<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/NCT03229382</url>
  </required_header>
  <id_info>
    <org_study_id>ML29157</org_study_id>
    <secondary_id>2015-005439-41</secondary_id>
    <nct_id>NCT03229382</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Obinutuzumab Preemptive Treatment at the Time of the Molecular Relapse</brief_title>
  <acronym>OPERA-PLRG10</acronym>
  <official_title>Evaluation of Efficacy and Safety of Obinutuzumab Preemptive Treatment at the Time of the Molecular Relapse After First Line Immunochemotherapy With Autologous Stem Cell (ML29157).</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Polish Lymphoma Research Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Roche Pharma AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Polish Lymphoma Research Group</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of the study is the evaluation of efficacy and safety of obinutuzumab&#xD;
      preemptive treatment at the time of the molecular relapse after first line immunochemotherapy&#xD;
      with autologous stem cell transplantation in mantle cell lymphoma patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with evidence of MCL molecular relapse defined as an increasing copy number in&#xD;
      quantitative real-time polymerase chain reaction (RQ-PCR) of clone-specific immunoglobulin&#xD;
      heavy chain (IGH) gene rearrangements or BCL1-IGH fusion genes according to BIOMED-2&#xD;
      methodology and protocols in peripheral blood or/and bone marrow without evidence of clinical&#xD;
      relapse/progression after auto-HCT procedure with all inclusion and no exclusion clinical&#xD;
      trial criteria will receive 4 weekly infusions of obinutuzumab (1000 mg, iv) on day 1, 8, 15,&#xD;
      22.Response assessment in bone marrow and/or peripheral blood and CT/MRI imaging will be&#xD;
      performed 2 months after the obinutuzumab preemptive treatment. Patients with subsequent&#xD;
      molecular remission in peripheral blood and/or bone marrow confirmed in RQ-PCR (with 10-4&#xD;
      level of sensitivity) assessment and no signs of relapse/progression according to the Lugano&#xD;
      Classification will be further followed. From this moment, evaluation of response will be&#xD;
      performed every 6 months with computed tomography/magnetic resonance (CT/MR) imaging and bone&#xD;
      marrow aspiration to detect classical relapse/progression and/or to detect subsequent&#xD;
      molecular relapse by quantitative real-time polymerase chain reaction (RQ-PCR) of&#xD;
      clone-specific immunoglobulin heavy chain (IGH) gene rearrangements or BCL1-IGH fusion genes&#xD;
      with the use of consensus JH probes and specific ASO primers. Patients will be monitored&#xD;
      every 3 months (outpatient visits with peripheral blood samples for MRD assessment to detect&#xD;
      molecular relapse by quantitative RQ-PCR of clone-specific immunoglobulin heavy chain (IGH)&#xD;
      gene rearrangements or BCL1-IGH fusion genes). Preemptive treatment can be administered in&#xD;
      subsequent molecular relapses/progressions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Very slow recruitment due to lack of relapse in the observed group of patients&#xD;
  </why_stopped>
  <start_date type="Actual">May 14, 2018</start_date>
  <completion_date type="Actual">January 31, 2020</completion_date>
  <primary_completion_date type="Actual">January 31, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <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>MRD negativity defined as a MRD level</measure>
    <time_frame>2 months after obinutuzumab treatment</time_frame>
    <description>Molecular response rate (molRR) defined as a rate of molecular response with at least 10-4 sensitivity level assessed by quantitative RQ-PCR</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>3 years and 2 month</time_frame>
    <description>defined as the time from the date of the first obinutuzumab infusion to disease progression or relapse, as determined by the investigator using the Lugano Classification or death from any cause after the last dose of study drug</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to molecular relapse</measure>
    <time_frame>3 years and 2 month</time_frame>
    <description>as the time from the date of the first obinutuzumab infusion to the first occurrence of molecular disease relapse</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>3 years and 2 month</time_frame>
