Study to Assess Enzastaurin + R-CHOP in Subjects With DLBCL With the Genomic Biomarker DGM1™
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|ClinicalTrials.gov Identifier: NCT03263026|
Recruitment Status : Recruiting
First Posted : August 28, 2017
Last Update Posted : April 19, 2019
|Condition or disease||Intervention/treatment||Phase|
|Diffuse Large B-Cell Lymphoma||Drug: Enzastaurin Hydrochloride Other: R-CHOP + placebo||Phase 3|
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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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||235 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||
Subjects will be randomly assigned to receive one of the following: R-CHOP plus enzastaurin or R-CHOP plus placebo, during two treatment periods: induction and maintenance. Induction phase: all subjects will receive R-CHOP for up to six, 21-day cycles. Subjects in the enzastaurin arm will receive a 1125 mg loading dose on Day 2 followed by 500 mg daily. Subjects in the placebo arm will take an identical number of tablets.
After 4-<6 cycles of induction therapy treatment assignment will be unblinded. Subjects in the enzastaurin arm who have achieved a response will have the opportunity to continue in the single-agent, maintenance phase of the study, and will receive single-agent enzastaurin at 500 mg/day for up to 2 years. Eligible subjects must begin the maintenance phase of the study within 6 weeks of completing induction therapy.
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Masking Description:||Denovo Biopharma, the study Sponsor, will also be blinded.|
|Official Title:||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™|
|Actual Study Start Date :||March 20, 2018|
|Estimated Primary Completion Date :||October 2020|
|Estimated Study Completion Date :||September 2021|
Active Comparator: R-CHOP + 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.
Drug: Enzastaurin Hydrochloride
R-CHOP + Enzastaurin (Kinenza®) 125 mg
Other Name: Kinenza®
Placebo Comparator: 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.
Other: R-CHOP + placebo
R-CHOP + placebo
Other Name: Placebo
- Overall survival in subjects who possess the DGM1™ biomarker [ Time Frame: 3.5 years ]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.
- Overall survival in subjects who do not possess the DGM1™ biomarker [ Time Frame: 3.5 years ]A secondary 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 do not possess the DGM1™ biomarker.
- Safety of enzastaurin by assessing incidence of adverse events/serious adverse events, change of vital signs, ECG results, lab results, and physical exam findings from baseline [ Time Frame: 3.5 years ]
The safety analysis will include the following:
- 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 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 grade and relationship to study drug using CTCAE v4.03
- Presence of chromaturia as a predictor of efficacy [ Time Frame: 3.5 years ]Urine color will be analyzed by the central lab and overall survival will be determined for subjects with reddish discoloration of the urine. Testing may be performed to define the chemical profile of the urine.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03263026
|Contact: Ron Shazer, MD||1.858.799.1021 ext email@example.com|
|Contact: Steve Haynes||910-350-2306||Steve.Haynes@chiltern.com|
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|Study Director:||Ron Shazer, MD||Denovo Biopharma LLC|