Study to Assess Enzastaurin + R-CHOP in Subjects With DLBCL With the Genomic Biomarker DGM1™
- Conditions
- Diffuse Large B-Cell Lymphoma
- Interventions
- Other: R-CHOP + placebo
- Registration Number
- NCT03263026
- Lead Sponsor
- Denovo Biopharma LLC
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 256
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description R-CHOP + enzastaurin Enzastaurin Hydrochloride Subjects in the R-CHOP + enzastaurin Arm will receive R-CHOP (Rituximab-375 mg/m2 i.v., Cyclophosphamide-750 mg/m2 i.v., Doxorubicin-50 mg/m2 i.v., Vincristine-1.4 mg/m2 i.v. (2 mg max), and Prednisone-100 mg p.o.), as directed, plus a 1125 mg loading dose of enzastaurin on Day 2 followed by 500 mg daily. After completion of the combination phase of treatment, subjects will be reassessed using PET-CT and subsequently each subject's treatment assignment will be unblinded. Subjects randomized to the enzastaurin arm who have CR or PR at investigator's discretion by the Lugano Classification 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 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. R-CHOP + placebo R-CHOP + placebo Subjects in the R-CHOP + placebo Arm will receive R-CHOP (Rituximab-375 mg/m2 i.v., Cyclophosphamide-750 mg/m2 i.v., Doxorubicin-50 mg/m2 i.v., Vincristine-1.4 mg/m2 i.v. (2 mg max), and Prednisone-100 mg p.o.), as directed, plus an identical number of tablets as the subjects in the enzastaurin Arm. After completion of the combination phase of treatment, subjects will be reassessed using PET-CT and subsequently each subject's treatment assignment will be unblinded. All 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.
- Primary Outcome Measures
Name Time Method Overall Survival in Subjects Who Possess the DGM1™ Biomarker Primary Outcome evaluated at 12 months. The primary objective of this study is to compare the effect of R-CHOP/enzastaurin versus R-CHOP alone on overall survival in treatment naive, high-risk subjects with DLBCL who possess the DGM1™ biomarker.
- Secondary Outcome Measures
Name Time Method To Determine the Effect on Overall Survivor of Adding Enzastaurin to R-CHOP in Treatment naïve Subjects With High-risk DLBCL Regardless of DGM1 Biomarker Status. Secondary Outcome evaluated at 12 months. The secondary outcome of this study is 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.
Trial Locations
- Locations (39)
Mercy Research
🇺🇸Springfield, Missouri, United States
University of Texas Southwestern Medical Center - Harold C. Simmons Comprehensive Cancer Center
🇺🇸Dallas, Texas, United States
Seattle Cancer Center Alliance
🇺🇸Seattle, Washington, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
Desert Hematology
🇺🇸Rancho Mirage, California, United States
Oncology Specialties: Clearview Cancer Institute
🇺🇸Huntsville, Alabama, United States
Hematology & Oncology Associates, Inc.
🇺🇸Canton, Ohio, United States
Central Arkansas Radiation Therapy Institute
🇺🇸Little Rock, Arkansas, United States
Summit Medical Group
🇺🇸Morristown, New Jersey, United States
University of Arizona
🇺🇸Tucson, Arizona, United States
Stony Brook Cancer Center
🇺🇸Stony Brook, New York, United States
Swedish Cancer Institute
🇺🇸Seattle, Washington, United States
Tri-County Hematology & Oncology Associates, Inc.
🇺🇸Massillon, Ohio, United States
Fudan University Shanghai Cancer Hospital
🇨🇳Shanghai, China
Saint Louis University
🇺🇸Saint Louis, Missouri, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Oncology Consultants: Memorial City
🇺🇸Houston, Texas, United States
New York Medical College
🇺🇸Hawthorne, New York, United States
West China Hospital of Sichuan University (Hematology Dept)
🇨🇳Chengdu, China
Beijing Cancer Hospital
🇨🇳Beijing, China
Second Affiliated Hospital of Dalian Medical University
🇨🇳Dalian, China
ZheJiang Cancer Hospital ( Lymphoma Dept)
🇨🇳Hangzhou, China
Harbin Medical University Cancer Hospital (Oncology Internal)
🇨🇳Harbin, China
Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States
Atlantic Health System/ Morristown Meeical Center
🇺🇸Morristown, New Jersey, United States
University of Wisconsin Hospital and Clinics
🇺🇸Madison, Wisconsin, United States
Toledo Clinic Cancer Centers
🇺🇸Toledo, Ohio, United States
Peking University Third Hospital (Hematology Dept)
🇨🇳Beijing, China
JiLin Cancer Hospital（Lymphoma hematology Dept)
🇨🇳Changchun, China
HeNan Cancer Hospital (Hematology Dept)
🇨🇳Zhengzhou, China
GuangDong General Hospital
🇨🇳Guangzhou, China
Tianjin Medical University Cancer Institute and Hospital
🇨🇳Tianjin, China
The First Affiliated Hospital of ZhengZhou University (Oncology Dept)
🇨🇳Zhengzhou, China
Illinois CancerCare
🇺🇸Peoria, Illinois, United States
Norton Cancer Institute Oncology Practices - St. Matthews Location
🇺🇸Louisville, Kentucky, United States
Mayo Clinic, Rochester
🇺🇸Rochester, Minnesota, United States
Vince Lombardi Cancer Center (Aurora St. Luke's Medical Center)
🇺🇸Milwaukee, Wisconsin, United States