Clinical Trials /

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

NCT03263026

Description:

This randomized, placebo-controlled phase 3 study is planned to enroll approximately 235 treatment-naïve subjects with high-risk Diffuse Large B-Cell Lymphoma (DLBCL). Subjects will be randomized 1:1 to R-CHOP plus enzastaurin or R CHOP (plus placebo during induction). All subjects will receive up to 6 cycles (3 weeks per cycle) of treatment. PET/ CT will be used to assess radiographic response at the end of treatment. Each subject's treatment assignment will be unblinded after initial phase of treatment. Subjects randomized to the enzastaurin arm who have a response will be offered maintenance treatment of the study drug for up to 2 additional years.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: DB102-02
  • NCT ID: NCT03263026

Conditions

  • Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
Enzastaurin HydrochlorideKinenza®R-CHOP + enzastaurin hydrochloride

Purpose

This randomized, placebo-controlled phase 3 study is planned to enroll approximately 235 treatment-naïve subjects with high-risk Diffuse Large B-Cell Lymphoma (DLBCL). Subjects will be randomized 1:1 to R-CHOP plus enzastaurin or R CHOP (plus placebo during induction). All subjects will receive up to 6 cycles (3 weeks per cycle) of treatment. PET/ CT will be used to assess radiographic response at the end of treatment. Each subject's treatment assignment will be unblinded after initial phase of treatment. Subjects randomized to the enzastaurin arm who have a response will be offered maintenance treatment of the study drug 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.
    

Trial Arms

NameTypeDescriptionInterventions
R-CHOP + enzastaurin hydrochlorideActive ComparatorSubjects 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.
  • Enzastaurin Hydrochloride
R-CHOP + placeboPlacebo ComparatorSubjects 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.

    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); alanine
                      transaminase (ALT) and aspartate transaminase (AST) ≤1.5 times ULN (<5 times ULN
                      if liver involvement)
    
                   2. Renal: creatinine clearance of >50 mL/min by Cockcroft- Gault equation
    
                   3. Bone marrow: platelets ≥75 x 109/L, absolute neutrophil count (ANC) ≥1.5 x 109/L,
                      hemoglobin ≥10 g/dL. (Platelets ≥50 x 109/L, ANC ≥1.0 x 109/L, hemoglobin ≥8 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 Day1, NYHA Grade 2 or higher
                 congestive heart failure, ventricular arrhythmia requiring medication within 1 year of
                 Day 1, NYHA Grade 2 or higher peripheral vascular 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)
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Overall survival in subjects who possess the DGM1™ biomarker
    Time Frame:3.5 years
    Safety Issue:
    Description: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

    Measure:Overall survival in subjects who do not possess the DGM1™ biomarker
    Time Frame:3.5 years
    Safety Issue:
    Description: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.
    Measure: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
    Safety Issue:
    Description: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

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Denovo Biopharma LLC

    Trial Keywords

    • Lymphoma
    • Non-Hodgkin's Lymphoma
    • enzastaurin

    Last Updated