<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/NCT03749018</url>
  </required_header>
  <id_info>
    <org_study_id>OSU-18281</org_study_id>
    <secondary_id>NCI-2018-02699</secondary_id>
    <nct_id>NCT03749018</nct_id>
  </id_info>
  <brief_title>Nivolumab With DA-REPOCH Chemotherapy Regimen in Treating Patients With Aggressive B-Cell Non-Hodgkin's Lymphoma</brief_title>
  <official_title>A Phase II Study of Nivolumab in Combination With DA-REPOCH Followed by Short Course Nivolumab Consolidation in Patients With Aggressive B-Cell Non-Hodgkin's Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>David Bond, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Ohio State University Comprehensive Cancer Center</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 phase II trial studies how well nivolumab works with the DA-REPOCH chemotherapy regimen&#xD;
      in treating patients with aggressive B-cell non-Hodgkin lymphoma. Immunotherapy with&#xD;
      monoclonal antibodies, such as nivolumab, may help the body?s immune system attack the&#xD;
      cancer, and may interfere with the ability of cancer cells to grow and spread. Drugs used in&#xD;
      chemotherapy, such as dose-adjusted rituximab, etoposide, prednisone, vincristine sulfate,&#xD;
      cyclophosphamide, and doxorubicin hydrochloride (DA-REPOCH), work in different ways to stop&#xD;
      the growth of cancer cells, either by killing the cells, by stopping them from dividing, or&#xD;
      by stopping them from spreading. Giving nivolumab with DA-REPOCH may work better in treating&#xD;
      patients with aggressive B-cell non-Hodgkin lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine 2-year progression-free survival (PFS) of nivolumab in combination with&#xD;
      DA-REPOCH with short course nivolumab maintenance.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the objective response rate (ORR), complete response (CR) rate, and duration&#xD;
      of response to nivolumab in combination with DA REPOCH with short course nivolumab&#xD;
      maintenance.&#xD;
&#xD;
      II. To establish that nivolumab in combination with DA-REPOCH with short course nivolumab&#xD;
      maintenance is feasible at standard dosing.&#xD;
&#xD;
      III. To establish the toxicity profile of nivolumab in combination with DA-REPOCH with short&#xD;
      course nivolumab maintenance at standard dosing.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To correlate the presence of major histocompatibility complex (MHC) class I and II by&#xD;
      immunohistochemistry (IHC) with PFS.&#xD;
&#xD;
      II. To correlate tumor and microenvironment expression of PD-L1 and microenvironment&#xD;
      expression of PD-1 with PFS.&#xD;
&#xD;
      III. To correlate cell of origin, MYC and Bcl-2 expression, Epstein-Barr virus&#xD;
      (EBV)-positivity, and Ki67 proliferation index with response to treatment.&#xD;
&#xD;
      IV. To determine the effect of nivolumab in combination with DA-REPOCH on immune cell subsets&#xD;
      in the peripheral blood over time.&#xD;
&#xD;
      V. To correlate circulating tumor (ct) deoxyribonucleic acid (DNA) with disease response by&#xD;
      positron emission tomography (PET) imaging.&#xD;
&#xD;
      VI. To track clonal evolution and detect the emergence of treatment-resistance by ct-DNA&#xD;
      monitoring.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive rituximab intravenously (IV) and nivolumab IV over 60 minutes on day 1.&#xD;
      Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV&#xD;
      continuously over 96 hours, cyclophosphamide IV bolus, and prednisone orally (PO) on days&#xD;
      1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease&#xD;
      progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60&#xD;
      minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days, every 3 months for&#xD;
      3 years, and then every 6 months for 5 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 2, 2019</start_date>
  <completion_date type="Anticipated">July 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>From start of treatment to progression or death, whichever occurs first, assessed at 2 years</time_frame>
    <description>Will be estimated by the method of Kaplan-Meier and the estimate will be provided with 95% confidence intervals. Depending on the number of events, Cox regression model may be used to explore the association between baseline clinical variables and PFS in a univariable manner.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate</measure>
