<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/NCT01704963</url>
  </required_header>
  <id_info>
    <org_study_id>CR100896</org_study_id>
    <secondary_id>PCI-32765-JPN-101</secondary_id>
    <nct_id>NCT01704963</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate the Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Patients With Recurrent Mature B-Cell Neoplasms</brief_title>
  <official_title>A Phase 1 Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Subjects With Recurrent Mature B-Cell Neoplasms</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Janssen Pharmaceutical K.K.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pharmacyclics LLC.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Janssen Pharmaceutical K.K.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and tolerability of Bruton's Tyrosine&#xD;
      Kinase (Btk) Inhibitor PCI-32765 in Japanese patients with recurrent mature B-cell neoplasms.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label (all people know the identity of the intervention), multicenter (study&#xD;
      conducted at multiple sites), dose escalation study. The study consists of 3 phases,&#xD;
      including, the screening phase (within 14 days prior to the first study medication), the&#xD;
      treatment phase, and the follow up phase. In the treatment phase, patients with recurrent&#xD;
      mature B-cell neoplasms will be divided into 2 cohorts: Cohort 1 (consisting of between 3 and&#xD;
      12 patients), and Cohort 2 (consisting of between 6 and 12 patients). Cohort 1 will be&#xD;
      further divided into 2 phases: a single dose (SD) phase and a multiple dose (MD) phase.&#xD;
      During the initial SD phase, patients will first receive a single dose of PCI-32765 at 140&#xD;
      mg. After a washout period (period when the participant is not receiving any study&#xD;
      medication) of between 72 and 168 hours, patients will then receive a second single dose of&#xD;
      PCI-32765 at 280 mg. Following a second washout period, patients will enter the MD phase,&#xD;
      where they will receive PCI-32765 at multiple doses of 420 mg per day for 35 days during the&#xD;
      first cycle (35 days in Cycle 1) and for 28 days during the second cycle (28 days in Cycle 2)&#xD;
      and every cycle thereafter. In cohort 2, patients will receive multiple doses of 560 mg per&#xD;
      day for 35 days in Cycle 1, 28 days in Cycle 2, and every cycle thereafter. The patient's&#xD;
      registration in Cohort 2 will be started after tolerability of Cohort 1 is confirmed.&#xD;
      Tolerability of each dose level will be evaluated based on the dose-limiting toxicity (DLT)&#xD;
      occurrence rate in Cycle 1 of each Cohort. Following the tolerability of the 420 mg/day dose&#xD;
      level in subjects with mature B-cell neoplasms is confirmed in Cohort 1, a CLL/SLL Cohort&#xD;
      will be added to further evaluate the safety and tolerability of this dose in this specific&#xD;
      population in Japanese since 420 mg/day is the globally recommended dose for subjects with&#xD;
      CLL and SLL, which are specific disease entities within mature B-cell neoplasms. Between 6&#xD;
      and 12 subjects will be enrolled in the CLL/SLL Cohort and will receive continuous dosing of&#xD;
      PCI-32765 at 420 mg/day for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter.&#xD;
      Safety evaluations for adverse events, clinical laboratory tests, electrocardiogram, vital&#xD;
      signs, Eastern Cooperative Oncology Group (ECOG) performance status, physical examination,&#xD;
      and corneal eye examination will be monitored throughout the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 12, 2012</start_date>
  <completion_date type="Actual">February 1, 2017</completion_date>
  <primary_completion_date type="Actual">November 20, 2015</primary_completion_date>
  <phase>Phase 1</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>Number of patients with adverse events</measure>
    <time_frame>Screening (Day -14) to until 30 days after the last dose</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration (AUClast)</measure>
    <time_frame>Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort</time_frame>
    <description>Pharmacokinetic parameter AUClast of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time 0 to infinity time (AUC∞)</measure>
    <time_frame>Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort</time_frame>
    <description>Pharmacokinetic parameter AUC∞ of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum plasma concentration (Cmax)</measure>
    <time_frame>Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort</time_frame>
    <description>Pharmacokinetic parameter Cmax of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach maximum plasma concentration (tmax)</measure>
    <time_frame>Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort</time_frame>
    <description>Pharmacokinetic parameter tmax of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal elimination half-life (t1/2)</measure>
    <time_frame>Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort</time_frame>
    <description>Pharmacokinetic parameter t1/2 of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic evaluations</measure>
    <time_frame>Days 1-2, 8-9, 15, and 29 during Cycle 1, and on Days 1 and 15 during Cycle 3, 5, 7, 9, and 11 of each cohort</time_frame>
    <description>Pharmacodynamic evaluations of PCI-32765 will be conducted under supervision by collecting venous blood samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor response</measure>
