Diffuse Large B-Cell LymphomaPhase 3NCT03263026
Study to Assess Enzastaurin + R-CHOP in Subjects With DLBCL With the Genomic Biomarker DGM1™
A Phase 3 study testing Enzastaurin Hydrochloride in people with Diffuse Large B-Cell Lymphoma, run by Denovo Biopharma LLC at 39 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Diffuse Large B-Cell Lymphoma
- What is being tested?
- Enzastaurin Hydrochloride
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 256 participants
- Where
- 39 sitesin 2 countries
- Study dates
- 20 Mar 2018to 11 Aug 2022
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female at least 18 years of age and able to provide informed consent.
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
- International Prognostic Index (IPI) score of at least 3.
- Estimated life expectancy of at least 12 weeks.
- Adequate organ function as follows (within 14 days prior to randomization):
Show all 17Show fewer
- 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)
- Renal: creatinine clearance of ≥ 40 mL/min by Cockcroft- Gault equation
- 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)
- 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.
- Men are considered of reproductive potential unless they have undergone a vasectomy and confirmed sterile by a post-vasectomy semen analysis.
- 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).
- Left ventricular ejection fraction ≥50% by echocardiography or nuclear medicine multi-gated scan.
- Must be able to swallow tablets.
- Must be able to comply with study protocol procedures.
- Willing to consent to have blood stored for possible future biomarker and disease analysis.
- Must have available and willing to submit pre-systemic treatment DLBCL tumor biopsy tissue/slides for central pathology review.
Who cannot join
- Received treatment with an investigational drug within the last 30 days.
- 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).
- History of indolent lymphoma or follicular Grade 3b lymphoma.
- Primary mediastinal (thymic) large B-cell lymphoma.
- B-cell lymphoma, unclassifiable, with features. intermediate between DLBCL and classical Hodgkin lymphoma.
- Burkitt lymphoma.
Show all 23Show fewer
- Pregnancy or breastfeeding.
- Known central nervous system (CNS) involvement.
- 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.
- 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.
- 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.
- 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.
- 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.
- History of severe allergic or anaphylactic reaction to monoclonal antibody therapy.
- Confirmed diagnosis of progressive multifocal leukoencephalopathy.
- Ongoing grade 2 or higher peripheral neuropathy.
- 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.
- Received a live vaccine within 28 days of study Day 1.
- HIV positive.
- Evidence of chronic hepatitis C infection as indicated by antibody to HCV with positive HCV-RNA.
- Evidence of chronic hepatitis B infection as indicated by either:
- HBsAg+ or
- HBcAb+ with HBV-DNA+ (any detectable amount is considered positive)
Trial locations and contacts
39 sites in 2 countries.
39 sites in 2 countries
United States27 sites
Hematology & Oncology Associates, Inc.
Canton, Ohio, 44708
University of Texas Southwestern Medical Center - Harold C. Simmons Comprehensive Cancer Center
Dallas, Texas, 75235
New York Medical College
Hawthorne, New York, 10595
Oncology Consultants: Memorial City
Houston, Texas, 77024
Oncology Specialties: Clearview Cancer Institute
Huntsville, Alabama, 35805
Indiana University
Indianapolis, Indiana, 46202
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, 89169
Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, 03766
Central Arkansas Radiation Therapy Institute
Little Rock, Arkansas, 72205
Norton Cancer Institute Oncology Practices - St. Matthews Location
Louisville, Kentucky, 40241
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
Tri-County Hematology & Oncology Associates, Inc.
