<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/NCT03827603</url>
  </required_header>
  <id_info>
    <org_study_id>54179060CLL2013</org_study_id>
    <nct_id>NCT03827603</nct_id>
  </id_info>
  <brief_title>Ibrutinib in Steroid Refractory Autoimmune Hemolytic Anemia</brief_title>
  <acronym>ISRAEL</acronym>
  <official_title>Ibrutinib in Steroid Refractory Autoimmune Hemolytic Anemia: ELaboration of Treatment Approach</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Eugene Nikitin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Association of Oncological Hematologists</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open-labeled, single arm, Phase II, two staged study of combination of ibrutinib&#xD;
      and rituximab in patients with autoimmune cytopenia and underlying CLL. In stage I (remission&#xD;
      induction) patients will receive ibrutinib and rituximab for 6 months; in stage II&#xD;
      (maintenance) - only ibrutinib until relapse, progression or unacceptable toxicity. A total&#xD;
      of 50 patients will be enrolled into the trial. The results will be compared to historical&#xD;
      control, efficacy of rituximab as monotherapy or in combination with chemotherapy in patients&#xD;
      with AIC and underlying CLL.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Subjects will give informed consent before any protocol specific assessments. Blood samples,&#xD;
      physical examination, CT scan and bone marrow examination will be performed to determine&#xD;
      baseline disease status and study eligibility. All examinations must be performed ≤ 14 days&#xD;
      prior to first infusion, with the exception of the CT scan and bone marrow examination. The&#xD;
      CT scan and the bone marrow examination will be performed within 6 weeks of first infusion.&#xD;
&#xD;
      treatment regimen: Rituximab 375 mg/m2 8 weekly infusions (days 1, 8, 15, 22, 29, 36, 43, 50,&#xD;
      57), then 3 infusion every 28 days (days 85, 113, 141) Ibrutinib 420 mg (3 tablets) daily,&#xD;
      constantly for 6 months&#xD;
&#xD;
      Disease status assessments to determine subject response or progression will be performed&#xD;
      monthly according to NCI Criteria and will include:&#xD;
&#xD;
        -  Physical examination including lymph node examination, spleen and liver measurement, and&#xD;
           detection of constitutional symptoms&#xD;
&#xD;
        -  Peripheral blood sample evaluation of complete blood count (CBC) and differential&#xD;
           (expressed in % and absolutes)&#xD;
&#xD;
        -  Direct antiglobulin test&#xD;
&#xD;
        -  In addition, subjects will be monitored for safety, efficacy.&#xD;
&#xD;
      After completion of the induction phase, subjects achieving CR or PR (for AIC and CLL) will&#xD;
      continue maintenance phase. During maintenance phase patients will receive:&#xD;
&#xD;
      ibrutinib 420 mg (3 tablets) daily, constantly until progression or unacceptable toxicity&#xD;
      Survival and disease status assessments will be performed 1 month post treatment and every 2&#xD;
      months until total observation time.&#xD;
&#xD;
      In addition, subjects will be monitored for safety and efficacy.&#xD;
&#xD;
        -  Bone marrow examination is required for confirmation of CR 1 months post final rituximab&#xD;
           infusion. Minimal Residual Disease (MRD) assessment of the bone marrow aspirate will&#xD;
           also be performed for subjects demonstrating a CR.&#xD;
&#xD;
        -  In PRCA patients with clinical evidence of response for anemia the bone marrow&#xD;
           examination is required independently of CLL status at 1 month post last rituximab&#xD;
           infusion.&#xD;
&#xD;
        -  All subjects with clinical CR will receive MRD assessment of the peripheral blood during&#xD;
           maintenance phase. In subjects achieved MRD-negative result in blood in two consecutive&#xD;
           measurements bone marrow examination is required for confirmation of CR.&#xD;
&#xD;
        -  CT-Scans will be performed for patients achieving a CR, PR or SD at 1 month post last&#xD;
           rituximab infusion. CT-Scans must be repeated every 12 months beginning since final&#xD;
           assessment of response after induction phase.&#xD;
&#xD;
      Follow-up assessment for subjects experiencing CLL progression or relapse of AIC during the&#xD;
      maintenance phase requires a 1 month post-treatment safety assessment. Subsequent follow up&#xD;
      visits include assessment of survival status, date of next CLL therapy, type of therapy and&#xD;
      response to therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">February 21, 2017</start_date>
  <completion_date type="Anticipated">March 31, 2022</completion_date>
  <primary_completion_date type="Actual">December 1, 2019</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>Response rate</measure>
    <time_frame>3 month after treatment</time_frame>
    <description>Response rate defined by transfusion independence, hemoglobin level, DAT and duration of response of autoimmunity (DR-AI), defined as the interval between time point of best response and relapse of AIC. Relapses of CLL will be censored.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>AIHA - Warm Autoimmune Hemolytic Anemia</condition>