    <time_frame>Up to 8 years</time_frame>
    <description>Will be calculated with patients who achieve complete response (CR) or partial response (PR) at end of induction therapy as the numerator and all eligible patients who start treatment as the denominator, with a 95% binomial confidence interval provided. CR rate will be analyzed in the same way.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response defined for all patients who have achieved an objective response (CR or PR)</measure>
    <time_frame>From date of which patient?s response is documented to the date of progression or death, censoring event-free patients at the time of last follow-up, assessed up to 8 years</time_frame>
    <description>Will be described using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0</measure>
    <time_frame>Up to 30 days post-treatment</time_frame>
    <description>All adverse events will be summarized and tabulated across all patients who received any treatment with a focus on severe (grade 3+) adverse events and toxicities that are deemed at least possibly related to study treatment.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Major histocompatibility complex (MCH) class I and II expression</measure>
    <time_frame>Up to 8 years</time_frame>
    <description>Will be correlated with PFS and be explored using graphical methods such as Kaplan-Meier curves.</description>
  </other_outcome>
  <other_outcome>
    <measure>Expression of PD-1 and PD-L1 with PFS</measure>
    <time_frame>Up to 8 years</time_frame>
    <description>Will be correlated with PFS and explored using graphical methods such as Kaplan-Meier curves.</description>
  </other_outcome>
  <other_outcome>
    <measure>Somatic mutations detection by circulating tumor (ct)-deoxyribonucleic acid (DNA) over time</measure>
    <time_frame>Up to 8 years</time_frame>
    <description>Will be described using either box plots or individual time plots grouped by relevant subcategories (e.g. response) to help identify potential patterns. Wilcoxon signed rank test will be used to compare baseline expression with values measured at time of relapse.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Aggressive Non-Hodgkin Lymphoma</condition>
  <condition>Ann Arbor Stage I Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma</condition>
  <condition>Ann Arbor Stage II B-Cell Non-Hodgkin Lymphoma</condition>
  <condition>Ann Arbor Stage II Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma</condition>
  <condition>Ann Arbor Stage III B-Cell Non-Hodgkin Lymphoma</condition>
  <condition>Ann Arbor Stage III Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma</condition>
  <condition>Ann Arbor Stage IV B-Cell Non-Hodgkin Lymphoma</condition>
  <condition>Ann Arbor Stage IV Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma</condition>
  <condition>Diffuse Large B-Cell Lymphoma</condition>
  <condition>High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements</condition>
  <condition>High Grade B-Cell Lymphoma, Not Otherwise Specified</condition>
  <condition>Indolent Non-Hodgkin Lymphoma</condition>
  <condition>Mediastinal B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma</condition>
  <condition>Transformed Non-Hodgkin Lymphoma</condition>
  <arm_group>
    <arm_group_label>Treatment (nivolumab, DA-REPOCH)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nivolumab, DA-REPOCH)</arm_group_label>
    <other_name>(-)-Cyclophosphamide</other_name>
    <other_name>2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate</other_name>
    <other_name>Carloxan</other_name>
    <other_name>Ciclofosfamida</other_name>
    <other_name>Ciclofosfamide</other_name>
    <other_name>Cicloxal</other_name>
    <other_name>Clafen</other_name>
    <other_name>Claphene</other_name>
    <other_name>CP monohydrate</other_name>
    <other_name>CTX</other_name>
    <other_name>CYCLO-cell</other_name>
    <other_name>Cycloblastin</other_name>
    <other_name>Cycloblastine</other_name>
    <other_name>Cyclophospham</other_name>
    <other_name>Cyclophosphamid monohydrate</other_name>
    <other_name>Cyclophosphamidum</other_name>
    <other_name>Cyclophosphan</other_name>
    <other_name>Cyclophosphane</other_name>
    <other_name>Cyclophosphanum</other_name>