Massillon, Ohio, 44646
Loyola University Medical Center
Maywood, Illinois, 60153
Vince Lombardi Cancer Center (Aurora St. Luke's Medical Center)
Milwaukee, Wisconsin, 53215
Summit Medical Group
Morristown, New Jersey, 07960
Atlantic Health System/ Morristown Meeical Center
Morristown, New Jersey, 07972
Icahn School of Medicine at Mount Sinai
New York, New York, 10029
Illinois CancerCare
Peoria, Illinois, 61615
Desert Hematology
Rancho Mirage, California, 92270
Mayo Clinic, Rochester
Rochester, Minnesota, 55905
Swedish Cancer Institute
Seattle, Washington, 98104
Seattle Cancer Center Alliance
Seattle, Washington, 98109
Mercy Research
Springfield, Missouri, 65806
Saint Louis University
St Louis, Missouri, 63104
Stony Brook Cancer Center
Stony Brook, New York, 11794
Toledo Clinic Cancer Centers
Toledo, Ohio, 43623
University of Arizona
Tucson, Arizona, 85719
China12 sites
Beijing Cancer Hospital
Beijing, 100142
Peking University Third Hospital (Hematology Dept)
Beijing, 100191
JiLin Cancer Hospital（Lymphoma hematology Dept)
Changchun, 130012
West China Hospital of Sichuan University (Hematology Dept)
Chengdu, 637400
Second Affiliated Hospital of Dalian Medical University
Dalian, 116044
GuangDong General Hospital
Guangzhou, 510080
ZheJiang Cancer Hospital ( Lymphoma Dept)
Hangzhou, 310022
Harbin Medical University Cancer Hospital (Oncology Internal)
Harbin, 150081
Fudan University Shanghai Cancer Hospital
Shanghai, 200032
Tianjin Medical University Cancer Institute and Hospital
Tianjin, 300060
HeNan Cancer Hospital (Hematology Dept)
Zhengzhou, 450003
The First Affiliated Hospital of ZhengZhou University (Oncology Dept)
Zhengzhou, 450052
About this study
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™
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.
Read the 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
- Being tested
- Enzastaurin Hydrochloride, R-CHOP + placebo
- Keywords
- Lymphoma, Non-Hodgkin's Lymphoma, enzastaurin
- Medical subject headings
- Lymphoma, Large B-Cell, Diffuse, Lymphoma, Lymphoma, Non-Hodgkin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Enzastaurin HydrochlorideDrug
Also called Kinenza®
R-CHOP + Enzastaurin (Kinenza®) 125 mg
R-CHOP + placeboOther
Also called Placebo
R-CHOP + placebo
| Study group | Role | What they receive |
|---|---|---|
| R-CHOP + enzastaurin | Active comparator | 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. Receives: Drug: Enzastaurin Hydrochloride |
| R-CHOP + placebo | Placebo comparator | 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. Receives: Other: R-CHOP + placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival in Subjects Who Possess the DGM1™ Biomarker
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.
Measured: Primary Outcome evaluated at 12 months.
Secondary outcomes (1)
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.
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.
Measured: Secondary Outcome evaluated at 12 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Aug 2017
- Study start20 Mar 2018
- Primary completion11 Aug 2022
- Study completion11 Aug 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Diffuse Large B-Cell LymphomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Following screening (within 28 days), subjects will receive up to 6 cycles of R-CHOP immunochemotherapy (21-day cycles) plus study drug, during the combination phase. Combination Phase (6 x 21-day cycles with R-CHOP): Subjects will receive a loading dose of 1125 mg (3 tablets TID) followed by 500 mg (4 tablets QD) of study drug (enzastaurin/placebo) daily. Sigle-Agent Phase: Following completion of up to 6 cycles of R-CHOP, subjects in the enzastaurin arm who have a CR, or PR (at investigator's discretion) may continue to take single-agent study drug (enzastaurin 500 mg) daily for up to 2 additional years.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 256 participants (actual)
Sponsor and investigators
- Lead sponsor
- Denovo Biopharma LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03263026
- Sponsor's protocol ID
- DB102-02
- Status last verified
- Nov 2024
- First submitted
- 18 Aug 2017
- Last updated
- 23 Jan 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Nowakowski GS, Zhu J, Zhang Q, Brody J, Sun X, Maly J, Song Y, Rizvi S, Song Y, Lansigan F, Jing H, Cao J, Lue JK, Luo W, Zhang L, Li L, Han I, Sun J, Jivani M, Liu Y, Heineman T, Smith SD. ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1. Future Oncol. 2020 May;16(15):991-999. doi: 10.2217/fon-2020-0176. Epub 2020 Apr 6.
