<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03263026</url>
  </required_header>
  <id_info>
    <org_study_id>DB102-02</org_study_id>
    <nct_id>NCT03263026</nct_id>
  </id_info>
  <brief_title>Study to Assess Enzastaurin + R-CHOP in Subjects With DLBCL With the Genomic Biomarker DGM1™</brief_title>
  <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™</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Denovo Biopharma LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Denovo Biopharma LLC</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This randomized, placebo-controlled phase 3 study is planned to enroll approximately 235&#xD;
      treatment-naïve subjects with high-risk Diffuse Large B-Cell Lymphoma (DLBCL). Subjects will&#xD;
      be randomized 1:1 to R-CHOP plus enzastaurin or R CHOP (plus placebo during induction). All&#xD;
      subjects will receive up to 6 cycles (3 weeks per cycle) of treatment. PET/ CT will be used&#xD;
      to assess radiographic response at the end of treatment. Each subject's treatment assignment&#xD;
      will be unblinded after initial phase of treatment. Subjects randomized to the enzastaurin&#xD;
      arm who have a response will be offered maintenance treatment of the study drug for up to 2&#xD;
      additional years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the Non-Hodgkin's Lymphomas,&#xD;
      accounting for between 30%-40% of all cases. The incidence of DLBCL generally increases with&#xD;
      age and roughly half of all patients are over the age of 60 at the time of diagnosis.&#xD;
&#xD;
      DLBCL is classified as an aggressive lymphoma meaning that its clinical course can progress&#xD;
      rapidly to death. Nevertheless, patients with DLBCL can be cured with the appropriate&#xD;
      treatment. The current standard of care treatment for DLBCL consists of rituximab added to&#xD;
      the anthracycline-containing combination chemotherapy regimen of cyclophosphamide,&#xD;
      doxorubicin, vincristine and prednisone (NCCN Treatment Guidelines). This regimen is referred&#xD;
      to as R-CHOP immunochemotherapy. For DLBCL as a whole, R-CHOP immunochemotherapy has resulted&#xD;
      in cure rates of approximately 60%. However, for individual patients 5-year survival rates&#xD;
      can range from 90% for low-risk patients to less than 50% for high-risk patients.&#xD;
&#xD;
      Most important, for those subjects refractory to R-CHOP therapy less than 10% achieve a&#xD;
      durable remission with secondary therapy. Thus, while R-CHOP remains the standard treatment&#xD;
      for high-risk, advanced-stage DLBCL, approximately 30-40% of patients fail front-line therapy&#xD;
      with most not achieving complete response or with early relapse. An essential step to move&#xD;
      forward and improve the outcomes of these patients is to increase the rate of complete&#xD;
      response to front-line R-CHOP therapy.&#xD;
&#xD;
      For this reason, there has been a great deal of effort placed on attempting to define disease&#xD;
      characteristics that predispose patients to a poorer prognosis with R-CHOP therapy. Molecular&#xD;
      and gene expression profiling of tumors and a variety of clinical prognostic indices have&#xD;
      been used to identify patients at higher risk of failing R-CHOP immunochemotherapy. While&#xD;
      this work has identified subgroups of patients who do not respond well to R-CHOP, to date&#xD;
      these efforts have not resulted in substantial gains in response to front-line therapy.&#xD;
&#xD;
      Denovo Biopharma (Denovo) has pioneered an alternative approach to this challenging problem.&#xD;
      Denovo has developed a model that employs sophisticated pharmacogenomic testing to detect&#xD;
      somatic biomarkers that identify those subjects who responded to a particular study treatment&#xD;
      with the aim of re-studying the drug of interest, in this case enzastaurin, in an enriched&#xD;
      population.&#xD;
&#xD;
      Applying this technology to archived DNA samples from completed studies of enzastaurin in&#xD;
      subjects with DLBCL, Denovo has identified a somatic biomarker that reliably identified&#xD;
      subjects for whom the study treatment significantly prolonged survival. Enzastaurin is an&#xD;
      oral serine/threonine kinase inhibitor, that targets the PKC, and phosphoinositide 3-kinase&#xD;
      (PI3K) and AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and&#xD;
      suppress tumor-induced angiogenesis.&#xD;
&#xD;
      The purpose of the current study is to prospectively assess the effect on survival of adding&#xD;
      enzastaurin to R-CHOP immunochemotherapy in the front-line treatment of an enriched&#xD;
      population of subjects with DLBCL.&#xD;
&#xD;
      Enzastaurin, an acyclic bisindolylmaleimide, is a potent and selective inhibitor of PKC-beta.&#xD;
      At plasma concentrations achieved clinically, enzastaurin and its metabolites suppress&#xD;
      signaling not only through PKC, but also through the PI3K/AKT pathway; these pathways promote&#xD;
      tumor-induced angiogenesis, as well as tumor cell survival and proliferation. Accordingly,&#xD;
      inhibition of signaling pathways by enzastaurin suppresses the phosphorylation of glycogen&#xD;
      synthase kinase 3 beta (GSK3-beta) at ser9, induces cell death (apoptosis), and suppresses&#xD;
      proliferation in cultured cell lines from human colon cancers, glioblastoma and lymphomas.&#xD;
      Oral dosing with enzastaurin to achieve exposure levels similar to that in human clinical&#xD;
      studies suppresses vascular endothelial growth factor (VEGF)-induced angiogenesis and the&#xD;
      growth of human colon cancer and glioblastoma xenografts. These studies have demonstrated&#xD;
