<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/NCT03301207</url>
  </required_header>
  <id_info>
    <org_study_id>CR108347</org_study_id>
    <secondary_id>2017-000496-84</secondary_id>
    <secondary_id>54179060CLL1017</secondary_id>
    <nct_id>NCT03301207</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate the Effect of Ibrutinib on the Pharmacokinetics of Oral Contraceptives, CYP2B6, and CYP3A4 Substrates in Female Participants With B Cell Malignancy</brief_title>
  <official_title>A Drug-Drug Interaction Study to Evaluate the Effect of Ibrutinib on the Pharmacokinetics of Oral Contraceptives, CYP2B6, and CYP3A4 Substrates in Female Subjects With B Cell Malignancy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Janssen Research &amp; Development, LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Janssen Research &amp; Development, LLC</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main purpose of this study is to evaluate the effects of repeat dosing of ibrutinib on&#xD;
      the single-dose pharmacokinetics (PK) of oral contraceptives (OC - ethinylestradiol [EE] and&#xD;
      levonorgestrel [LN]), the cytochrome P450 (CYP)2B6 probe bupropion and the CYP3A4 probe&#xD;
      midazolam; and to evaluate the effects of single-dose ibrutinib on the single-dose PK of the&#xD;
      CYP3A4 probe midazolam in female participants with B cell malignancy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicenter study of ibrutinib (first-in-class, potent, covalently-binding&#xD;
      inhibitor of Bruton's tyrosine kinase [BTK]) in female participants with B cell malignancy.&#xD;
      The study consists of 3 phases: Screening Phase (up to 28 days), 7-day Pretreatment Phase&#xD;
      (Days 1 to 7), Treatment Phase including PK assessment period (Days 8 to 26) and a Follow-up&#xD;
      Phase (Day 27 to end of Cycle 6). The study procedures includes electrocardiogram (ECG),&#xD;
      vital signs, blood samples withdrawal to evaluate PK and safety. The Antitumor activity will&#xD;
      be assessed by means of computed tomography (CT) imaging and positron emission tomography&#xD;
      (PET) scans. No formal statistical hypothesis will be tested. This is an estimation study&#xD;
      designed to determine if an increase or decrease in exposure to OC or probe drugs occurs in&#xD;
      the presence of ibrutinib.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 20, 2017</start_date>
  <completion_date type="Actual">December 4, 2018</completion_date>
  <primary_completion_date type="Actual">July 17, 2018</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum Observed Plasma Concentration (Cmax) of Ethinylestradiol (EE) and Levonorgestrel (LN) When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone</measure>
    <time_frame>Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 hours (h) post-dose</time_frame>
    <description>The Cmax is the maximum observed plasma concentration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Observed Plasma Concentration (Cmax) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone</measure>
    <time_frame>Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose</time_frame>
    <description>The Cmax is the maximum observed plasma concentration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib</measure>
    <time_frame>Day 3: predose, 15 minutes (min), and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose</time_frame>
    <description>The Cmax is the maximum observed plasma concentration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib</measure>
    <time_frame>Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose</time_frame>
    <description>The Cmax is the maximum observed plasma concentration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of EE and LN When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone</measure>
    <time_frame>Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose</time_frame>
    <description>The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone</measure>
    <time_frame>Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose</time_frame>
    <description>The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib</measure>
    <time_frame>Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose</time_frame>
    <description>The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib</measure>
    <time_frame>Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose</time_frame>
    <description>The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of EE and LN When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone</measure>
    <time_frame>Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose</time_frame>
    <description>The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone</measure>
    <time_frame>Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose</time_frame>
    <description>The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib</measure>
    <time_frame>Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose</time_frame>
    <description>The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib</measure>
    <time_frame>Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose</time_frame>
    <description>The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma Concentration of Ibrutinib and its Metabolite PCI-45227</measure>
    <time_frame>Predose, 1, 2, 4, and 6 h post-dose on Days 8, 22, and 24</time_frame>