PubMed 32250167
Study at a glance
From the registry record, last updated by the sponsor on 23 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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™
- ClinicalTrials.gov ID
- NCT03263026
- Acronym / sponsor ID
- DB102-02
- Conditions
- Diffuse Large B-Cell Lymphoma
- Keywords
- Lymphoma, Non-Hodgkin's Lymphoma, enzastaurin
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 256 participants (actual)
- Lead sponsor
- Denovo Biopharma LLCIndustry (pharma, biotech, devices)
- Study start
- 20 Mar 2018 (actual)
- Primary completion
- 11 Aug 2022 (actual)
- Study completion
- 11 Aug 2022 (actual)
- First posted
- 28 Aug 2017 (actual)
- Results
- Posted 23 Jan 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- Following screening (within 28 days), subjects will receive up to 6 cycles of R-CHOP immunochemotherapy (21-day cycles) plus study drug, during the combination phase. Combination Phase (6 x 21-day cycles with R-CHOP): Subjects will receive a loading dose of 1125 mg (3 tablets TID) followed by 500 mg (4 tablets QD) of study drug (enzastaurin/placebo) daily. Sigle-Agent Phase: Following completion of up to 6 cycles of R-CHOP, subjects in the enzastaurin arm who have a CR, or PR (at investigator's discretion) may continue to take single-agent study drug (enzastaurin 500 mg) daily for up to 2 additional years.
| Arm | Type | Receives |
|---|---|---|
| R-CHOP + enzastaurin | Active comparator | Drug: Enzastaurin HydrochlorideSubjects 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 | Placebo comparator | Other: R-CHOP + placeboSubjects 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Male or female at least 18 years of age and able to provide informed consent.
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
- International Prognostic Index (IPI) score of at least 3.
- Estimated life expectancy of at least 12 weeks.
Key exclusion criteria (23 listed)
- Received treatment with an investigational drug within the last 30 days.
- 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).
- History of indolent lymphoma or follicular Grade 3b lymphoma.
- Primary mediastinal (thymic) large B-cell lymphoma.
- B-cell lymphoma, unclassifiable, with features. intermediate between DLBCL and classical Hodgkin lymphoma.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Enzastaurin HydrochlorideAlso: Kinenza®R-CHOP + Enzastaurin (Kinenza®) 125 mg | Drug | R-CHOP + enzastaurin |
| R-CHOP + placeboAlso: PlaceboR-CHOP + placebo | Other | R-CHOP + placebo |
Primary outcome
Overall Survival in Subjects Who Possess the DGM1™ Biomarker
Time frame: 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.
1 secondary outcome
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.
Time frame: Secondary Outcome evaluated at 12 months.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jan 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32250167Nowakowski GS, Zhu J, Zhang Q, Brody J, Sun X, Maly J, Song Y, Rizvi S, Song Y, Lansigan F, Jing H, Cao J, Lue JK, Luo W, Zhang L, Li L, Han I, Sun J, Jivani M, Liu Y, Heineman T, Smith SD. ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1. Future Oncol. 2020 May;16(15):991-999. doi: 10.2217/fon-2020-0176. Epub 2020 Apr 6.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
39 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Enzastaurin Hydrochloride in people with Diffuse Large B-Cell Lymphoma, run by Denovo Biopharma LLC at 39 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 39 sites in United States, China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Survival in Subjects Who Possess the DGM1™ Biomarker (time frame: Primary Outcome evaluated at 12 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03263026, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jan 2025.