<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/NCT02991638</url>
  </required_header>
  <id_info>
    <org_study_id>HKUBTK01</org_study_id>
    <nct_id>NCT02991638</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Ibrutinib in Patients With CLL and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers</brief_title>
  <official_title>Efficacy and Safety of Ibrutinib in Patients With Chronic Lymphocytic Leukemia and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Janssen, LP</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>The University of Hong Kong</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Efficacy and Safety of ibrutinib in patients with chronic lymphocytic leukemia and other&#xD;
      indolent B-cell lymphomas who are chronic hepatitis B virus carriers or occult hepatitis B&#xD;
      virus carriers&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ibrutinib is a selective oral Burton tyrosine kinase inhibitor. Through interfering with the&#xD;
      downstream pathways of B-cell receptor signaling, it inhibits proliferation and induces&#xD;
      apoptosis in many B-cell lymphoid malignancies. The clinical benefit of ibrutinib has been&#xD;
      demonstrated in patients with relapsed/refractory chronic lymphocytic leukaemia, mantle cell&#xD;
      lymphoma, small lymphocytic lymphoma, and other indolent B-cell non-Hodgkin lymphomas.&#xD;
&#xD;
      The pivotal trials of ibrutinib excluded HBsAg+ patients. Therefore, the effects of ibrutinib&#xD;
      on HBsAg+ and anti-HBc+ patients remain entirely undefined. In view of the B-cell signaling&#xD;
      inhibitory activity of ibrutinib, which might be more potent than rituximab in suppressing&#xD;
      B-cells, HBV reactivation in patients exposed previously to HBV infection, including chronic&#xD;
      HBV carriers and occult HBV carriers, could be a major clinical problem.&#xD;
&#xD;
      To enable ibrutinib to be prescribed in Asia and other regions of the world where HBV is&#xD;
      endemic, evidence-based recommendations on prevention of HBV reactivation in at-risk&#xD;
      populations, including chronic HBV carriers (HBsAg+), and occult HBV carriers (HBsAg- but&#xD;
      anti-HBc+), are urgently needed.&#xD;
&#xD;
      The following treatment regimens will be adopted. Relapsed / refractory chronic lymphocytic&#xD;
      leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily.&#xD;
&#xD;
      Relapsed / refractory mantle cell lymphoma: 560 mg daily. Relapsed / refractory indolent&#xD;
      B-cell non-Hodgkin lymphoma: 560 mg daily. Treatment is continued until disease progression.&#xD;
&#xD;
      A total of 62 patients will be recruited, including 16 HBsAg+ patients, and 46 occult HBV&#xD;
      carriers&#xD;
&#xD;
      Sample size calculation of occult HBV carriers For occult HBV carriers, the sample size is&#xD;
      calculated according to the following information, based on our previous observations (as&#xD;
      detailed in reference 3). The HBV reactivation rate in HBsAg-, anti-HBc+, anti-HBs+ patients&#xD;
      is hypothesized to be 34%, which may increase to 68% in HBsAg-, anti-HBc+, but anti-HBs-&#xD;
      patients [3]. Assuming a power of 80% and an alpha-risk of 0.1, together with the ratio of&#xD;
      anti-HBs+ : anti-HBs- patients to be 2:1, we expect to recruit 42 HBsAg-, anti-HBc+ patients.&#xD;
      With a dropout rate of 10%, the total number of patients to be recruited in this group will&#xD;
      be 46.&#xD;
&#xD;
      Sample size calculation of HBsAg+ patients For HBsAg+ patients, the sample size is calculated&#xD;
      according to the following information, based on our previous observations (as detailed in&#xD;
      reference 3). The ratio of occult carriers (HBsAg-, anti-HBc+) : HBsAg+ patients is about 3:&#xD;
      1.3 Hence, the total number of HBsAg+ to be recruited will be 14 (42 divided by 3). With a&#xD;
      drop-out rate of 10%, the total number of patients to be recruited in this group will be 16.&#xD;
&#xD;
      Approximate breakdown of number of patients in each category to be recruited Based on our&#xD;
      previous observations on the proportions of low-grade B-cell lymphoid malignancies,8 an&#xD;
      approximate breakdown of number of patients is as follows: follicular lymphoma (N=32),&#xD;
      chronic lymphocytic leukemia/small lymphocytic lymphoma (N=11), marginal zone B-cell lymphoma&#xD;
      (N=11), mantle cell lymphoma (N=5), and Waldenstrom macroglobulinemia (N=5).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 1, 2016</start_date>
  <completion_date type="Anticipated">June 2021</completion_date>
  <primary_completion_date type="Anticipated">December 2020</primary_completion_date>
  <phase>Phase 3</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>Overall response rate (ORR)</measure>
    <time_frame>2 years</time_frame>
    <description>proportion of patients achieving CR or partial remission (PR)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Duration of remission</measure>
    <time_frame>two year</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Rates of HBV Reactivation while on Ibrutinib therapy</measure>
    <time_frame>two year</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Adverse events and severe adverse events</measure>
    <time_frame>two year</time_frame>
    <description>Incidence of AE and SAE by severity grading as assessed according to CTCAE v4.03</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">62</enrollment>
  <condition>Chronic Lymphocytic Leukemia</condition>
  <condition>Indolent B-cell Lymphomas</condition>
  <condition>Chronic Hepatitis B</condition>
  <condition>Lymphoma, Small Lymphocytic</condition>
  <condition>Mantle-Cell Lymphoma</condition>
  <condition>Waldenstrom's Macroglobulinaemia</condition>
  <condition>Follicular Lymphoma</condition>
  <arm_group>
    <arm_group_label>Ibrutinib</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily Relapsed / refractory mantle cell lymphoma: 560 mg daily Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily Treatment is continued until disease progression</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib</intervention_name>