    <other_name>Cyclostin</other_name>
    <other_name>Cyclostine</other_name>
    <other_name>Cytophosphan</other_name>
    <other_name>Cytophosphane</other_name>
    <other_name>Cytoxan</other_name>
    <other_name>Fosfaseron</other_name>
    <other_name>Genoxal</other_name>
    <other_name>Genuxal</other_name>
    <other_name>Ledoxina</other_name>
    <other_name>Mitoxan</other_name>
    <other_name>Neosar</other_name>
    <other_name>Revimmune</other_name>
    <other_name>Syklofosfamid</other_name>
    <other_name>WR- 138719</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin Hydrochloride</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nivolumab, DA-REPOCH)</arm_group_label>
    <other_name>5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)</other_name>
    <other_name>ADM</other_name>
    <other_name>Adriacin</other_name>
    <other_name>Adriamycin</other_name>
    <other_name>Adriamycin Hydrochloride</other_name>
    <other_name>Adriamycin PFS</other_name>
    <other_name>Adriamycin RDF</other_name>
    <other_name>ADRIAMYCIN, HYDROCHLORIDE</other_name>
    <other_name>Adriamycine</other_name>
    <other_name>Adriblastina</other_name>
    <other_name>Adriblastine</other_name>
    <other_name>Adrimedac</other_name>
    <other_name>Chloridrato de Doxorrubicina</other_name>
    <other_name>DOX</other_name>
    <other_name>DOXO-CELL</other_name>
    <other_name>Doxolem</other_name>
    <other_name>Doxorubicin.HCl</other_name>
    <other_name>Doxorubin</other_name>
    <other_name>Farmiblastina</other_name>
    <other_name>FI 106</other_name>
    <other_name>FI-106</other_name>
    <other_name>hydroxydaunorubicin</other_name>
    <other_name>Rubex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etoposide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nivolumab, DA-REPOCH)</arm_group_label>
    <other_name>Demethyl Epipodophyllotoxin Ethylidine Glucoside</other_name>
    <other_name>EPEG</other_name>
    <other_name>Lastet</other_name>
    <other_name>Toposar</other_name>
    <other_name>Vepesid</other_name>
    <other_name>VP 16-213</other_name>
    <other_name>VP-16</other_name>
    <other_name>VP-16-213</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nivolumab, DA-REPOCH)</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>MDX-1106</other_name>
    <other_name>NIVO</other_name>
    <other_name>ONO-4538</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (nivolumab, DA-REPOCH)</arm_group_label>
    <other_name>.delta.1-Cortisone</other_name>
    <other_name>1, 2-Dehydrocortisone</other_name>
    <other_name>Adasone</other_name>
    <other_name>Cortancyl</other_name>
    <other_name>Dacortin</other_name>
    <other_name>DeCortin</other_name>
    <other_name>Decortisyl</other_name>
    <other_name>Decorton</other_name>
    <other_name>Delta 1-Cortisone</other_name>
    <other_name>Delta-Dome</other_name>
    <other_name>Deltacortene</other_name>
    <other_name>Deltacortisone</other_name>
    <other_name>Deltadehydrocortisone</other_name>
    <other_name>Deltasone</other_name>
    <other_name>Deltison</other_name>
    <other_name>Deltra</other_name>
    <other_name>Econosone</other_name>
    <other_name>Lisacort</other_name>
    <other_name>Meprosona-F</other_name>
    <other_name>Metacortandracin</other_name>
    <other_name>Meticorten</other_name>
    <other_name>Ofisolona</other_name>
    <other_name>Orasone</other_name>
    <other_name>Panafcort</other_name>
    <other_name>Panasol-S</other_name>
    <other_name>Paracort</other_name>
    <other_name>PRED</other_name>
    <other_name>Predicor</other_name>
    <other_name>Predicorten</other_name>
    <other_name>Prednicen-M</other_name>
    <other_name>Prednicort</other_name>
    <other_name>Prednidib</other_name>
    <other_name>Prednilonga</other_name>
    <other_name>Predniment</other_name>
    <other_name>Prednisonum</other_name>
    <other_name>Prednitone</other_name>
    <other_name>Promifen</other_name>
    <other_name>Servisone</other_name>
    <other_name>SK-Prednisone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nivolumab, DA-REPOCH)</arm_group_label>
    <other_name>ABP 798</other_name>
    <other_name>BI 695500</other_name>
    <other_name>C2B8 Monoclonal Antibody</other_name>
    <other_name>Chimeric Anti-CD20 Antibody</other_name>
    <other_name>CT-P10</other_name>
    <other_name>IDEC-102</other_name>
    <other_name>IDEC-C2B8</other_name>
