<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/NCT03043989</url>
  </required_header>
  <id_info>
    <org_study_id>J16144</org_study_id>
    <secondary_id>IRB00117591</secondary_id>
    <nct_id>NCT03043989</nct_id>
  </id_info>
  <brief_title>Cohorts of Docetaxel or Cabazitaxel in Combination With the Potent CYP3A4 Inhibitor, Clarithromycin</brief_title>
  <official_title>Two Independent Phase 1b Cohorts of Docetaxel or Cabazitaxel in Combination With the Potent CYP3A4 Inhibitor, Clarithromycin</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Maryland Technology Development Corporation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical trial is being conducted to recommend a safe and tolerable phase 2 dose of&#xD;
      docetaxel or cabazitaxel when combined with clarithromycin in men who have developed&#xD;
      castrate-resistant prostate cancer.&#xD;
&#xD;
      In the castrate-resistant setting, resistance to taxane therapy inevitably develops. Men who&#xD;
      develop resistance to taxanes have a very poor prognosis, and few treatment options.&#xD;
&#xD;
      It is believed that CYP enzymes contribute to docetaxel and cabazitaxel resistance in&#xD;
      metastatic prostate cancer, and this resistance can be mitigated through pharmacologic CYP&#xD;
      inhibition. In this study a potent CYP3A inhibitor, clarithromycin, will be co-administered&#xD;
      concurrently with either docetaxel or cabazitaxel, whose systemic metabolism is dependent of&#xD;
      CYP3A4, with the intent to overcome resistance to taxanes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a dose-escalation study designed to determine the maximum tolerated dose of docetaxel&#xD;
      or cabazitaxel when given in combination with clarithromycin. Eligible patients will be&#xD;
      assigned to docetaxel or cabazitaxel, based on which drug they were previously administered&#xD;
      prior to study entry. Enrollment to dose levels will be in a 3+3 cohort design until the&#xD;
      maximum tolerated dose is achieved.&#xD;
&#xD;
      Docetaxel or cabazitaxel will be administered on day 1 of each (3 week) cycle for a total of&#xD;
      6 cycles. Subjects in both arms will be administered clarithromycin on days -1, 1 and 2 of&#xD;
      each 3 week cycle.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Low accrual&#xD;
  </why_stopped>
  <start_date type="Actual">March 21, 2017</start_date>
  <completion_date type="Actual">July 26, 2019</completion_date>
  <primary_completion_date type="Actual">July 26, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</measure>
    <time_frame>3 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Escalate dose up the maximum tolerated dose achieved, and initiate this as the recommended phase 2 dose of docetaxel and of cabazitaxel when it is combined with clarithromycin.</measure>
    <time_frame>3 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Compare docetaxel OR cabazitaxel exposure (maximal [Cmax] when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare docetaxel OR cabazitaxel exposure ( total [AUC]) when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">4</enrollment>
  <condition>Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Docetaxel and clarithromycin combination</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Docetaxel will be administered by intravenous infusion over 1 hour every 3 weeks on day 1 of each (3 week) cycle for a total of 18 weeks.&#xD;
Clarithromycin will be administered orally at 500mg twice a day for 3 days per cycle on days -1, 1, and 2.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cabazitaxel and clarithromycin combination</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cabazitaxel will be administered by intravenous infusion over 1 hour every 3 weeks on day 1 of each (3 week) cycle for a total of 18 weeks.&#xD;
Clarithromycin will be administered orally at 500mg twice a day for 3 days per cycle on days -1, 1, and 2.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Docetaxel</intervention_name>
    <description>6 infusions of Docetaxel with 18 doses clarithromycin</description>
    <arm_group_label>Docetaxel and clarithromycin combination</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabazitaxel</intervention_name>
    <description>6 infusions of Cabazitaxel with 18 doses clarithromycin</description>
    <arm_group_label>Cabazitaxel and clarithromycin combination</arm_group_label>
    <other_name>JEVTANA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clarithromycin</intervention_name>
    <description>18 doses of clarithromycin with either Docetaxel or Cabazitaxel</description>
    <arm_group_label>Cabazitaxel and clarithromycin combination</arm_group_label>
    <arm_group_label>Docetaxel and clarithromycin combination</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men with metastatic castrate-resistant prostate cancer (prostate cancer progressing&#xD;
             despite castrate levels of testosterone &lt;50 ng/dL), using standard measures of&#xD;
             progression defined by PCWG2&#xD;
&#xD;
          2. Have received at least 4 cycles of docetaxel or cabazitaxel, and less than ten, with&#xD;
             two consecutive rising PSA values, checked at least 7 days apart. No PSA decline in&#xD;
             last 42 day&#xD;
&#xD;
          3. Bone disease documented by either: a positive bone scan, CT scan, or MRI; or&#xD;
             biopsy-proven bony metastases&#xD;
&#xD;
          4. Age ≥18 years&#xD;
&#xD;
          5. ECOG performance status ≤ 2 (Karnofsky ≥ 60%)&#xD;
&#xD;
          6. Have normal organ and marrow function defined as:&#xD;
&#xD;
               -  absolute neutrophil count ≥1,500/mcL&#xD;
&#xD;
               -  platelets ≥100,000/mcL&#xD;
&#xD;
               -  total bilirubin (within normal institutional limits)&#xD;
&#xD;
               -  AST/ALT ≤ 2.5 × ULN (or ≤ 1.5 x ULN in conjunction with alk phos &gt;2.5 x ULN for&#xD;
                  Docetaxel&#xD;
&#xD;
               -  AST ≤ 1.5 x ULN for Cabazitaxel&#xD;
&#xD;
               -  creatinine clearance-no minimum for Docetaxel&#xD;
&#xD;
               -  creatinine clearance- ≥ 30 mL/min/1.73 m2 for Cabazitaxel&#xD;
&#xD;
          7. No evidence of clinical progression, in the form of increased lesions on&#xD;
             cross-sectional imaging, or new cancer-attributable symptoms or worsening of existing&#xD;
             symptoms&#xD;
&#xD;
          8. Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients who have residual toxicities &gt; Grade 2 attributed to taxane therapy, except&#xD;
             for neuropathy, who are excluded if &gt; grade 1&#xD;
&#xD;
          2. Patients who are receiving any other investigational agents or have within the last 28&#xD;
             day.&#xD;
&#xD;
          3. History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to clarithromycin or taxanes&#xD;
&#xD;
          4. Patients receiving any medications or substances that are inhibitors or inducers of&#xD;
             CYP3A4 are ineligible&#xD;
&#xD;
          5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          6. Received more than 10 cycles of docetaxel [for docetaxel cohort only] or 6 of&#xD;
             cabazitaxel [for cabazitaxel cohort only]&#xD;
&#xD;
          7. Last docetaxel or cabazitaxel dose &gt; 6 weeks prior to enrollment&#xD;
&#xD;
          8. Patients with a documented history of QT prolongation or ventricular cardiac&#xD;
             arrhythmia, including torsades de pointes, or taking drugs that are known to prolong&#xD;
             the QT&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael A Carducci, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins Hospital</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>January 26, 2017</study_first_submitted>
  <study_first_submitted_qc>February 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 6, 2017</study_first_posted>
  <last_update_submitted>February 13, 2020</last_update_submitted>
  <last_update_submitted_qc>February 13, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>docetaxel</keyword>
  <keyword>cabazitaxel</keyword>
  <keyword>phase 1b</keyword>
  <keyword>castration-resistant</keyword>
  <keyword>bone metastasis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clarithromycin</mesh_term>
    <mesh_term>Docetaxel</mesh_term>
  </intervention_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/NCT03043989
org study id: J16144
secondary id: IRB00117591
nct id: NCT03043989
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This clinical trial is being conducted to recommend a safe and tolerable phase 2 dose of
      docetaxel or cabazitaxel when combined with clarithromycin in men who have developed
      castrate-resistant prostate cancer.