    <description>Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily Relapsed / refractory mantle cell lymphoma: 560 mg daily Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily Treatment is continued until disease progression</description>
    <arm_group_label>Ibrutinib</arm_group_label>
    <other_name>Imbruvica</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult patients between age of 18 - 80 years&#xD;
&#xD;
          2. Patients with indolent B-cell lymphoproliferative neoplasms that have relapsed or are&#xD;
             refractory after at least one standard line of therapy that contains rituximab&#xD;
&#xD;
          3. Pathologically proven B-cell lymphoproliferative neoplasms including chronic&#xD;
             lymphocytic leukaemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal-zone&#xD;
             B-cell lymphoma, and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma).&#xD;
&#xD;
          4. Pathologically proven follicular lymphoma, with relapse or disease progression &gt; 12&#xD;
             months after previous rituximab therapy.&#xD;
&#xD;
          5. Chronic HBV carriers (HBsAg+)&#xD;
&#xD;
          6. Occult HBV carriers (HBsAg-, anti-HBc+ and HBV DNA-)&#xD;
&#xD;
          7. Haematology values within the following limits:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC)1000/mm3 independent of growth factor support&#xD;
&#xD;
               2. Platelets 100,000/mm3, or 50,000/mm3 if bone marrow is involved, and independent&#xD;
                  of transfusion support in either situation&#xD;
&#xD;
          8. Biochemical values within the following limits:&#xD;
&#xD;
               1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2 x upper&#xD;
                  limit of normal (ULN)&#xD;
&#xD;
               2. Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or&#xD;
                  of non-hepatic origin&#xD;
&#xD;
               3. Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockcroft&#xD;
                  Gault) ≥ 40 mL/min/1.73m2&#xD;
&#xD;
          9. Competent to give an informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Concomitant chronic liver diseases not related to HBV&#xD;
&#xD;
          2. Known history of drug-induced liver injury, chronic active hepatitis C infection,&#xD;
             alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis,&#xD;
             on-going extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver&#xD;
             and portal hypertension&#xD;
&#xD;
          3. Known history of drug induced pneumonitis&#xD;
&#xD;
          4. Known history of inflammatory bowel disease&#xD;
&#xD;
          5. Woman who are pregnant or breast-feeding&#xD;
&#xD;
          6. Patients who do not consent to the use of effective contraception during the study&#xD;
&#xD;
          7. Active infections.&#xD;
&#xD;
          8. Evidence of ongoing active HBV hepatitis (ALT and/or AST &gt; 2x upper limit of normal,&#xD;
             and detectable HBV DNA)&#xD;
&#xD;
          9. Patients known to have histological transformation of CLL to an aggressive lymphoma&#xD;
&#xD;
         10. Vaccinated with live, attenuated vaccines within 4 weeks of enrolment&#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>Yok Lam Kwong, MD(HK),</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Hong Kong</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>King Hei Lu, MMedSc</last_name>
    <phone>852-22554361</phone>
    <phone_ext>1654</phone_ext>
    <email>khlu@hku.hk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Zoe Chan, BNs</last_name>
    <phone>852-22551654</phone>
    <email>zoechan1@hku.hk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>The University of Hong Kong</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>King Hei Lu, MMedSc</last_name>
      <phone>852-22554361</phone>
      <phone_ext>1654</phone_ext>
      <email>khlu@hku.hk</email>
    </contact>
    <contact_backup>
      <last_name>Zoe Chan, BNs</last_name>
      <phone>852-22551654</phone>
      <email>zoechan1@hku.hk</email>
    </contact_backup>
    <investigator>
      <last_name>Yok Lam Kwong, MD(HK)</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Eric Tse, MBBS(HK), PhD(Cantab)</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <verification_date>April 2018</verification_date>
  <study_first_submitted>December 2, 2016</study_first_submitted>
  <study_first_submitted_qc>December 8, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 13, 2016</study_first_posted>
  <last_update_submitted>April 11, 2018</last_update_submitted>
  <last_update_submitted_qc>April 11, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The University of Hong Kong</investigator_affiliation>
    <investigator_full_name>Professor Yok-lam Kwong</investigator_full_name>
    <investigator_title>Chair Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis B</mesh_term>
    <mesh_term>Hepatitis B, Chronic</mesh_term>
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
    <mesh_term>Waldenstrom Macroglobulinemia</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Hepatitis, Chronic</mesh_term>
  </condition_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/NCT02991638
org study id: HKUBTK01
nct id: NCT02991638
lead sponsor: 
collaborator: 
has dmc: No
Efficacy and Safety of ibrutinib in patients with chronic lymphocytic leukemia and other
      indolent B-cell lymphomas who are chronic hepatitis B virus carriers or occult hepatitis B
      virus carriers
Ibrutinib is a selective oral Burton tyrosine kinase inhibitor. Through interfering with the
      downstream pathways of B-cell receptor signaling, it inhibits proliferation and induces
      apoptosis in many B-cell lymphoid malignancies. The clinical benefit of ibrutinib has been
      demonstrated in patients with relapsed/refractory chronic lymphocytic leukaemia, mantle cell
      lymphoma, small lymphocytic lymphoma, and other indolent B-cell non-Hodgkin lymphomas.