  <arm_group>
    <arm_group_label>patients with AIHA and CLL</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>patients with CLL and in Steroid Refractory AIHA receive ibrutinib 420 mg per day till progression or intolerance</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib</intervention_name>
    <description>Ibrutinib and rituximab combination for the treatment of steroid refractory AIC (warm type AIHA and PRCA) with underlying CLL.</description>
    <arm_group_label>patients with AIHA and CLL</arm_group_label>
    <other_name>Imbruvica</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Flow cytometry confirmation of immunophenotype with CD5, CD19, CD20, CD23, CD79b, and&#xD;
             surface Ig prior to Visit 2&#xD;
&#xD;
          2. Proven diagnosis autoimmune hemolytic anemia or pure red cell aplasia&#xD;
&#xD;
          3. Relapse of AIHA/PRCA after steroids, splenectomy or rituximab or refractoriness to&#xD;
             glucocorticosteroid hormones&#xD;
&#xD;
          4. No more than 2 lines of antileukemia treatment&#xD;
&#xD;
          5. Hematology values must be within the following limits:&#xD;
&#xD;
               1. Absolute neutrophil count 1000/mm3 independent of growth factor support&#xD;
&#xD;
               2. Platelets 100.000/mm3 or 50.000/mm3 if bone marrow involvement independent of&#xD;
                  transfusion support in either situation&#xD;
&#xD;
          6. Biochemical values within the following limits:&#xD;
&#xD;
               1. Alanine aminotransferase and aspartate aminotransferase less 3 upper limit of&#xD;
                  normal (ULN)&#xD;
&#xD;
               2. Total bilirubin less 1.5x ULN unless bilirubin rise is due to Gilbert's syndrome&#xD;
                  or of non-hepatic origin&#xD;
&#xD;
               3. Serum creatinine less 2 x ULN or estimated Glomerular Filtration Rate more 40&#xD;
                  mL/min/1.73 m2&#xD;
&#xD;
          7. Age ≥ 18 years&#xD;
&#xD;
          8. ECOG Performance Status of 0-2&#xD;
&#xD;
          9. Life expectancy of at least 6 months&#xD;
&#xD;
         10. Women of childbearing potential and men who are sexually active must be practicing a&#xD;
             highly effective method of birth control during and after the study consistent with&#xD;
             local regulations regarding the use of birth control methods for subjects&#xD;
             participating in clinical trials. Men must agree to not donate sperm during and after&#xD;
             the study. For females, these restrictions apply for 1 month after the last dose of&#xD;
             study drug. For males, these restrictions apply for 3 months after the last dose of&#xD;
             study drug.&#xD;
&#xD;
         11. Women who are pregnant or breastfeeding are ineligible for this study.&#xD;
&#xD;
         12. Sign (or their legally-acceptable representatives must sign) an informed consent&#xD;
             document indicating that they understand the purpose of and procedures required for&#xD;
             the study, including biomarkers, and are willing to participate in the study.&#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>Eugene Nikitin</name>
      <address>
        <city>Moscow</city>
        <zip>125284</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>January 24, 2019</study_first_submitted>
  <study_first_submitted_qc>January 31, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 1, 2019</study_first_posted>
  <last_update_submitted>January 8, 2020</last_update_submitted>
  <last_update_submitted_qc>January 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Association of Oncological Hematologists</investigator_affiliation>
    <investigator_full_name>Eugene Nikitin</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia</mesh_term>
    <mesh_term>Anemia, Hemolytic</mesh_term>
    <mesh_term>Anemia, Hemolytic, Autoimmune</mesh_term>
    <mesh_term>Hemolysis</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/NCT03827603
org study id: 54179060CLL2013
nct id: NCT03827603
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is an open-labeled, single arm, Phase II, two staged study of combination of ibrutinib
      and rituximab in patients with autoimmune cytopenia and underlying CLL. In stage I (remission
      induction) patients will receive ibrutinib and rituximab for 6 months; in stage II
      (maintenance) - only ibrutinib until relapse, progression or unacceptable toxicity. A total
      of 50 patients will be enrolled into the trial. The results will be compared to historical
      control, efficacy of rituximab as monotherapy or in combination with chemotherapy in patients
      with AIC and underlying CLL.
Subjects will give informed consent before any protocol specific assessments. Blood samples,
      physical examination, CT scan and bone marrow examination will be performed to determine
      baseline disease status and study eligibility. All examinations must be performed ≤ 14 days
      prior to first infusion, with the exception of the CT scan and bone marrow examination. The
      CT scan and the bone marrow examination will be performed within 6 weeks of first infusion.