    <description>defined as the time from the date of the initiation of the first line treatment to the death from any reason</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to relapse/progression</measure>
    <time_frame>3 years and 2 month</time_frame>
    <description>defined as the time from the date of the first obinutuzumab infusion to the first evidence of disease progression or relapse, as determined by the investigator using the Lugano Classification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-free survival (EFS)</measure>
    <time_frame>3 years and 2 month</time_frame>
    <description>defined as the time from the date of the first obinutuzumab infusion to the first evidence of disease progression or relapse (as determined by the investigator using the Lugano Classification), death from any reason, start of the another anti-lymphoma treatment, SAE preventing continuation of the protocol treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health status measured with EQ-5D from EuroQoL Group</measure>
    <time_frame>3 years and 2 month</time_frame>
    <description>with EQ-5D from EuroQoL Group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment tolerability assessment</measure>
    <time_frame>3 years and 2 month</time_frame>
    <description>reporting of serious adverse events (SAEs), adverse events (AEs) and adverse events of special interest</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Mantle Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>Obinutuzumab 1000 mg IV infusion, day: 1, 8, 15, 22</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with evidence of MCL molecular relapse defined as an increasing copy number in quantitative real-time polymerase chain reaction (RQ-PCR) of clone-specific immunoglobulin heavy chain (IGH) gene rearrangements or BCL1-IGH fusion genes according to BIOMED-2 methodology and protocols in peripheral blood or/and bone marrow without evidence of clinical relapse/progression after auto-HCT procedure with all inclusion and no exclusion clinical trial criteria will receive 4 weekly infusions of obinutuzumab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Obinutuzumab</intervention_name>
    <description>Patients, in whom all inclusion criteria have been confirmed and all exclusion criteria have been ruled out, will receive 4 intravenous infusions of obinutuzumab (GA101, Gazyvaro) at a dose of 1000 mg on Days 1, 8, 15 and 22.</description>
    <arm_group_label>Obinutuzumab 1000 mg IV infusion, day: 1, 8, 15, 22</arm_group_label>
    <other_name>Gazyvaro</other_name>
    <other_name>GA101</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with evidence of MCL molecular relapse in peripheral blood or/and bone&#xD;
             marrow,&#xD;
&#xD;
          -  Diagnosis of mantle cell lymphoma confirmed by histopathology&#xD;
&#xD;
          -  Presence of clone-specific immunoglobulin heavy chain (IGH) gene rearrangements or&#xD;
             BCL1-IGH fusion gene as a molecular marker used for minimal residual disease (MRD)&#xD;
             assessment,&#xD;
&#xD;
          -  Patients in CR/PR after first-line treatment with myeloablative consolidation and&#xD;
             ASCT,&#xD;
&#xD;
          -  Patients without evidence of mantle cell lymphoma progression/relapse according to the&#xD;
             Lugano Classification criteria (2014),&#xD;
&#xD;
          -  ECOG performance status ≤ 2,&#xD;
&#xD;
          -  Signed patient's informed consent form,&#xD;
&#xD;
          -  Survival prognosis &gt; 6 months,&#xD;
&#xD;
          -  Women of childbearing potential must have a negative pregnancy test result prior to&#xD;
             initiation of treatment with the study medication and must consent to undergo&#xD;
             pregnancy tests during the treatment period.,&#xD;
&#xD;
          -  Women of child-bearing potential must consent either to sexual abstinence or to using&#xD;
             effective contraception (that results in a failure rate of &lt; 1% per year) while&#xD;
             receiving the study medication and for 18 months after its discontinuation,&#xD;
&#xD;
          -  Men must consent either to using an acceptable contraception method (that results in a&#xD;
             failure rate of &lt; 1% per year) or continued sexual abstinence while receiving the&#xD;