      that enzastaurin can suppress tumor growth through multiple mechanisms: the direct effect of&#xD;
      inducing tumor cell death, suppressing tumor cell proliferation, and the indirect effect of&#xD;
      suppressing tumor-induced angiogenesis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 20, 2018</start_date>
  <completion_date type="Actual">July 12, 2022</completion_date>
  <primary_completion_date type="Actual">July 12, 2022</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <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.&#xD;
After 4-&lt;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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Denovo Biopharma, the study Sponsor, will also be blinded.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival in subjects who possess the DGM1™ biomarker</measure>
    <time_frame>3.5 years</time_frame>
    <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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival in subjects who do not possess the DGM1™ biomarker</measure>
    <time_frame>3.5 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <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</measure>
    <time_frame>3.5 years</time_frame>
    <description>The safety analysis will include the following:&#xD;
Summary of extent of exposure&#xD;
Summary of the number of blood transfusions required&#xD;
Summary of adverse events, serious adverse events, and subjects discontinuing for adverse events rates&#xD;
Summary of laboratory findings and change from baseline&#xD;
Summary of QTc data and change from baseline according to ICH E14&#xD;
Summary of other relevant safety observations&#xD;
Listings of laboratory and non-laboratory adverse events by maximum CTCAE grade and relationship to study drug using CTCAE v4.03</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Presence of chromaturia as a predictor of efficacy</measure>
    <time_frame>3.5 years</time_frame>
    <description>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.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">256</enrollment>
  <condition>Diffuse Large B-Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>R-CHOP + enzastaurin hydrochloride</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R-CHOP + placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enzastaurin Hydrochloride</intervention_name>
    <description>R-CHOP + Enzastaurin (Kinenza®) 125 mg</description>
    <arm_group_label>R-CHOP + enzastaurin hydrochloride</arm_group_label>
    <other_name>Kinenza®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>R-CHOP + placebo</intervention_name>
    <description>R-CHOP + placebo</description>
    <arm_group_label>R-CHOP + placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Male or female at least 18 years of age and able to provide informed consent.&#xD;
&#xD;
          2. Histologically-confirmed diagnosis of CD20-positive DLBCL based on the WHO&#xD;
             classification (2016); the diagnosis must be confirmed at the enrolling site. Subjects&#xD;
             with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements and&#xD;
             high-grade B-cell lymphoma, NOS are eligible.&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.&#xD;
&#xD;
          4. International Prognostic Index (IPI) score of at least 3.&#xD;
&#xD;
          5. Estimated life expectancy of at least 12 weeks.&#xD;
&#xD;
          6. Adequate organ function as follows (within 14 days prior to randomization):&#xD;
&#xD;
               1. Hepatic: total bilirubin ≤1.5 times upper limit of normal (ULN); alanine&#xD;
                  transaminase (ALT) and aspartate transaminase (AST) ≤1.5 times ULN (&lt;5 times ULN&#xD;
                  if liver involvement)&#xD;
&#xD;
               2. Renal: creatinine clearance of &gt;50 mL/min by Cockcroft- Gault equation&#xD;
&#xD;
               3. Bone marrow: platelets ≥75 x 109/L, absolute neutrophil count (ANC) ≥1.5 x 109/L,&#xD;
                  hemoglobin ≥10 g/dL. (Platelets ≥50 x 109/L, ANC ≥1.0 x 109/L, hemoglobin ≥8 g/dL&#xD;
                  permitted if documented bone marrow involvement)&#xD;
&#xD;
          7. Male or female with reproductive potential, must be willing to use an approved&#xD;
             contraceptive method (for example, intrauterine device (IUD), birth control pills, or&#xD;
             barrier device) during and for 3 months after discontinuation of study treatment.&#xD;
             Women of childbearing potential must have a negative serum pregnancy test within 7&#xD;
             days prior to randomization.&#xD;
&#xD;
               1. Men are considered of reproductive potential unless they have undergone a&#xD;
                  vasectomy and confirmed sterile by a post-vasectomy semen analysis.&#xD;
&#xD;
               2. Women are considered of reproductive potential unless they have undergone&#xD;
                  hysterectomy and/or surgical sterilization (at least 6 weeks following a&#xD;
                  bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive&#xD;
                  procedure that has been confirmed in accordance with the device's label) or&#xD;
                  achieved postmenopausal status (defined as cessation of regular menses for&#xD;
                  greater than 12 consecutive months in women at least 45 years of age).&#xD;
&#xD;
          8. Left ventricular ejection fraction ≥50% by echocardiography or nuclear medicine&#xD;
             multi-gated scan.&#xD;
&#xD;
          9. Must be able to swallow tablets.&#xD;
&#xD;
         10. Must be able to comply with study protocol procedures.&#xD;
&#xD;
         11. Willing to consent to have blood stored for possible future biomarker and disease&#xD;
