NCT03263026

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

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™

• Status: Completed
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 256 (actual)
• Sponsor: Denovo Biopharma LLC · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

• Diffuse Large B-Cell Lymphoma

Interventions

Type	Name	Description
DRUG	Enzastaurin Hydrochloride	R-CHOP + Enzastaurin (Kinenza®) 125 mg
OTHER	R-CHOP + placebo	R-CHOP + placebo

Timeline

• Start date: 2018-03-20
• Primary completion: 2022-08-11
• Completion: 2022-08-11
• First posted: 2017-08-28
• Last updated: 2025-01-23
• Results posted: 2025-01-23

Locations

39 sites across 2 countries: United States, China

Regulatory

• FDA-regulated drug study