      The pivotal trials of ibrutinib excluded HBsAg+ patients. Therefore, the effects of ibrutinib
      on HBsAg+ and anti-HBc+ patients remain entirely undefined. In view of the B-cell signaling
      inhibitory activity of ibrutinib, which might be more potent than rituximab in suppressing
      B-cells, HBV reactivation in patients exposed previously to HBV infection, including chronic
      HBV carriers and occult HBV carriers, could be a major clinical problem.

      To enable ibrutinib to be prescribed in Asia and other regions of the world where HBV is
      endemic, evidence-based recommendations on prevention of HBV reactivation in at-risk
      populations, including chronic HBV carriers (HBsAg+), and occult HBV carriers (HBsAg- but
      anti-HBc+), are urgently needed.

      The following treatment regimens will be adopted. Relapsed / refractory chronic lymphocytic
      leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily.

      Relapsed / refractory mantle cell lymphoma: 560 mg daily. Relapsed / refractory indolent
      B-cell non-Hodgkin lymphoma: 560 mg daily. Treatment is continued until disease progression.

      A total of 62 patients will be recruited, including 16 HBsAg+ patients, and 46 occult HBV
      carriers

      Sample size calculation of occult HBV carriers For occult HBV carriers, the sample size is
      calculated according to the following information, based on our previous observations (as
      detailed in reference 3). The HBV reactivation rate in HBsAg-, anti-HBc+, anti-HBs+ patients
      is hypothesized to be 34%, which may increase to 68% in HBsAg-, anti-HBc+, but anti-HBs-
      patients [3]. Assuming a power of 80% and an alpha-risk of 0.1, together with the ratio of
      anti-HBs+ : anti-HBs- patients to be 2:1, we expect to recruit 42 HBsAg-, anti-HBc+ patients.
      With a dropout rate of 10%, the total number of patients to be recruited in this group will
      be 46.

      Sample size calculation of HBsAg+ patients For HBsAg+ patients, the sample size is calculated
      according to the following information, based on our previous observations (as detailed in
      reference 3). The ratio of occult carriers (HBsAg-, anti-HBc+) : HBsAg+ patients is about 3:
      1.3 Hence, the total number of HBsAg+ to be recruited will be 14 (42 divided by 3). With a
      drop-out rate of 10%, the total number of patients to be recruited in this group will be 16.

      Approximate breakdown of number of patients in each category to be recruited Based on our
      previous observations on the proportions of low-grade B-cell lymphoid malignancies,8 an
      approximate breakdown of number of patients is as follows: follicular lymphoma (N=32),
      chronic lymphocytic leukemia/small lymphocytic lymphoma (N=11), marginal zone B-cell lymphoma
      (N=11), mantle cell lymphoma (N=5), and Waldenstrom macroglobulinemia (N=5).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate (ORR)
time frame: 2 years
description: proportion of patients achieving CR or partial remission (PR)
measure: Duration of remission
time frame: two year
measure: Rates of HBV Reactivation while on Ibrutinib therapy
time frame: two year
measure: Adverse events and severe adverse events
time frame: two year
description: Incidence of AE and SAE by severity grading as assessed according to CTCAE v4.03
arm group label: Ibrutinib
arm group type: Other
description: Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily Relapsed / refractory mantle cell lymphoma: 560 mg daily Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily Treatment is continued until disease progression
intervention type: Drug
intervention name: Ibrutinib
description: Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily Relapsed / refractory mantle cell lymphoma: 560 mg daily Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily Treatment is continued until disease progression
arm group label: Ibrutinib
other name: Imbruvica
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Yok Lam Kwong, MD(HK),
role: Principal Investigator
affiliation: The University of Hong Kong
last name: King Hei Lu, MMedSc
phone: 852-22554361
phone ext: 1654
email: khlu@hku.hk
last name: Zoe Chan, BNs
phone: 852-22551654
email: zoechan1@hku.hk
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: Hong Kong
responsible party type: Principal Investigator
investigator affiliation: The University of Hong Kong
investigator full name: Professor Yok-lam Kwong
investigator title: Chair Professor
mesh term: Hepatitis A
mesh term: Hepatitis B
mesh term: Hepatitis B, Chronic
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Lymphoma, B-Cell
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Lymphoma, Mantle-Cell
mesh term: Waldenstrom Macroglobulinemia
mesh term: Hepatitis
mesh term: Hepatitis, Chronic
sharing ipd: Undecided