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

NCT ID: NCT03263026

Last Updated: 2025-01-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 256 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-20
• Study Completion Date: 2022-08-11

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.

Conditions

Diffuse Large B-Cell Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

R-CHOP + enzastaurin

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.

Group Type: ACTIVE_COMPARATOR

Enzastaurin Hydrochloride

Intervention Type: DRUG

R-CHOP + Enzastaurin (Kinenza®) 125 mg

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.

Group Type: PLACEBO_COMPARATOR

R-CHOP + placebo

Intervention Type: OTHER

R-CHOP + placebo

Interventions

Enzastaurin Hydrochloride

R-CHOP + Enzastaurin (Kinenza®) 125 mg

Intervention Type: DRUG

R-CHOP + placebo

R-CHOP + placebo

Intervention Type: OTHER

Other Intervention Names

Kinenza®; Placebo

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Denovo Biopharma LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Oncology Specialties: Clearview Cancer Institute

Huntsville, Alabama, United States

University of Arizona

Tucson, Arizona, United States

Central Arkansas Radiation Therapy Institute

Little Rock, Arkansas, United States

Desert Hematology

Rancho Mirage, California, United States

Loyola University Medical Center

Maywood, Illinois, United States

Illinois CancerCare

Peoria, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

Norton Cancer Institute Oncology Practices - St. Matthews Location

Louisville, Kentucky, United States

Mayo Clinic, Rochester

Rochester, Minnesota, United States

Mercy Research

Springfield, Missouri, United States

Saint Louis University

St Louis, Missouri, United States

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States

Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

Summit Medical Group

Morristown, New Jersey, United States

Atlantic Health System/ Morristown Meeical Center

Morristown, New Jersey, United States

New York Medical College

Hawthorne, New York, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Stony Brook Cancer Center

Stony Brook, New York, United States

Hematology & Oncology Associates, Inc.

Canton, Ohio, United States

Tri-County Hematology & Oncology Associates, Inc.

Massillon, Ohio, United States

Toledo Clinic Cancer Centers

Toledo, Ohio, United States

University of Texas Southwestern Medical Center - Harold C. Simmons Comprehensive Cancer Center

Dallas, Texas, United States

Oncology Consultants: Memorial City

Houston, Texas, United States

Swedish Cancer Institute

Seattle, Washington, United States

Seattle Cancer Center Alliance

Seattle, Washington, United States

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Vince Lombardi Cancer Center (Aurora St. Luke's Medical Center)

Milwaukee, Wisconsin, United States

Beijing Cancer Hospital

Beijing, , China

Peking University Third Hospital (Hematology Dept)

Beijing, , China

JiLin Cancer Hospital（Lymphoma hematology Dept)

Changchun, , China

West China Hospital of Sichuan University (Hematology Dept)

Chengdu, , China

Second Affiliated Hospital of Dalian Medical University

Dalian, , China

GuangDong General Hospital

Guangzhou, , China

ZheJiang Cancer Hospital ( Lymphoma Dept)

Hangzhou, , China

Harbin Medical University Cancer Hospital (Oncology Internal)

Harbin, , China

Fudan University Shanghai Cancer Hospital

Shanghai, , China

Tianjin Medical University Cancer Institute and Hospital

Tianjin, , China

HeNan Cancer Hospital (Hematology Dept)

Zhengzhou, , China

The First Affiliated Hospital of ZhengZhou University (Oncology Dept)

Zhengzhou, , China

Countries

United States; China

References

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.

Reference Type: DERIVED

PMID: 32250167 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

DB102-02

Identifier Type: -

Identifier Source: org_study_id