             analysis.&#xD;
&#xD;
         12. Must have available and willing to submit pre-systemic treatment DLBCL tumor biopsy&#xD;
             tissue/slides for central pathology review.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Received treatment with an investigational drug within the last 30 days.&#xD;
&#xD;
          2. Receiving or has received radiation or any other systemic anticancer treatment for&#xD;
             lymphoma (Up to 7 days of corticosteroids are permitted but must be administered after&#xD;
             eligibility IPI determination and imaging scans).&#xD;
&#xD;
          3. History of indolent lymphoma or follicular Grade 3b lymphoma.&#xD;
&#xD;
          4. Primary mediastinal (thymic) large B-cell lymphoma.&#xD;
&#xD;
          5. B-cell lymphoma, unclassifiable, with features. intermediate between DLBCL and&#xD;
             classical Hodgkin lymphoma.&#xD;
&#xD;
          6. Burkitt lymphoma.&#xD;
&#xD;
          7. Pregnancy or breastfeeding.&#xD;
&#xD;
          8. Known central nervous system (CNS) involvement.&#xD;
&#xD;
          9. Any significant concomitant disorder based on the discretion of the investigator,&#xD;
             including but not limited to active bacterial, fungal, or viral infection,&#xD;
             incompatible with participation in the study.&#xD;
&#xD;
         10. A second primary malignancy (except adequately treated non-melanoma skin cancer);&#xD;
             subjects who have had another malignancy in the past, but have been disease-free for&#xD;
             more than 5 years, and subjects who have had a localized malignancy treated with&#xD;
             curative intent and disease free for more than 2 years are eligible.&#xD;
&#xD;
         11. Use of a strong inducer or moderate or strong inhibitor of CYP3A4 within 7 days prior&#xD;
             to start of study therapy or expected requirement for use on study therapy.&#xD;
&#xD;
         12. Personal or immediate family history of long QT syndrome, QTc interval &gt;450 msec&#xD;
             (males) or &gt;470 msec (females) at screening (recommended that QTc be calculated using&#xD;
             Fridericia correction formula, QTcF: see Section 6.2.1), or a history of unexplained&#xD;
             syncope.&#xD;
&#xD;
         13. Use of any medication that can prolong the QT/QTc interval within 7 days prior to&#xD;
             start of study therapy or expected requirement for use on study therapy.&#xD;
&#xD;
         14. History of severe allergic or anaphylactic reaction to monoclonal antibody therapy.&#xD;
&#xD;
         15. Confirmed diagnosis of progressive multifocal leukoencephalopathy.&#xD;
&#xD;
         16. Ongoing grade 2 or higher peripheral neuropathy.&#xD;
&#xD;
         17. Have any of the following cardiac disorders: uncontrolled hypertension, unstable&#xD;
             angina, myocardial infarction within 8 weeks of Day1, NYHA Grade 2 or higher&#xD;
             congestive heart failure, ventricular arrhythmia requiring medication within 1 year of&#xD;
             Day 1, NYHA Grade 2 or higher peripheral vascular disease.&#xD;
&#xD;
         18. Received a live vaccine within 28 days of study Day 1.&#xD;
&#xD;
         19. HIV positive.&#xD;
&#xD;
         20. Evidence of chronic hepatitis C infection as indicated by antibody to HCV with&#xD;
             positive HCV-RNA.&#xD;
&#xD;
         21. Evidence of chronic hepatitis B infection as indicated by either:&#xD;
&#xD;
               1. HBsAg+ or&#xD;
&#xD;
               2. HBcAb+ with HBV-DNA+ (any detectable amount is considered positive)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Oncology Specialties: Clearview Cancer Institute</name>
      <address>
        <city>Huntsville</city>
        <state>Alabama</state>
        <zip>35805</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Arizona</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85719</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Arkansas Radiation Therapy Institute</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Desert Hematology</name>
      <address>
        <city>Rancho Mirage</city>
        <state>California</state>
        <zip>92270</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Loyola University Medical Center</name>
      <address>
        <city>Maywood</city>
        <state>Illinois</state>
        <zip>60153</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Illinois CancerCare</name>
      <address>
        <city>Peoria</city>
        <state>Illinois</state>
        <zip>61615</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norton Cancer Institute Oncology Practices - St. Matthews Location</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40241</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic, Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Louis University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mercy Research</name>
      <address>
        <city>Springfield</city>
        <state>Missouri</state>
        <zip>65806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Comprehensive Cancer Centers of Nevada</name>
      <address>
        <city>Las Vegas</city>
        <state>Nevada</state>
        <zip>89169</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center</name>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <zip>03766</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Summit Medical Group</name>
      <address>
        <city>Morristown</city>
        <state>New Jersey</state>
        <zip>07960</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Atlantic Health System/ Morristown Meeical Center</name>
      <address>
        <city>Morristown</city>
        <state>New Jersey</state>