    <other_name>IDEC-C2B8 Monoclonal Antibody</other_name>
    <other_name>MabThera</other_name>
    <other_name>Monoclonal Antibody IDEC-C2B8</other_name>
    <other_name>PF-05280586</other_name>
    <other_name>Rituxan</other_name>
    <other_name>Rituximab Biosimilar ABP 798</other_name>
    <other_name>Rituximab Biosimilar BI 695500</other_name>
    <other_name>Rituximab Biosimilar CT-P10</other_name>
    <other_name>Rituximab Biosimilar GB241</other_name>
    <other_name>Rituximab Biosimilar IBI301</other_name>
    <other_name>Rituximab Biosimilar PF-05280586</other_name>
    <other_name>Rituximab Biosimilar RTXM83</other_name>
    <other_name>Rituximab Biosimilar SAIT101</other_name>
    <other_name>RTXM83</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vincristine Sulfate</intervention_name>
    <description>Give IV</description>
    <arm_group_label>Treatment (nivolumab, DA-REPOCH)</arm_group_label>
    <other_name>Kyocristine</other_name>
    <other_name>Leurocristine sulfate</other_name>
    <other_name>Leurocristine, sulfate</other_name>
    <other_name>Oncovin</other_name>
    <other_name>Vincasar</other_name>
    <other_name>Vincosid</other_name>
    <other_name>Vincrex</other_name>
    <other_name>Vincristine, sulfate</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Be willing and able to provide written informed consent/assent for the trial.&#xD;
&#xD;
          -  Measurable disease (defined as &gt;= 1.5 cm in diameter) or at least one PET avid area of&#xD;
             disease.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,000 /mcL (within 16 days of treatment&#xD;
             initiation).&#xD;
&#xD;
          -  Platelets &gt;= 75,000 / mcL in the absence of transfusion support within 7 days of&#xD;
             determining eligibility (within 16 days of treatment initiation).&#xD;
&#xD;
          -  Hemoglobin &gt;= 8 g/dL (within 16 days of treatment initiation).&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 X upper limit of normal (ULN) OR measured or calculated&#xD;
             creatinine clearance &gt;= 40 mL/min creatinine clearance (glomerular filtration rate&#xD;
             [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (within&#xD;
             16 days of treatment initiation).&#xD;
&#xD;
               -  Creatinine clearance should be calculated per institutional standard.&#xD;
&#xD;
          -  Serum total bilirubin =&lt; 1.5 X ULN OR except subjects with Gilbert syndrome, who can&#xD;
             have total bilirubin &lt; 3.0 mg/dL (within 16 days of treatment initiation).&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and&#xD;
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 3.0 X&#xD;
             ULN (within 16 days of treatment initiation).&#xD;
&#xD;
          -  Female subject of childbearing potential should have a negative serum pregnancy at&#xD;
             screening.&#xD;
&#xD;
          -  Female subjects of childbearing potential should be willing to use 2 methods of birth&#xD;
             control or be surgically sterile, or abstain from heterosexual activity for the course&#xD;
             of the study through 5 months following the last dose of nivolumab. Subjects should&#xD;
             agree to ongoing pregnancy testing during the course of the study and after the end of&#xD;
             study therapy. Female subjects of childbearing potential are those who have not been&#xD;
             surgically sterilized or have not been free from menses for &gt; 1 year.&#xD;
&#xD;
          -  Male subjects should agree to use an adequate method of contraception starting with&#xD;
             the first dose of study therapy through 7 months following the last dose of nivolumab.&#xD;
             Males must refrain from donating sperm during study participation and for 7 months&#xD;
             after the last dose of nivolumab.&#xD;
&#xD;
          -  Revised Ann Arbor stage II-IV disease&#xD;
&#xD;
               -  Stage I primary mediastinal B-cell lymphoma or mediastinal B cell lymphoma&#xD;
                  unclassifiable with features intermediate between DLBCL and classical Hodgkin?s&#xD;
                  lymphoma will also be eligible.&#xD;
&#xD;
          -  Be willing and able to understand and give written informed consent and comply with&#xD;
             all study related procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known hypersensitivity to any of the study drugs.&#xD;