    <description>Plasma concentrations of Ibrutinib and its Metabolite PCI-45227 will be measured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events as a Measure of Safety and Tolerability</measure>
    <time_frame>Screening up to end of the 6 month treatment or 30 days after the last dose of study drug for Participants discontinuing treatment before 6 months</time_frame>
    <description>An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Laboratory Abnormalities as a Measure of Safety and Tolerability</measure>
    <time_frame>Screening, Days 8 and 36, and End of Treatment (approximately 7 months)</time_frame>
    <description>Blood samples for serum chemistry and hematology will be collected at predefined time points for clinical laboratory testing.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Electrocardiogram (ECG) Abnormalities Findings as a Measure of Safety and Tolerability</measure>
    <time_frame>Screening and End of Treatment (approximately 7 months)</time_frame>
    <description>Triplicate ECG will be performed at screening and a single time point ECG will be performed at end of treatment visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Vital Sign Abnormalities as a Measure of Safety and Tolerability</measure>
    <time_frame>Screening, Days 8 and 36, and End of Treatment (approximately 7 months)</time_frame>
    <description>Vital signs includes Temperature, Heart Rate, Respiratory Rate and Blood Pressure.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Leukemia, Lymphocytic, Chronic, B-Cell</condition>
  <arm_group>
    <arm_group_label>Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pre-treatment Phase: Participants will receive a single dose of oral contraceptive (OC) consisting of ethinylestradiol (EE) 30 microgram (mcg) and levonorgestrel (LN) 150 mcg on Study Day 1, and probe drugs (CYP) consisting of bupropion 75 milligram (mg) and midazolam 2 mg on Study Day 3, followed by a washout period from Study Days 4 to 7. Treatment Phase: Participants will receive ibrutinib 560 mg (4*140 mg capsules) once daily (QD) on Days 8 to 26 along with midazolam 2 mg once orally on Study Day 8 (Cycle 1 Day 1), OC once orally on Study Day 22 (Cycle 1 Day 15; EE and LN), and bupropion 75 mg and midazolam 2 mg once orally on Study Day 24 (Cycle 1 Day 17). From Study Day 27 (Cycle 1 Day 20) and onwards participants will continue oral treatment with ibrutinib 420 mg (3*140 mg capsules) or 560 mg QD (depending on the subtype of B-cell malignancy) up to the end of Cycle 6 (each cycle will consist of 28 days).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib</intervention_name>
    <description>Ibrutinib capsule (at dose of 420 or 560 mg) will be taken orally QD.</description>
    <arm_group_label>Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)</arm_group_label>
    <other_name>Imbruvica</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>OC: Ethinylestradiol (EE) 30 mcg and Levonorgestrel (LN) 150 mcg</intervention_name>
    <description>Single dose of oral contraceptives (OC) (1 tablet containing 30 mcg EE and 150 mcg LN) will be taken orally on Study Days 1 and 22.</description>
    <arm_group_label>Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)</arm_group_label>
    <other_name>Microgynon 30</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupropion</intervention_name>
    <description>Bupropion 75 mg tablet as a part of CYP cocktail will be taken on Study Days 3 and 24.</description>
    <arm_group_label>Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>Midazolam 2 mg (1 milliliter [mL]) oral solution will be taken on Study Days 3 and 24 (as a part of CYP cocktail) and on Study Day 8 (alone).</description>
    <arm_group_label>Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed chronic lymphocytic leukemia (CLL)/small&#xD;
             lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL),&#xD;
             or Waldenstrom's macroglobulinemia (WM)&#xD;
&#xD;
               1. Participants with MCL must have relapsed or refractory disease after at least 1&#xD;
                  prior line of systemic therapy&#xD;
&#xD;
               2. Participants with MZL must have failed an anti-cluster of differentiation (CD)20&#xD;
                  monoclonal antibody-based therapy&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1&#xD;
&#xD;
          -  Adequate hematologic, hepatic, and renal functions&#xD;
&#xD;
          -  Before the first dose of oral contraceptive (OC), a woman must be either:&#xD;
&#xD;
               1. Not of childbearing potential: postmenopausal (greater than [&gt;]45 years of age&#xD;
                  with amenorrhea for at least 12 months and a serum follicle stimulating hormone&#xD;
                  level &gt;40 international unit per Liter [IU/L] or milli international unit per&#xD;
                  milli Liter [mIU/mL]); permanently sterilized&#xD;
&#xD;
               2. Of childbearing potential and practicing a highly effective non-hormonal method&#xD;
                  of birth control&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum (Beta-human chorionic&#xD;
             gonadotropin [Beta-hCG]) or urine pregnancy test at screening&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Major surgery planned within 2 weeks of the first dose of ibrutinib or during study&#xD;
             participation up to Cycle 2 Day 1&#xD;
&#xD;
          -  History of other malignancies, except:&#xD;
&#xD;
               1. Malignancy treated with curative intent and with no known active disease present&#xD;