        <zip>07972</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New York Medical College</name>
      <address>
        <city>Hawthorne</city>
        <state>New York</state>
        <zip>10595</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stony Brook Cancer Center</name>
      <address>
        <city>Stony Brook</city>
        <state>New York</state>
        <zip>11794</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hematology &amp; Oncology Associates, Inc.</name>
      <address>
        <city>Canton</city>
        <state>Ohio</state>
        <zip>44708</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tri-County Hematology &amp; Oncology Associates, Inc.</name>
      <address>
        <city>Massillon</city>
        <state>Ohio</state>
        <zip>44646</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Toledo Clinic Cancer Centers</name>
      <address>
        <city>Toledo</city>
        <state>Ohio</state>
        <zip>43623</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center - Harold C. Simmons Comprehensive Cancer Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75235</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Consultants: Memorial City</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77024</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Swedish Cancer Institute</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Cancer Center Alliance</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin Hospital and Clinics</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vince Lombardi Cancer Center (Aurora St. Luke's Medical Center)</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beijing Cancer Hospital</name>
      <address>
        <city>Beijing</city>
        <zip>100142</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peking University Third Hospital (Hematology Dept)</name>
      <address>
        <city>Beijing</city>
        <zip>100191</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>JiLin Cancer Hospital（Lymphoma hematology Dept)</name>
      <address>
        <city>Changchun</city>
        <zip>130012</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West China Hospital of Sichuan University (Hematology Dept)</name>
      <address>
        <city>Chengdu</city>
        <zip>637400</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Second Affiliated Hospital of Dalian Medical University</name>
      <address>
        <city>Dalian</city>
        <zip>116044</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GuangDong General Hospital</name>
      <address>
        <city>Guangzhou</city>
        <zip>510080</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ZheJiang Cancer Hospital ( Lymphoma Dept)</name>
      <address>
        <city>Hangzhou</city>
        <zip>310022</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Harbin Medical University Cancer Hospital (Oncology Internal)</name>
      <address>
        <city>Harbin</city>
        <zip>150081</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fudan University Shanghai Cancer Hospital</name>
      <address>
        <city>Shanghai</city>
        <zip>200032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tianjin Medical University Cancer Institute and Hospital</name>
      <address>
        <city>Tianjin</city>
        <zip>300060</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HeNan Cancer Hospital (Hematology Dept)</name>
      <address>
        <city>Zhengzhou</city>
        <zip>450003</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital of ZhengZhou University (Oncology Dept)</name>
      <address>
        <city>Zhengzhou</city>
        <zip>450052</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>August 18, 2017</study_first_submitted>
  <study_first_submitted_qc>August 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 28, 2017</study_first_posted>
  <last_update_submitted>July 28, 2022</last_update_submitted>
  <last_update_submitted_qc>July 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Lymphoma</keyword>
  <keyword>Non-Hodgkin's Lymphoma</keyword>
  <keyword>enzastaurin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03263026
org study id: DB102-02
nct id: NCT03263026
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: Randomized
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.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Denovo Biopharma, the study Sponsor, will also be blinded.
measure: Overall survival in subjects who possess the DGM1™ biomarker
time frame: 3.5 years
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.
measure: Overall survival in subjects who do not possess the DGM1™ biomarker
time frame: 3.5 years
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
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
measure: Presence of chromaturia as a predictor of efficacy
time frame: 3.5 years
description: 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.
arm group label: R-CHOP + enzastaurin hydrochloride
arm group type: Active Comparator
description: 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.
arm group label: R-CHOP + placebo
arm group type: Placebo Comparator
description: 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.
intervention type: Drug
intervention name: Enzastaurin Hydrochloride
description: R-CHOP + Enzastaurin (Kinenza®) 125 mg
arm group label: R-CHOP + enzastaurin hydrochloride
other name: Kinenza®
intervention type: Other
intervention name: R-CHOP + placebo
description: R-CHOP + placebo
arm group label: R-CHOP + placebo
other name: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
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country: China
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
sharing ipd: No