<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/NCT03259529</url>
  </required_header>
  <id_info>
    <org_study_id>DLBCL BeGeRN 1/2</org_study_id>
    <nct_id>NCT03259529</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Bendamustine, Gemcitabine, Rituximab, Nivolumab (BeGeRN) in Patients With r/r DLBCL</brief_title>
  <acronym>BeGeRN</acronym>
  <official_title>A Phase I/II Clinical Trial to Evaluate the Safety and Efficacy of Bendamustine, Gemcitabine, Rituximab, Nivolumab Combination (BeGeRN) in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Petersburg State Pavlov Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>St. Petersburg State Pavlov Medical University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Despite the current advances in clinical oncology, the prognosis of patients with resistant&#xD;
      diffuse large B cell lymphoma or relapse after high dose chemotherapy is dismal. Therefore&#xD;
      there is a need for the introduction of novel treatment regimens. This phase I/II trial&#xD;
      evaluates the safety and efficacy of combination bendamustine, gemcitabine, nivolumab and&#xD;
      rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. The safety&#xD;
      of combination treatment will be evaluated with the determination of recommended dose&#xD;
      schedule prior to expansion of enrollment to evaluate the antitumor activity of bendamustine,&#xD;
      gemcitabine, rituximab, and nivolumab.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 27, 2017</start_date>
  <completion_date type="Actual">January 27, 2020</completion_date>
  <primary_completion_date type="Actual">January 27, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>There will be 2 parts in this study. In Part 1, the safety of combination treatment will be evaluated prior to expansion of enrollment to evaluate treatment effect in Part 2. The arms in Part 1 include 3 different dosage regimens of gemcitabine (500 / 700 / 1000). Part 2 of the study will further characterize the safety and evaluate the antitumor activity of drug combination by enrolling patients at the recommended dose schedule determined in Part 1.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The recommended phase 2 dose (RP2D)</measure>
    <time_frame>6 months</time_frame>
    <description>The recommended phase 2 dose (RP2D) of Bendamustine Hydrochloride and Gemcitabine in combination with Nivolumab and Rituximab in patients with Diffuse Large B-cell Lymphoma</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>12 months</time_frame>
    <description>Overall response rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR) in measurable lesions as defined by LYRIC criteria and duration of response.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Frequency of grade 3 or higher treatment-related adverse events by CTCAE 4.03</measure>
    <time_frame>12 months</time_frame>
    <description>Toxicity parameters based on NCI CTCAE 4.03 grades: hematological toxicity (CBC), hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), fatigue (attending physician assessment), rash (attending physician assessment), colitis (attending physician assessment), pneumonitis (attending physician assessment), autoimmune disorders (level of hormones, presence of autoimmune antibodies, attending physician assessment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DOR)</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-Free Survival (PFS)</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Diffuse Large B Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>Gemcitabine 500</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 500 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv.&#xD;
Duration of cycle 28 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Gemcitabine 700</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 700 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv.&#xD;
Duration of cycle 28 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Gemcitabine 1000</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 1000 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv.&#xD;
Duration of cycle 28 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bendamustine hydrochloride</intervention_name>
    <description>70 mg/m2 by intravenous (IV) infusion for up to 2 cycles</description>
    <arm_group_label>Gemcitabine 1000</arm_group_label>
    <arm_group_label>Gemcitabine 500</arm_group_label>
    <arm_group_label>Gemcitabine 700</arm_group_label>
    <other_name>Ribomustin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine 500 mg</intervention_name>
    <description>500 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles</description>
    <arm_group_label>Gemcitabine 500</arm_group_label>
    <other_name>Gemzar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine 700 mg</intervention_name>
    <description>700 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles</description>
    <arm_group_label>Gemcitabine 700</arm_group_label>
    <other_name>Gemzar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine 1000 mg</intervention_name>
    <description>1000 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles</description>
    <arm_group_label>Gemcitabine 1000</arm_group_label>
    <other_name>Gemzar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>1 mg/kg by intravenous (IV) infusion on day 1,15 for up to 2 cycles</description>
    <arm_group_label>Gemcitabine 1000</arm_group_label>
    <arm_group_label>Gemcitabine 500</arm_group_label>
    <arm_group_label>Gemcitabine 700</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>375 mg/m2 by intravenous (IV) infusion on day 0 for up to 2 cycles</description>
    <arm_group_label>Gemcitabine 1000</arm_group_label>
    <arm_group_label>Gemcitabine 500</arm_group_label>
    <arm_group_label>Gemcitabine 700</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis: Histologically confirmed diffuse large B-cell lymphoma&#xD;
&#xD;
          -  Refractory or relapsed after at least two prior lines of treatment (i.e. induction and&#xD;
             salvage regimen) for diffuse large B-cell lymphoma.&#xD;
&#xD;
          -  Age 18-70 years old&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  No severe concurrent illness&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled bacterial or fungal infection at the time of enrollment&#xD;
&#xD;
          -  Requirement for vasopressor support at the time of enrollment&#xD;
&#xD;