&#xD;
          -  History of other malignancy that could affect compliance with the protocol or&#xD;
             interpretation of the results.&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency excluding human immunodeficiency virus (HIV)&#xD;
             infection or is receiving systemic steroid therapy or any other form of&#xD;
             immunosuppressive therapy within 7 days prior to the first dose of trial treatment.&#xD;
             Subjects may use topical or inhaled corticosteroids or low-dose steroids (=&lt; 10 mg of&#xD;
             prednisone or equivalent per day) as therapy for comorbid conditions. During study&#xD;
             participation, subjects may receive systemic or enteric corticosteroids as needed for&#xD;
             treatment-emergent comorbid conditions.&#xD;
&#xD;
          -  Has a known history of active TB (Bacillus tuberculosis).&#xD;
&#xD;
          -  Prior systemic chemotherapy for lymphoma with the exception of corticosteroids for&#xD;
             palliation of symptoms and patients with prior indolent non-Hodgkin lymphoma (NHL)&#xD;
             treated with single agent rituximab.&#xD;
&#xD;
          -  Has known active central nervous system (CNS) lymphoma.&#xD;
&#xD;
          -  Richter?s transformation from chronic lymphocytic leukemia (CLL).&#xD;
&#xD;
          -  Major surgery within 3 weeks prior to start of study treatment.&#xD;
&#xD;
          -  Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment. Conditions expected to not recur in the absence of an&#xD;
             external trigger.&#xD;
&#xD;
          -  Has an active infection requiring intravenous systemic therapy or uncontrolled&#xD;
             systemic infection including viral, bacterial, or fungal.&#xD;
&#xD;
          -  Is unable to swallow capsules or malabsorption syndrome, disease or condition&#xD;
             significantly affecting gastrointestinal function.&#xD;
&#xD;
          -  Clinically significant cardiovascular disease, including uncontrolled arrhythmia, New&#xD;
             York Association class 2- 4 congestive heart failure, or history of myocardial&#xD;
             infarction within 6 months.&#xD;
&#xD;
          -  Known contraindication to any medication in the treatment plan, including clinically&#xD;
             significant peripheral neuropathy.&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the pre-screening or screening visit&#xD;
             through 120 days after the last dose of trial treatment.&#xD;
&#xD;
          -  Female patients who are not surgically sterile or postmenopausal (for at least 1 year)&#xD;
             must practice at least one of the following methods of birth control throughout the&#xD;
             duration of study participation and for at least 5 months after study treatment:&#xD;
&#xD;
               -  Total abstinence from hetero-sexual intercourse&#xD;
&#xD;
               -  A vasectomized partner&#xD;
&#xD;
               -  Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that&#xD;
                  started at least 3 months prior to study drug administration&#xD;
&#xD;
               -  Double-barrier method (condom + diaphragm or cervical cup with spermicidal&#xD;
                  contraceptive sponge, jellies, or cream)&#xD;
&#xD;
               -  Non-vasectomized male patients must comply with at least one of the following&#xD;
                  methods of birth control throughout the duration of study participation and for&#xD;
                  at least 3 months after study treatment:&#xD;
&#xD;
               -  A partner who is surgically sterile or postmenopausal (for at least 1 year) or&#xD;
                  who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or&#xD;
                  transdermal) for at least 3 months prior to study drug administration&#xD;
&#xD;
               -  Total abstinence from hetero-sexual intercourse&#xD;
&#xD;
               -  Double-barrier method (condom + diaphragm or cervical cup with spermicidal,&#xD;
                  contraceptive sponge, jellies, or cream).&#xD;
&#xD;
          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.&#xD;
&#xD;
          -  Acute hepatitis C (defined as positive hepatitis C virus (HCV) ribonucleic acid (RNA)&#xD;
             [qualitative] and diagnosis within the past 6 months).&#xD;
&#xD;
          -  Positive hepatitis C antibody with evidence of cirrhosis.&#xD;
