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

NCT03263026 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: DB102-02
• Study Type: interventional
• Target: 256
• Locations: 2 countries
• Sites: 39

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.

Conditions

Diffuse Large B-Cell Lymphoma

Keywords

Lymphoma; Non-Hodgkin's Lymphoma; enzastaurin

Outcome Measures

Primary Outcomes (1)

• 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.

  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.

  Secondary Outcome evaluated at 12 months.

Other Outcomes (1)

• Presence of Chromaturia as a Predictor of Efficacy

  3.5 years

Study Arms (2)

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.

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.

Other: R-CHOP + placebo

Interventions

Enzastaurin Hydrochloride DRUG

R-CHOP + Enzastaurin (Kinenza®) 125 mg

Also known as: Kinenza®

R-CHOP + enzastaurin

R-CHOP + placebo OTHER

R-CHOP + placebo

Also known as: Placebo

R-CHOP + placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Denovo Biopharma LLC: lead

Study Sites (39)

Oncology Specialties: Clearview Cancer Institute

Huntsville, Alabama, 35805, United States

Location

University of Arizona

Tucson, Arizona, 85719, United States

Location

Central Arkansas Radiation Therapy Institute

Little Rock, Arkansas, 72205, United States

Location

Desert Hematology

Rancho Mirage, California, 92270, United States

Location

Loyola University Medical Center

Maywood, Illinois, 60153, United States

Location

Illinois CancerCare

Peoria, Illinois, 61615, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Norton Cancer Institute Oncology Practices - St. Matthews Location

Louisville, Kentucky, 40241, United States

Location

Mayo Clinic, Rochester

Rochester, Minnesota, 55905, United States

Location

Mercy Research

Springfield, Missouri, 65806, United States

Location

Saint Louis University

St Louis, Missouri, 63104, United States

Location

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, 89169, United States

Location

Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03766, United States

Location

Summit Medical Group

Morristown, New Jersey, 07960, United States

Location

Atlantic Health System/ Morristown Meeical Center

Morristown, New Jersey, 07972, United States

Location

New York Medical College

Hawthorne, New York, 10595, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Stony Brook Cancer Center

Stony Brook, New York, 11794, United States

Location

Hematology & Oncology Associates, Inc.

Canton, Ohio, 44708, United States

Location

Tri-County Hematology & Oncology Associates, Inc.

Massillon, Ohio, 44646, United States

Location

Toledo Clinic Cancer Centers

Toledo, Ohio, 43623, United States

Location

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

Dallas, Texas, 75235, United States

Location

Oncology Consultants: Memorial City

Houston, Texas, 77024, United States

Location

Swedish Cancer Institute

Seattle, Washington, 98104, United States

Location

Seattle Cancer Center Alliance

Seattle, Washington, 98109, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

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

Milwaukee, Wisconsin, 53215, United States

Location

Beijing Cancer Hospital

Beijing, 100142, China

Location

Peking University Third Hospital (Hematology Dept)

Beijing, 100191, China

Location

JiLin Cancer Hospital（Lymphoma hematology Dept)

Changchun, 130012, China

Location

West China Hospital of Sichuan University (Hematology Dept)

Chengdu, 637400, China

Location

Second Affiliated Hospital of Dalian Medical University

Dalian, 116044, China

Location

GuangDong General Hospital

Guangzhou, 510080, China

Location

ZheJiang Cancer Hospital ( Lymphoma Dept)

Hangzhou, 310022, China

Location

Harbin Medical University Cancer Hospital (Oncology Internal)

Harbin, 150081, China

Location

Fudan University Shanghai Cancer Hospital

Shanghai, 200032, China

Location

Tianjin Medical University Cancer Institute and Hospital

Tianjin, 300060, China

Location

HeNan Cancer Hospital (Hematology Dept)

Zhengzhou, 450003, China

Location

The First Affiliated Hospital of ZhengZhou University (Oncology Dept)

Zhengzhou, 450052, China

Location

Related Publications (1)

• 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.

  PMID: 32250167 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma; Lymphoma, Non-Hodgkin

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: Gracielli Hage-Kautz, Associate Director Clinical Operations
• Organization: DeNovo Biopharma

gkautz@denovobiopharma.com

858-799-1021

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Denovo Biopharma, the study Sponsor, will also be blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 18, 2017
• First Posted: August 28, 2017
• Study Start: March 20, 2018
• Primary Completion: August 11, 2022
• Study Completion: August 11, 2022
• Last Updated: January 23, 2025
• Results First Posted: January 23, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

CN (12); US (27)