                  for greater than or equal to (&gt;=)3 years before the first dose of ibrutinib and&#xD;
                  felt to be at low risk for recurrence by treating physician&#xD;
&#xD;
               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence&#xD;
                  of disease&#xD;
&#xD;
               3. Adequately treated in-situ cancer without evidence of disease&#xD;
&#xD;
          -  History of breast or endometrial cancer&#xD;
&#xD;
          -  Prior treatment/exposure with ibrutinib or other Bruton's tyrosine kinase (BTK)&#xD;
             inhibitor&#xD;
&#xD;
          -  Requires ongoing anticoagulation treatment with warfarin or equivalent vitamin K&#xD;
             antagonists (for example, phenprocoumon)&#xD;
&#xD;
          -  Requires therapies that must be discontinued or substituted 7 days prior to Study Day&#xD;
             1, or must be temporally interrupted during the course of the study, including the&#xD;
             following:&#xD;
&#xD;
               1. Medications known to induce or inhibit drug metabolizing enzymes (CYP3A4 and&#xD;
                  CYP2B6)&#xD;
&#xD;
               2. Medication which are not allowed to be used in combination with EE, LN,&#xD;
                  bupropion, or midazolam&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Janssen Research &amp; Development, LLC Clinical Trial</last_name>
    <role>Study Director</role>
    <affiliation>Janssen Research &amp; Development, LLC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Pratia MCM Krakow</name>
      <address>
        <city>Krakow</city>
        <zip>30-510</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu</name>
      <address>
        <city>Wroclaw</city>
        <zip>50-367</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hosp. Univ. Fund. Jimenez Diaz</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinica Univ. de Navarra</name>
      <address>
        <city>Pamplona</city>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Poland</country>
    <country>Spain</country>
  </location_countries>
  <link>
    <url>https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217051&amp;amp;parentIdentifier=CR108347&amp;amp;attachmentIdentifier=81191578-48db-427d-b269-9351a0c2e39a&amp;amp;fileName=CR108347_CSR_Synopsis.pdf&amp;amp;versionIdentifier=</url>
    <description>A Drug-Drug Interaction Study to Evaluate the Effect of Ibrutinib on the Pharmacokinetics of Oral Contraceptives, CYP2B6, and CYP3A4 Substrates in Female Subjects with B Cell Malignancy</description>
  </link>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>September 29, 2017</study_first_submitted>
  <study_first_submitted_qc>September 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 4, 2017</study_first_posted>
  <last_update_submitted>December 3, 2019</last_update_submitted>
  <last_update_submitted_qc>December 3, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 5, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Midazolam</mesh_term>
    <mesh_term>Bupropion</mesh_term>
    <mesh_term>Levonorgestrel</mesh_term>
    <mesh_term>Ethinyl Estradiol</mesh_term>
    <mesh_term>Ethinyl estradiol, levonorgestrel drug combination</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/NCT03301207
org study id: CR108347
secondary id: 2017-000496-84
secondary id: 54179060CLL1017
nct id: NCT03301207
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The main purpose of this study is to evaluate the effects of repeat dosing of ibrutinib on
      the single-dose pharmacokinetics (PK) of oral contraceptives (OC - ethinylestradiol [EE] and
      levonorgestrel [LN]), the cytochrome P450 (CYP)2B6 probe bupropion and the CYP3A4 probe
      midazolam; and to evaluate the effects of single-dose ibrutinib on the single-dose PK of the
      CYP3A4 probe midazolam in female participants with B cell malignancy.
This is a multicenter study of ibrutinib (first-in-class, potent, covalently-binding
      inhibitor of Bruton's tyrosine kinase [BTK]) in female participants with B cell malignancy.
      The study consists of 3 phases: Screening Phase (up to 28 days), 7-day Pretreatment Phase
      (Days 1 to 7), Treatment Phase including PK assessment period (Days 8 to 26) and a Follow-up
      Phase (Day 27 to end of Cycle 6). The study procedures includes electrocardiogram (ECG),
      vital signs, blood samples withdrawal to evaluate PK and safety. The Antitumor activity will
      be assessed by means of computed tomography (CT) imaging and positron emission tomography
      (PET) scans. No formal statistical hypothesis will be tested. This is an estimation study
      designed to determine if an increase or decrease in exposure to OC or probe drugs occurs in
      the presence of ibrutinib.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Maximum Observed Plasma Concentration (Cmax) of Ethinylestradiol (EE) and Levonorgestrel (LN) When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
time frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 hours (h) post-dose
description: The Cmax is the maximum observed plasma concentration.
measure: Maximum Observed Plasma Concentration (Cmax) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
time frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
description: The Cmax is the maximum observed plasma concentration.
measure: Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib
time frame: Day 3: predose, 15 minutes (min), and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose
description: The Cmax is the maximum observed plasma concentration.