&#xD;
          -  Active hepatitis B (subjects with a positive hepatitis B virus [HBV] core antibody or&#xD;
             surface antigen are eligible as long as they have an undetectable HBV DNA polymerase&#xD;
             chain reaction [PCR] and receive concurrent antiviral therapy with entecavir or&#xD;
             tenofovir, and continued for a minimum of 6 months after completion of therapy).&#xD;
&#xD;
          -  HIV infection AND CD4 count &lt; 100 cells/ mm^3, evidence of resistant strain of HIV, or&#xD;
             HIV viral load &gt;= 50 copies HIV RNA/mL if on highly active antiretroviral therapy&#xD;
             (HAART) or HIV viral load &gt;= 10,000 copies HIV RNA/mL if not on anti-HIV therapy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David A Bond, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ohio State University Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://cancer.osu.edu</url>
    <description>The Jamesline</description>
  </link>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>November 19, 2018</study_first_submitted>
  <study_first_submitted_qc>November 19, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 21, 2018</study_first_posted>
  <last_update_submitted>August 18, 2022</last_update_submitted>
  <last_update_submitted_qc>August 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Ohio State University Comprehensive Cancer Center</investigator_affiliation>
    <investigator_full_name>David Bond, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
    <mesh_term>Aggression</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Cortisone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Liposomal doxorubicin</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Etoposide phosphate</mesh_term>
    <mesh_term>Podophyllotoxin</mesh_term>
    <mesh_term>Antineoplastic Agents, Immunological</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
  </intervention_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/NCT03749018
org study id: OSU-18281
secondary id: NCI-2018-02699
nct id: NCT03749018
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well nivolumab works with the DA-REPOCH chemotherapy regimen
      in treating patients with aggressive B-cell non-Hodgkin lymphoma. Immunotherapy with
      monoclonal antibodies, such as nivolumab, may help the body?s immune system attack the
      cancer, and may interfere with the ability of cancer cells to grow and spread. Drugs used in
      chemotherapy, such as dose-adjusted rituximab, etoposide, prednisone, vincristine sulfate,
      cyclophosphamide, and doxorubicin hydrochloride (DA-REPOCH), work in different ways to stop
      the growth of cancer cells, either by killing the cells, by stopping them from dividing, or
      by stopping them from spreading. Giving nivolumab with DA-REPOCH may work better in treating
      patients with aggressive B-cell non-Hodgkin lymphoma.
PRIMARY OBJECTIVES:

      I. To determine 2-year progression-free survival (PFS) of nivolumab in combination with
      DA-REPOCH with short course nivolumab maintenance.

      SECONDARY OBJECTIVES:

      I. To determine the objective response rate (ORR), complete response (CR) rate, and duration
      of response to nivolumab in combination with DA REPOCH with short course nivolumab
      maintenance.

      II. To establish that nivolumab in combination with DA-REPOCH with short course nivolumab
      maintenance is feasible at standard dosing.

      III. To establish the toxicity profile of nivolumab in combination with DA-REPOCH with short
      course nivolumab maintenance at standard dosing.

      EXPLORATORY OBJECTIVES:

      I. To correlate the presence of major histocompatibility complex (MHC) class I and II by
      immunohistochemistry (IHC) with PFS.

      II. To correlate tumor and microenvironment expression of PD-L1 and microenvironment
      expression of PD-1 with PFS.

      III. To correlate cell of origin, MYC and Bcl-2 expression, Epstein-Barr virus
      (EBV)-positivity, and Ki67 proliferation index with response to treatment.

      IV. To determine the effect of nivolumab in combination with DA-REPOCH on immune cell subsets
      in the peripheral blood over time.

      V. To correlate circulating tumor (ct) deoxyribonucleic acid (DNA) with disease response by
      positron emission tomography (PET) imaging.