          -  Karnofsky index &lt;30%&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Somatic or psychiatric disorder making the patient unable to sign informed consent&#xD;
&#xD;
          -  Active or prior documented autoimmune disease requiring systemic treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Boris V Afanasyev, Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Petersburg State Pavlov Medical University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>First Pavlov State Medical University of St. Petersburg</name>
      <address>
        <city>Saint-Petersburg</city>
        <zip>197089</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>August 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 23, 2017</study_first_posted>
  <last_update_submitted>June 2, 2021</last_update_submitted>
  <last_update_submitted_qc>June 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 7, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>St. Petersburg State Pavlov Medical University</investigator_affiliation>
    <investigator_full_name>Ivan S Moiseev</investigator_full_name>
    <investigator_title>Vice-director for science of R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation</investigator_title>
  </responsible_party>
  <keyword>Diffuse Large B-cell Lymphoma</keyword>
  <keyword>Nivolumab</keyword>
  <keyword>Bendamustine Hydrochloride</keyword>
  <keyword>Gemcitabine</keyword>
  <keyword>Rituximab</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Bendamustine Hydrochloride</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03259529
org study id: DLBCL BeGeRN 1/2
nct id: NCT03259529
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Despite the current advances in clinical oncology, the prognosis of patients with resistant
      diffuse large B cell lymphoma or relapse after high dose chemotherapy is dismal. Therefore
      there is a need for the introduction of novel treatment regimens. This phase I/II trial
      evaluates the safety and efficacy of combination bendamustine, gemcitabine, nivolumab and
      rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. The safety
      of combination treatment will be evaluated with the determination of recommended dose
      schedule prior to expansion of enrollment to evaluate the antitumor activity of bendamustine,
      gemcitabine, rituximab, and nivolumab.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: There will be 2 parts in this study. In Part 1, the safety of combination treatment will be evaluated prior to expansion of enrollment to evaluate treatment effect in Part 2. The arms in Part 1 include 3 different dosage regimens of gemcitabine (500 / 700 / 1000). Part 2 of the study will further characterize the safety and evaluate the antitumor activity of drug combination by enrolling patients at the recommended dose schedule determined in Part 1.
primary purpose: Treatment
masking: None (Open Label)
measure: The recommended phase 2 dose (RP2D)
time frame: 6 months
description: The recommended phase 2 dose (RP2D) of Bendamustine Hydrochloride and Gemcitabine in combination with Nivolumab and Rituximab in patients with Diffuse Large B-cell Lymphoma
measure: Overall Response Rate (ORR)
time frame: 12 months
description: Overall response rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR) in measurable lesions as defined by LYRIC criteria and duration of response.
measure: Frequency of grade 3 or higher treatment-related adverse events by CTCAE 4.03
time frame: 12 months
description: Toxicity parameters based on NCI CTCAE 4.03 grades: hematological toxicity (CBC), hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), fatigue (attending physician assessment), rash (attending physician assessment), colitis (attending physician assessment), pneumonitis (attending physician assessment), autoimmune disorders (level of hormones, presence of autoimmune antibodies, attending physician assessment).
measure: Duration of Response (DOR)
time frame: 12 months
measure: Progression-Free Survival (PFS)
time frame: 12 months
measure: Overall Survival (OS)
time frame: 12 months
arm group label: Gemcitabine 500
arm group type: Experimental
description: Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 500 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv.
Duration of cycle 28 days
arm group label: Gemcitabine 700
arm group type: Experimental
description: Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 700 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv.
Duration of cycle 28 days
arm group label: Gemcitabine 1000
arm group type: Experimental
description: Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 1000 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv.
Duration of cycle 28 days
intervention type: Drug
intervention name: Bendamustine hydrochloride
description: 70 mg/m2 by intravenous (IV) infusion for up to 2 cycles
arm group label: Gemcitabine 1000
arm group label: Gemcitabine 500
arm group label: Gemcitabine 700
other name: Ribomustin
intervention type: Drug
intervention name: Gemcitabine 500 mg
description: 500 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles
arm group label: Gemcitabine 500
other name: Gemzar
intervention type: Drug
intervention name: Gemcitabine 700 mg
description: 700 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles
arm group label: Gemcitabine 700
other name: Gemzar
intervention type: Drug
intervention name: Gemcitabine 1000 mg
description: 1000 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles
arm group label: Gemcitabine 1000
other name: Gemzar
intervention type: Drug
intervention name: Nivolumab
description: 1 mg/kg by intravenous (IV) infusion on day 1,15 for up to 2 cycles
arm group label: Gemcitabine 1000
arm group label: Gemcitabine 500
arm group label: Gemcitabine 700
other name: Opdivo
intervention type: Drug
intervention name: Rituximab
description: 375 mg/m2 by intravenous (IV) infusion on day 0 for up to 2 cycles
arm group label: Gemcitabine 1000
arm group label: Gemcitabine 500
arm group label: Gemcitabine 700
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Boris V Afanasyev, Ph.D
role: Principal Investigator
affiliation: St. Petersburg State Pavlov Medical University
facility: 
country: Russian Federation
responsible party type: Principal Investigator
investigator affiliation: St. Petersburg State Pavlov Medical University
investigator full name: Ivan S Moiseev
investigator title: Vice-director for science of R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
mesh term: Rituximab
mesh term: Nivolumab
mesh term: Gemcitabine
mesh term: Bendamustine Hydrochloride
sharing ipd: Undecided