measure: Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib
time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose
description: The Cmax is the maximum observed plasma concentration.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of EE and LN When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
time frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose
description: The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
time frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
description: The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib
time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose
description: The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib
time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose
description: The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of EE and LN When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
time frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose
description: The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
time frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
description: The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib
time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose
description: The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib
time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose
description: The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
measure: Plasma Concentration of Ibrutinib and its Metabolite PCI-45227
time frame: Predose, 1, 2, 4, and 6 h post-dose on Days 8, 22, and 24
description: Plasma concentrations of Ibrutinib and its Metabolite PCI-45227 will be measured.
measure: Number of Participants With Adverse Events as a Measure of Safety and Tolerability
time frame: Screening up to end of the 6 month treatment or 30 days after the last dose of study drug for Participants discontinuing treatment before 6 months
description: An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
measure: Number of Participants With Laboratory Abnormalities as a Measure of Safety and Tolerability
time frame: Screening, Days 8 and 36, and End of Treatment (approximately 7 months)
description: Blood samples for serum chemistry and hematology will be collected at predefined time points for clinical laboratory testing.
measure: Number of Participants With Electrocardiogram (ECG) Abnormalities Findings as a Measure of Safety and Tolerability
time frame: Screening and End of Treatment (approximately 7 months)
description: Triplicate ECG will be performed at screening and a single time point ECG will be performed at end of treatment visit.
measure: Number of Participants With Vital Sign Abnormalities as a Measure of Safety and Tolerability
time frame: Screening, Days 8 and 36, and End of Treatment (approximately 7 months)
description: Vital signs includes Temperature, Heart Rate, Respiratory Rate and Blood Pressure.
arm group label: Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)
arm group type: Experimental
description: Pre-treatment Phase: Participants will receive a single dose of oral contraceptive (OC) consisting of ethinylestradiol (EE) 30 microgram (mcg) and levonorgestrel (LN) 150 mcg on Study Day 1, and probe drugs (CYP) consisting of bupropion 75 milligram (mg) and midazolam 2 mg on Study Day 3, followed by a washout period from Study Days 4 to 7. Treatment Phase: Participants will receive ibrutinib 560 mg (4*140 mg capsules) once daily (QD) on Days 8 to 26 along with midazolam 2 mg once orally on Study Day 8 (Cycle 1 Day 1), OC once orally on Study Day 22 (Cycle 1 Day 15; EE and LN), and bupropion 75 mg and midazolam 2 mg once orally on Study Day 24 (Cycle 1 Day 17). From Study Day 27 (Cycle 1 Day 20) and onwards participants will continue oral treatment with ibrutinib 420 mg (3*140 mg capsules) or 560 mg QD (depending on the subtype of B-cell malignancy) up to the end of Cycle 6 (each cycle will consist of 28 days).
intervention type: Drug
intervention name: Ibrutinib
description: Ibrutinib capsule (at dose of 420 or 560 mg) will be taken orally QD.
arm group label: Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)
other name: Imbruvica
intervention type: Drug
intervention name: OC: Ethinylestradiol (EE) 30 mcg and Levonorgestrel (LN) 150 mcg
description: Single dose of oral contraceptives (OC) (1 tablet containing 30 mcg EE and 150 mcg LN) will be taken orally on Study Days 1 and 22.
arm group label: Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)
other name: Microgynon 30
intervention type: Drug
intervention name: Bupropion
description: Bupropion 75 mg tablet as a part of CYP cocktail will be taken on Study Days 3 and 24.
arm group label: Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)
intervention type: Drug
intervention name: Midazolam
description: Midazolam 2 mg (1 milliliter [mL]) oral solution will be taken on Study Days 3 and 24 (as a part of CYP cocktail) and on Study Day 8 (alone).
arm group label: Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Janssen Research & Development, LLC Clinical Trial
role: Study Director
affiliation: Janssen Research & Development, LLC
facility: 
facility: 
facility: 
facility: 
country: Poland
country: Spain
url: https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217051&amp;parentIdentifier=CR108347&amp;attachmentIdentifier=81191578-48db-427d-b269-9351a0c2e39a&amp;fileName=CR108347_CSR_Synopsis.pdf&amp;versionIdentifier=
description: A Drug-Drug Interaction Study to Evaluate the Effect of Ibrutinib on the Pharmacokinetics of Oral Contraceptives, CYP2B6, and CYP3A4 Substrates in Female Subjects with B Cell Malignancy
responsible party type: Sponsor
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Midazolam
mesh term: Bupropion
mesh term: Levonorgestrel
mesh term: Ethinyl Estradiol
mesh term: Ethinyl estradiol, levonorgestrel drug combination