      In the castrate-resistant setting, resistance to taxane therapy inevitably develops. Men who
      develop resistance to taxanes have a very poor prognosis, and few treatment options.

      It is believed that CYP enzymes contribute to docetaxel and cabazitaxel resistance in
      metastatic prostate cancer, and this resistance can be mitigated through pharmacologic CYP
      inhibition. In this study a potent CYP3A inhibitor, clarithromycin, will be co-administered
      concurrently with either docetaxel or cabazitaxel, whose systemic metabolism is dependent of
      CYP3A4, with the intent to overcome resistance to taxanes.
This is a dose-escalation study designed to determine the maximum tolerated dose of docetaxel
      or cabazitaxel when given in combination with clarithromycin. Eligible patients will be
      assigned to docetaxel or cabazitaxel, based on which drug they were previously administered
      prior to study entry. Enrollment to dose levels will be in a 3+3 cohort design until the
      maximum tolerated dose is achieved.

      Docetaxel or cabazitaxel will be administered on day 1 of each (3 week) cycle for a total of
      6 cycles. Subjects in both arms will be administered clarithromycin on days -1, 1 and 2 of
      each 3 week cycle.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
time frame: 3 years
measure: Escalate dose up the maximum tolerated dose achieved, and initiate this as the recommended phase 2 dose of docetaxel and of cabazitaxel when it is combined with clarithromycin.
time frame: 3 years
measure: Compare docetaxel OR cabazitaxel exposure (maximal [Cmax] when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.
time frame: 3 years
measure: Compare docetaxel OR cabazitaxel exposure ( total [AUC]) when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.
time frame: 3 years
arm group label: Docetaxel and clarithromycin combination
arm group type: Active Comparator
description: Docetaxel will be administered by intravenous infusion over 1 hour every 3 weeks on day 1 of each (3 week) cycle for a total of 18 weeks.
Clarithromycin will be administered orally at 500mg twice a day for 3 days per cycle on days -1, 1, and 2.
arm group label: Cabazitaxel and clarithromycin combination
arm group type: Active Comparator
description: Cabazitaxel will be administered by intravenous infusion over 1 hour every 3 weeks on day 1 of each (3 week) cycle for a total of 18 weeks.
Clarithromycin will be administered orally at 500mg twice a day for 3 days per cycle on days -1, 1, and 2.
intervention type: Drug
intervention name: Docetaxel
description: 6 infusions of Docetaxel with 18 doses clarithromycin
arm group label: Docetaxel and clarithromycin combination
intervention type: Drug
intervention name: Cabazitaxel
description: 6 infusions of Cabazitaxel with 18 doses clarithromycin
arm group label: Cabazitaxel and clarithromycin combination
other name: JEVTANA
intervention type: Drug
intervention name: Clarithromycin
description: 18 doses of clarithromycin with either Docetaxel or Cabazitaxel
arm group label: Cabazitaxel and clarithromycin combination
arm group label: Docetaxel and clarithromycin combination
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael A Carducci, MD
role: Principal Investigator
affiliation: Johns Hopkins University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Clarithromycin
mesh term: Docetaxel
sharing ipd: No