      VI. To track clonal evolution and detect the emergence of treatment-resistance by ct-DNA
      monitoring.

      OUTLINE:

      Patients receive rituximab intravenously (IV) and nivolumab IV over 60 minutes on day 1.
      Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV
      continuously over 96 hours, cyclophosphamide IV bolus, and prednisone orally (PO) on days
      1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease
      progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60
      minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 3 months for
      3 years, and then every 6 months for 5 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free survival (PFS)
time frame: From start of treatment to progression or death, whichever occurs first, assessed at 2 years
description: Will be estimated by the method of Kaplan-Meier and the estimate will be provided with 95% confidence intervals. Depending on the number of events, Cox regression model may be used to explore the association between baseline clinical variables and PFS in a univariable manner.
measure: Objective response rate
time frame: Up to 8 years
description: Will be calculated with patients who achieve complete response (CR) or partial response (PR) at end of induction therapy as the numerator and all eligible patients who start treatment as the denominator, with a 95% binomial confidence interval provided. CR rate will be analyzed in the same way.
measure: Duration of response defined for all patients who have achieved an objective response (CR or PR)
time frame: From date of which patient?s response is documented to the date of progression or death, censoring event-free patients at the time of last follow-up, assessed up to 8 years
description: Will be described using the method of Kaplan-Meier.
measure: Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
time frame: Up to 30 days post-treatment
description: All adverse events will be summarized and tabulated across all patients who received any treatment with a focus on severe (grade 3+) adverse events and toxicities that are deemed at least possibly related to study treatment.
measure: Major histocompatibility complex (MCH) class I and II expression
time frame: Up to 8 years
description: Will be correlated with PFS and be explored using graphical methods such as Kaplan-Meier curves.
measure: Expression of PD-1 and PD-L1 with PFS
time frame: Up to 8 years
description: Will be correlated with PFS and explored using graphical methods such as Kaplan-Meier curves.
measure: Somatic mutations detection by circulating tumor (ct)-deoxyribonucleic acid (DNA) over time
time frame: Up to 8 years
description: Will be described using either box plots or individual time plots grouped by relevant subcategories (e.g. response) to help identify potential patterns. Wilcoxon signed rank test will be used to compare baseline expression with values measured at time of relapse.
arm group label: Treatment (nivolumab, DA-REPOCH)
arm group type: Experimental
description: Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Cyclophosphamide
description: Given IV
arm group label: Treatment (nivolumab, DA-REPOCH)
other name: (-)-Cyclophosphamide
other name: 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
other name: Carloxan
other name: Ciclofosfamida
other name: Ciclofosfamide
other name: Cicloxal
other name: Clafen
other name: Claphene
other name: CP monohydrate
other name: CTX
other name: CYCLO-cell
other name: Cycloblastin
other name: Cycloblastine
other name: Cyclophospham
other name: Cyclophosphamid monohydrate
other name: Cyclophosphamidum
other name: Cyclophosphan
other name: Cyclophosphane
other name: Cyclophosphanum
other name: Cyclostin
other name: Cyclostine
other name: Cytophosphan
other name: Cytophosphane
other name: Cytoxan
other name: Fosfaseron
other name: Genoxal
other name: Genuxal
other name: Ledoxina
other name: Mitoxan
other name: Neosar
other name: Revimmune
other name: Syklofosfamid
other name: WR- 138719
intervention type: Drug
intervention name: Doxorubicin Hydrochloride
description: Given IV
arm group label: Treatment (nivolumab, DA-REPOCH)
other name: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
