randomized to the enzastaurin arm who have a complete response (CR) or partial response (PR) (at investigator's discretion) by Lugano Classification had the opportunity to continue in the single-agent phase of the study and receive single-agent enzastaurin for up to 2 additional years.

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.

Eligibility Criteria:
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) (≤ 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)
   2. Renal: creatinine clearance of ≥ 40 mL/min by Cockcroft- Gault equation
   3. 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 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 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 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)