      treatment regimen: Rituximab 375 mg/m2 8 weekly infusions (days 1, 8, 15, 22, 29, 36, 43, 50,
      57), then 3 infusion every 28 days (days 85, 113, 141) Ibrutinib 420 mg (3 tablets) daily,
      constantly for 6 months

      Disease status assessments to determine subject response or progression will be performed
      monthly according to NCI Criteria and will include:

        -  Physical examination including lymph node examination, spleen and liver measurement, and
           detection of constitutional symptoms

        -  Peripheral blood sample evaluation of complete blood count (CBC) and differential
           (expressed in % and absolutes)

        -  Direct antiglobulin test

        -  In addition, subjects will be monitored for safety, efficacy.

      After completion of the induction phase, subjects achieving CR or PR (for AIC and CLL) will
      continue maintenance phase. During maintenance phase patients will receive:

      ibrutinib 420 mg (3 tablets) daily, constantly until progression or unacceptable toxicity
      Survival and disease status assessments will be performed 1 month post treatment and every 2
      months until total observation time.

      In addition, subjects will be monitored for safety and efficacy.

        -  Bone marrow examination is required for confirmation of CR 1 months post final rituximab
           infusion. Minimal Residual Disease (MRD) assessment of the bone marrow aspirate will
           also be performed for subjects demonstrating a CR.

        -  In PRCA patients with clinical evidence of response for anemia the bone marrow
           examination is required independently of CLL status at 1 month post last rituximab
           infusion.

        -  All subjects with clinical CR will receive MRD assessment of the peripheral blood during
           maintenance phase. In subjects achieved MRD-negative result in blood in two consecutive
           measurements bone marrow examination is required for confirmation of CR.

        -  CT-Scans will be performed for patients achieving a CR, PR or SD at 1 month post last
           rituximab infusion. CT-Scans must be repeated every 12 months beginning since final
           assessment of response after induction phase.

      Follow-up assessment for subjects experiencing CLL progression or relapse of AIC during the
      maintenance phase requires a 1 month post-treatment safety assessment. Subsequent follow up
      visits include assessment of survival status, date of next CLL therapy, type of therapy and
      response to therapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Response rate
time frame: 3 month after treatment
description: Response rate defined by transfusion independence, hemoglobin level, DAT and duration of response of autoimmunity (DR-AI), defined as the interval between time point of best response and relapse of AIC. Relapses of CLL will be censored.
arm group label: patients with AIHA and CLL
arm group type: Experimental
description: patients with CLL and in Steroid Refractory AIHA receive ibrutinib 420 mg per day till progression or intolerance
intervention type: Drug
intervention name: Ibrutinib
description: Ibrutinib and rituximab combination for the treatment of steroid refractory AIC (warm type AIHA and PRCA) with underlying CLL.
arm group label: patients with AIHA and CLL
other name: Imbruvica
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Russian Federation
responsible party type: Sponsor-Investigator
investigator affiliation: Association of Oncological Hematologists
investigator full name: Eugene Nikitin
investigator title: Professor
mesh term: Anemia
mesh term: Anemia, Hemolytic
mesh term: Anemia, Hemolytic, Autoimmune
mesh term: Hemolysis
sharing ipd: No