    <time_frame>Days 22 to 28 of Cycles 2, 4, 6, and every even-numbered cycle thereafter</time_frame>
    <description>Patients will be evaluated for tumor response according to the International Working Group (IWG) Revised Criteria for Malignant Lymphoma or the Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Recurrent Mature B-cell Neoplasms</condition>
  <arm_group>
    <arm_group_label>PCI-32765</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive oral doses of PCI-32765 in Cohort 1, Cohort 2 and CLL/SLL Cohort. In Cohort 1, single oral dose of PCI-32765 140 mg and 280 mg will be given before administration of daily oral doses of 420 mg per day for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter. In Cohort 2 and CLL/SLL Cohort, PCI-32765 560 mg and 420 mg per day, respectively will be administered daily for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PCI-32765</intervention_name>
    <description>PCI-32765 will be administered in Cohort 1, Cohort 2 and CLL/SLL Cohort. In Cohort 1, single oral dose of PCI-32765 140 mg and 280 mg will be administered before daily oral doses of 420 mg per day for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter. In Cohort 2 and CLL/SLL Cohort, PCI-32765 560 mg and 420 mg per day, respectively will be administered daily for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter.</description>
    <arm_group_label>PCI-32765</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have body weight at least 40 kilogram (kg)&#xD;
&#xD;
          -  Patients with recurrent mature B-cell neoplasms as defined according to WHO&#xD;
             classification, including small lymphocytic lymphoma/ chronic lymphocytic leukemia,&#xD;
             mantle cell lymphoma, and follicular lymphoma&#xD;
&#xD;
          -  Have measurable disease [for Non-Hodgkin's Lymphoma (NHL) bi-dimensional disease more&#xD;
             than or equal to 2 cm diameter in at least one dimension and for chronic lymphocytic&#xD;
             leukemia more than or equal to 5000 leukemia cells/cubic mm]&#xD;
&#xD;
          -  Have failed more than or equal to 1 previous treatment and no standard therapy is&#xD;
             available&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with plasma cell neoplasm as defined according to WHO classification&#xD;
&#xD;
          -  Patients who have received prior allogeneic hematopoietic stem cell transplant&#xD;
&#xD;
          -  Patients who have received immunotherapy, chemotherapy, radiotherapy or experimental&#xD;
             therapy within 4 weeks before first day of study medication&#xD;
&#xD;
          -  Past history of major surgery within 4 weeks before the first day of study medication&#xD;
&#xD;
          -  Patients with central nervous system involvement&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Janssen Pharmaceutical K.K., Japan Clinical Trial</last_name>
    <role>Study Director</role>
    <affiliation>Janssen Pharmaceutical K.K.</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Kyoto</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nagoya</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sendai</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tokyo</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <link>
    <url>http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_JNJ_7051&amp;studyid=3564&amp;filename=CR100896_CSR.pdf</url>
    <description>A Phase 1 Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Subjects With Recurrent Mature B-Cell Neoplasms</description>
  </link>
  <results_reference>
    <citation>Tobinai K, Ogura M, Ishizawa K, Suzuki T, Munakata W, Uchida T, Aoki T, Morishita T, Ushijima Y, Takahara S. Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies. Int J Hematol. 2016 Jan;103(1):86-94. doi: 10.1007/s12185-015-1900-3. Epub 2015 Nov 20.</citation>
    <PMID>26588924</PMID>
  </results_reference>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>October 9, 2012</study_first_submitted>
  <study_first_submitted_qc>October 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 12, 2012</study_first_posted>
  <last_update_submitted>February 1, 2018</last_update_submitted>
  <last_update_submitted_qc>February 1, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 5, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Recurrent mature B-cell neoplasms</keyword>
  <keyword>B-cell malignancies</keyword>
  <keyword>Bruton's Tyrosine Kinase (Btk) Inhibitor</keyword>
  <keyword>PCI-32765</keyword>
  <keyword>Tumor</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Japanese</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_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/NCT01704963
org study id: CR100896
secondary id: PCI-32765-JPN-101
nct id: NCT01704963
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
The purpose of this study is to evaluate the safety and tolerability of Bruton's Tyrosine
      Kinase (Btk) Inhibitor PCI-32765 in Japanese patients with recurrent mature B-cell neoplasms.
This is an open-label (all people know the identity of the intervention), multicenter (study
      conducted at multiple sites), dose escalation study. The study consists of 3 phases,
      including, the screening phase (within 14 days prior to the first study medication), the
      treatment phase, and the follow up phase. In the treatment phase, patients with recurrent
      mature B-cell neoplasms will be divided into 2 cohorts: Cohort 1 (consisting of between 3 and
      12 patients), and Cohort 2 (consisting of between 6 and 12 patients). Cohort 1 will be
      further divided into 2 phases: a single dose (SD) phase and a multiple dose (MD) phase.