other name: ADM
other name: Adriacin
other name: Adriamycin
other name: Adriamycin Hydrochloride
other name: Adriamycin PFS
other name: Adriamycin RDF
other name: ADRIAMYCIN, HYDROCHLORIDE
other name: Adriamycine
other name: Adriblastina
other name: Adriblastine
other name: Adrimedac
other name: Chloridrato de Doxorrubicina
other name: DOX
other name: DOXO-CELL
other name: Doxolem
other name: Doxorubicin.HCl
other name: Doxorubin
other name: Farmiblastina
other name: FI 106
other name: FI-106
other name: hydroxydaunorubicin
other name: Rubex
intervention type: Drug
intervention name: Etoposide
description: Given IV
arm group label: Treatment (nivolumab, DA-REPOCH)
other name: Demethyl Epipodophyllotoxin Ethylidine Glucoside
other name: EPEG
other name: Lastet
other name: Toposar
other name: Vepesid
other name: VP 16-213
other name: VP-16
other name: VP-16-213
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Treatment (nivolumab, DA-REPOCH)
other name: BMS-936558
other name: MDX-1106
other name: NIVO
other name: ONO-4538
other name: Opdivo
intervention type: Drug
intervention name: Prednisone
description: Given PO
arm group label: Treatment (nivolumab, DA-REPOCH)
other name: .delta.1-Cortisone
other name: 1, 2-Dehydrocortisone
other name: Adasone
other name: Cortancyl
other name: Dacortin
other name: DeCortin
other name: Decortisyl
other name: Decorton
other name: Delta 1-Cortisone
other name: Delta-Dome
other name: Deltacortene
other name: Deltacortisone
other name: Deltadehydrocortisone
other name: Deltasone
other name: Deltison
other name: Deltra
other name: Econosone
other name: Lisacort
other name: Meprosona-F
other name: Metacortandracin
other name: Meticorten
other name: Ofisolona
other name: Orasone
other name: Panafcort
other name: Panasol-S
other name: Paracort
other name: PRED
other name: Predicor
other name: Predicorten
other name: Prednicen-M
other name: Prednicort
other name: Prednidib
other name: Prednilonga
other name: Predniment
other name: Prednisonum
other name: Prednitone
other name: Promifen
other name: Servisone
other name: SK-Prednisone
intervention type: Biological
intervention name: Rituximab
description: Given IV
arm group label: Treatment (nivolumab, DA-REPOCH)
other name: ABP 798
other name: BI 695500
other name: C2B8 Monoclonal Antibody
other name: Chimeric Anti-CD20 Antibody
other name: CT-P10
other name: IDEC-102
other name: IDEC-C2B8
other name: IDEC-C2B8 Monoclonal Antibody
other name: MabThera
other name: Monoclonal Antibody IDEC-C2B8
other name: PF-05280586
other name: Rituxan
other name: Rituximab Biosimilar ABP 798
other name: Rituximab Biosimilar BI 695500
other name: Rituximab Biosimilar CT-P10
other name: Rituximab Biosimilar GB241
other name: Rituximab Biosimilar IBI301
other name: Rituximab Biosimilar PF-05280586
other name: Rituximab Biosimilar RTXM83
other name: Rituximab Biosimilar SAIT101
other name: RTXM83
intervention type: Drug
intervention name: Vincristine Sulfate
description: Give IV
arm group label: Treatment (nivolumab, DA-REPOCH)
other name: Kyocristine
other name: Leurocristine sulfate
other name: Leurocristine, sulfate
other name: Oncovin
other name: Vincasar
other name: Vincosid
other name: Vincrex
other name: Vincristine, sulfate
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: David A Bond, MD
role: Principal Investigator
affiliation: Ohio State University Comprehensive Cancer Center
facility: 
country: United States
url: http://cancer.osu.edu
description: The Jamesline
responsible party type: Sponsor-Investigator
investigator affiliation: Ohio State University Comprehensive Cancer Center
investigator full name: David Bond, MD
investigator title: Principal Investigator
mesh term: Lymphoma
mesh term: Lymphoma, Non-Hodgkin
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
mesh term: Aggression
mesh term: Prednisone
mesh term: Cortisone
mesh term: Cyclophosphamide
mesh term: Rituximab
mesh term: Doxorubicin
mesh term: Liposomal doxorubicin
mesh term: Nivolumab
mesh term: Etoposide
mesh term: Vincristine
mesh term: Etoposide phosphate
mesh term: Podophyllotoxin
mesh term: Antineoplastic Agents, Immunological
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal
sharing ipd: No