             study medication and for 6 months after its discontinuation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Central nervous system involvement,&#xD;
&#xD;
          -  Chemotherapy, radiation therapy or any other antineoplastic treatment (including&#xD;
             steroids, monoclonal antibodies or medications at the stage of clinical studies,&#xD;
             before receiving marketing authorisation) after ASCT and before administration of the&#xD;
             study medication,&#xD;
&#xD;
          -  Major surgery within 28 days prior to the study treatment initiation,&#xD;
&#xD;
          -  Renal impairment (plasma creatinine concentration &gt; 1.5 × upper limit of normal and/or&#xD;
             creatinine clearance ≤ 40 ml/h),&#xD;
&#xD;
          -  Hepatic impairment (total bilirubin concentration &gt; 1.5 × upper limit of normal, AST&#xD;
             and ALT &gt; 2.5 × upper limit of normal),&#xD;
&#xD;
          -  Hb&lt; 9 g/dl, ANC &lt; 1.5 G/l, platelets &lt; 75 G/l,&#xD;
&#xD;
          -  International normalized ratio (INR) &gt; 1.5,&#xD;
&#xD;
          -  Clinically significant heart disease, including uncontrolled arrhythmias, unstable&#xD;
             coronary artery disease, serious congestive circulatory failure (NYHA III-IV),&#xD;
             myocardial infarction within 6 months before enrolment,&#xD;
&#xD;
          -  Other comorbidities, not responding to treatment, including, but not limited to:&#xD;
             hematopoietic system diseases, gastrointestinal system diseases, endocrine system&#xD;
             diseases, respiratory system diseases, neurological diseases, cerebral diseases and&#xD;
             mental diseases that could affect compliance with the protocol or interpretation of&#xD;
             results,&#xD;
&#xD;
          -  Active infections (viral, bacterial, fungal),&#xD;
&#xD;
          -  Coexistence of another neoplasm or a history of neoplastic disease (except for&#xD;
             adequately treated basal cell carcinoma or squamous cell skin carcinoma, in situ&#xD;
             cervical cancer or other neoplasm if the patient is in complete remission after at&#xD;
             least 5 years of treatment discontinuation),&#xD;
&#xD;
          -  Active HIV, HBV or HCV infection,&#xD;
&#xD;
          -  Positive test results for chronic hepatitis B. All patients must be tested for both&#xD;
             HBsAg and HBcAb at screening, if either of the tests is positive, the patient is not&#xD;
             eligible for inclusion in the trial. Patients who have protective titers of HBsAb&#xD;
             after vaccination are eligible provided they are negative for both HBsAg and HBcAb,&#xD;
&#xD;
          -  Positive testing for hepatitis C (hepatitis C virus [HCV] antibody serology testing).&#xD;
             Patients positive for HCV antibody are eligible only if polymerase chain reaction is&#xD;
             negative for HCV RNA,&#xD;
&#xD;
          -  Vaccination with live vaccines within 28 days prior to start of the preemptive&#xD;
             treatment,&#xD;
&#xD;
          -  Known or suspected hypersensitivity to the study medication,&#xD;
&#xD;
          -  Women who are pregnant or breastfeeding.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michał Szymczyk, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institute of Oncology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centrum Onkologii - Instytut im. Marii Skłodowskiej- Curie Klinika Nowotworów Układu Chłonnego</name>
      <address>
        <city>Warszawa</city>
        <zip>02-781</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Poland</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 10, 2017</study_first_submitted>
  <study_first_submitted_qc>July 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 25, 2017</study_first_posted>
  <last_update_submitted>August 14, 2023</last_update_submitted>
  <last_update_submitted_qc>August 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MCL, obinutuzumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Obinutuzumab</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03229382
org study id: ML29157
secondary id: 2015-005439-41
nct id: NCT03229382
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
The objective of the study is the evaluation of efficacy and safety of obinutuzumab
      preemptive treatment at the time of the molecular relapse after first line immunochemotherapy
      with autologous stem cell transplantation in mantle cell lymphoma patients.