      During the initial SD phase, patients will first receive a single dose of PCI-32765 at 140
      mg. After a washout period (period when the participant is not receiving any study
      medication) of between 72 and 168 hours, patients will then receive a second single dose of
      PCI-32765 at 280 mg. Following a second washout period, patients will enter the MD phase,
      where they will receive PCI-32765 at multiple doses of 420 mg per day for 35 days during the
      first cycle (35 days in Cycle 1) and for 28 days during the second cycle (28 days in Cycle 2)
      and every cycle thereafter. In cohort 2, patients will receive multiple doses of 560 mg per
      day for 35 days in Cycle 1, 28 days in Cycle 2, and every cycle thereafter. The patient's
      registration in Cohort 2 will be started after tolerability of Cohort 1 is confirmed.
      Tolerability of each dose level will be evaluated based on the dose-limiting toxicity (DLT)
      occurrence rate in Cycle 1 of each Cohort. Following the tolerability of the 420 mg/day dose
      level in subjects with mature B-cell neoplasms is confirmed in Cohort 1, a CLL/SLL Cohort
      will be added to further evaluate the safety and tolerability of this dose in this specific
      population in Japanese since 420 mg/day is the globally recommended dose for subjects with
      CLL and SLL, which are specific disease entities within mature B-cell neoplasms. Between 6
      and 12 subjects will be enrolled in the CLL/SLL Cohort and will receive continuous dosing of
      PCI-32765 at 420 mg/day for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter.
      Safety evaluations for adverse events, clinical laboratory tests, electrocardiogram, vital
      signs, Eastern Cooperative Oncology Group (ECOG) performance status, physical examination,
      and corneal eye examination will be monitored throughout the study.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients with adverse events
time frame: Screening (Day -14) to until 30 days after the last dose
measure: Area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration (AUClast)
time frame: Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort
description: Pharmacokinetic parameter AUClast of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.
measure: Area under the plasma concentration-time curve from time 0 to infinity time (AUC∞)
time frame: Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort
description: Pharmacokinetic parameter AUC∞ of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.
measure: Maximum plasma concentration (Cmax)
time frame: Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort
description: Pharmacokinetic parameter Cmax of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.
measure: Time to reach maximum plasma concentration (tmax)
time frame: Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort
description: Pharmacokinetic parameter tmax of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.
measure: Terminal elimination half-life (t1/2)
time frame: Days 1-2, 8-9, 15, 22 and 29 during Cycle 1 of each cohort
description: Pharmacokinetic parameter t1/2 of PCI-32765 and its metabolite PCI-45227 will be measured when PCI-32765 is administered daily as oral doses in each cohort.
measure: Pharmacodynamic evaluations
time frame: Days 1-2, 8-9, 15, and 29 during Cycle 1, and on Days 1 and 15 during Cycle 3, 5, 7, 9, and 11 of each cohort
description: Pharmacodynamic evaluations of PCI-32765 will be conducted under supervision by collecting venous blood samples.
measure: Tumor response
time frame: Days 22 to 28 of Cycles 2, 4, 6, and every even-numbered cycle thereafter
description: Patients will be evaluated for tumor response according to the International Working Group (IWG) Revised Criteria for Malignant Lymphoma or the Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia.
arm group label: PCI-32765
arm group type: Experimental
description: Patients will receive oral doses of PCI-32765 in Cohort 1, Cohort 2 and CLL/SLL Cohort. In Cohort 1, single oral dose of PCI-32765 140 mg and 280 mg will be given before administration of daily oral doses of 420 mg per day for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter. In Cohort 2 and CLL/SLL Cohort, PCI-32765 560 mg and 420 mg per day, respectively will be administered daily for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter.
intervention type: Drug
intervention name: PCI-32765
description: PCI-32765 will be administered in Cohort 1, Cohort 2 and CLL/SLL Cohort. In Cohort 1, single oral dose of PCI-32765 140 mg and 280 mg will be administered before daily oral doses of 420 mg per day for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter. In Cohort 2 and CLL/SLL Cohort, PCI-32765 560 mg and 420 mg per day, respectively will be administered daily for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter.
arm group label: PCI-32765
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Janssen Pharmaceutical K.K., Japan Clinical Trial
role: Study Director
affiliation: Janssen Pharmaceutical K.K.
facility: 
facility: 
facility: 
facility: 
country: Japan
url: http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_JNJ_7051&studyid=3564&filename=CR100896_CSR.pdf
description: A Phase 1 Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Subjects With Recurrent Mature B-Cell Neoplasms
citation: Tobinai K, Ogura M, Ishizawa K, Suzuki T, Munakata W, Uchida T, Aoki T, Morishita T, Ushijima Y, Takahara S. Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies. Int J Hematol. 2016 Jan;103(1):86-94. doi: 10.1007/s12185-015-1900-3. Epub 2015 Nov 20.
PMID: 26588924
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Lymphoma, B-Cell
mesh term: Recurrence