Patients with evidence of MCL molecular relapse defined as an increasing copy number in
      quantitative real-time polymerase chain reaction (RQ-PCR) of clone-specific immunoglobulin
      heavy chain (IGH) gene rearrangements or BCL1-IGH fusion genes according to BIOMED-2
      methodology and protocols in peripheral blood or/and bone marrow without evidence of clinical
      relapse/progression after auto-HCT procedure with all inclusion and no exclusion clinical
      trial criteria will receive 4 weekly infusions of obinutuzumab (1000 mg, iv) on day 1, 8, 15,
      22.Response assessment in bone marrow and/or peripheral blood and CT/MRI imaging will be
      performed 2 months after the obinutuzumab preemptive treatment. Patients with subsequent
      molecular remission in peripheral blood and/or bone marrow confirmed in RQ-PCR (with 10-4
      level of sensitivity) assessment and no signs of relapse/progression according to the Lugano
      Classification will be further followed. From this moment, evaluation of response will be
      performed every 6 months with computed tomography/magnetic resonance (CT/MR) imaging and bone
      marrow aspiration to detect classical relapse/progression and/or to detect subsequent
      molecular relapse by quantitative real-time polymerase chain reaction (RQ-PCR) of
      clone-specific immunoglobulin heavy chain (IGH) gene rearrangements or BCL1-IGH fusion genes
      with the use of consensus JH probes and specific ASO primers. Patients will be monitored
      every 3 months (outpatient visits with peripheral blood samples for MRD assessment to detect
      molecular relapse by quantitative RQ-PCR of clone-specific immunoglobulin heavy chain (IGH)
      gene rearrangements or BCL1-IGH fusion genes). Preemptive treatment can be administered in
      subsequent molecular relapses/progressions.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: MRD negativity defined as a MRD level
time frame: 2 months after obinutuzumab treatment
description: Molecular response rate (molRR) defined as a rate of molecular response with at least 10-4 sensitivity level assessed by quantitative RQ-PCR
measure: Progression-free survival (PFS)
time frame: 3 years and 2 month
description: defined as the time from the date of the first obinutuzumab infusion to disease progression or relapse, as determined by the investigator using the Lugano Classification or death from any cause after the last dose of study drug
measure: Time to molecular relapse
time frame: 3 years and 2 month
description: as the time from the date of the first obinutuzumab infusion to the first occurrence of molecular disease relapse
measure: Overall survival (OS)
time frame: 3 years and 2 month
description: defined as the time from the date of the initiation of the first line treatment to the death from any reason
measure: Time to relapse/progression
time frame: 3 years and 2 month
description: defined as the time from the date of the first obinutuzumab infusion to the first evidence of disease progression or relapse, as determined by the investigator using the Lugano Classification
measure: Event-free survival (EFS)
time frame: 3 years and 2 month
description: defined as the time from the date of the first obinutuzumab infusion to the first evidence of disease progression or relapse (as determined by the investigator using the Lugano Classification), death from any reason, start of the another anti-lymphoma treatment, SAE preventing continuation of the protocol treatment
measure: Health status measured with EQ-5D from EuroQoL Group
time frame: 3 years and 2 month
description: with EQ-5D from EuroQoL Group
measure: Treatment tolerability assessment
time frame: 3 years and 2 month
description: reporting of serious adverse events (SAEs), adverse events (AEs) and adverse events of special interest
arm group label: Obinutuzumab 1000 mg IV infusion, day: 1, 8, 15, 22
arm group type: Experimental
description: Patients with evidence of MCL molecular relapse defined as an increasing copy number in quantitative real-time polymerase chain reaction (RQ-PCR) of clone-specific immunoglobulin heavy chain (IGH) gene rearrangements or BCL1-IGH fusion genes according to BIOMED-2 methodology and protocols in peripheral blood or/and bone marrow without evidence of clinical relapse/progression after auto-HCT procedure with all inclusion and no exclusion clinical trial criteria will receive 4 weekly infusions of obinutuzumab.
intervention type: Drug
intervention name: Obinutuzumab
description: Patients, in whom all inclusion criteria have been confirmed and all exclusion criteria have been ruled out, will receive 4 intravenous infusions of obinutuzumab (GA101, Gazyvaro) at a dose of 1000 mg on Days 1, 8, 15 and 22.
arm group label: Obinutuzumab 1000 mg IV infusion, day: 1, 8, 15, 22
other name: Gazyvaro
other name: GA101
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Michał Szymczyk, MD
role: Principal Investigator
affiliation: Institute of Oncology
facility: 
country: Poland
responsible party type: Sponsor
mesh term: Lymphoma, Mantle-Cell
mesh term: Obinutuzumab