<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/NCT03002493</url>
  </required_header>
  <id_info>
    <org_study_id>E7389-E044-111</org_study_id>
    <nct_id>NCT03002493</nct_id>
  </id_info>
  <brief_title>To Assess the Effect of Rifampicin on the Pharmacokinetics of Eribulin Mesylate in Participants With Advanced Solid Tumors</brief_title>
  <official_title>An Open-Label Phase I Study to Assess the Effect of Rifampicin on the Pharmacokinetics of Eribulin Mesylate (E7389) in Subjects With Advanced Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Eisai Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Eisai Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study was to assess the effect of cytochrome P450 3A4 enzyme&#xD;
      (CYP3A4) induction by rifampicin on the pharmacokinetics (PK) of eribulin mesylate following&#xD;
      intravenous (IV) administration in participants with advanced solid tumors. The secondary&#xD;
      objectives of this study were to assess the safety of eribulin mesylate when co-administered&#xD;
      with rifampicin and assess the safety and activity of eribulin mesylate as a single agent.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study consisted of 3 phases: Pre-Treatment, Treatment, and Extension. Pre-Treatment Phase&#xD;
      had 2 periods: Screening and Baseline. Treatment Phase consisted of intensive PK assessment&#xD;
      with eribulin mesylate given IV alone on Day 1 followed by eribulin mesylate given IV on Day&#xD;
      15 with rifampicin given orally from Days 9 to 20. Extension Phase allowed eribulin mesylate&#xD;
      treatment to continue for participants without progressive disease or unacceptable toxicity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2009</start_date>
  <completion_date type="Actual">June 2011</completion_date>
  <primary_completion_date type="Actual">February 2011</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>Best overall tumor response</measure>
    <time_frame>From signing of Informed consent until disease progression, undue toxicity, withdrawal by participant, at the discretion of the investigator or up to approximately 8 Months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the concentration-time curve from zero (pre-dose) extrapolated to infinite time (AUC 0-infinity) for eribulin mesylate +/- rifampicin</measure>
    <time_frame>Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 minute (min), and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum observed plasma concentration (Cmax) for eribulin mesylate +/- rifampicin</measure>
    <time_frame>Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the concentration-time curve from zero (pre-dose) to time of last quantifiable concentration (AUC 0-t) for eribulin mesylate</measure>
    <time_frame>Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Time of maximum observed plasma concentration (Tmax) for eribulin mesylate</measure>
    <time_frame>Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Half-life (t1/2) for eribulin mesylate</measure>
    <time_frame>Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Clearance (CL) for eribulin mesylate</measure>
    <time_frame>Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Volume of distribution at steady state (Vss) for eribulin mesylate</measure>
    <time_frame>Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with adverse events (AEs) and serious adverse events (SAEs) as a measure of safety</measure>
    <time_frame>From date of administration of first dose up to 30 days after the last dose of study treatment, up to approximately 8 months.</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Tumor</condition>
  <arm_group>
    <arm_group_label>Eribulin mesylate + Rifampicin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eribulin mesylate</intervention_name>
    <description>Treatment phase: During Cycle 1, eribulin mesylate was administered as a 2 to 5 minute (min) intravenous (IV) infusion at 1.4 mg/m2 on Day 1 and Day 15 of 21-day cycle. During subsequent cycles, eribulin mesylate administration as a 2 to 5 min IV infusion at 1.4 mg/m2 on Day 1 and Day 8 of a 21-day cycle.&#xD;
Extension phase: Eribulin mesylate was administered continuously as a 2 to 5 min IV infusion at 1.4 mg/m2 on Day 1 and Day 8 of 21-day cycles, as long as the Investigator considered eribulin mesylate therapy to be clinically appropriate.</description>
    <arm_group_label>Eribulin mesylate + Rifampicin</arm_group_label>
    <other_name>E7389</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eribulin mesylate</intervention_name>
    <arm_group_label>Eribulin mesylate + Rifampicin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampicin</intervention_name>
    <description>Treatment phase: Rifampicin 600 mg was administered orally once a day, from Day 9 to Day 20 of 28-day cycle of Cycle 1.</description>
    <arm_group_label>Eribulin mesylate + Rifampicin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically or cytologically confirmed advanced solid tumors that have progressed&#xD;
             following standard therapy or for which no standard therapy exists (including surgery&#xD;
             or radiation therapy)&#xD;
&#xD;
          2. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or&#xD;
             lower, except for stable sensory neuropathy and alopecia Grade 2&#xD;
&#xD;
          3. Age greater than or equal to 18 years&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2&#xD;
&#xD;
          5. Life expectancy of greater than or equal to 3 months&#xD;
&#xD;
          6. Adequate renal function as evidenced by serum creatinine less than or equal to 2.0&#xD;
             mg/dL (less than or equal to 176 umol/L) or calculated creatinine clearance greater&#xD;
             than or equal to 40 mL/minute per the Cockcroft and Gault formula&#xD;
&#xD;
          7. Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the&#xD;
             upper limit of normal (ULN) and alkaline phosphatase (ALP), alanine aminotransferase&#xD;
             (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times the ULN (in&#xD;
             the case of liver metastasis less than or equal to 5 times ULN). In the case ALP&#xD;
             greater than 3 times the ULN (in the absence of liver metastasis) or greater than 5&#xD;
             times the ULN (in the presence of liver metastasis), and the participant was also&#xD;
             known to have bone metastasis, the liver specific ALP were separated from the total&#xD;
             and used to assess the liver function instead of the total ALP&#xD;
&#xD;
          8. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater&#xD;
             than or equal to 1.5 x 109/L, hemoglobin greater than or equal to 10.0 g/dL or greater&#xD;
             than or equal to 6.2 mmol/L (hemoglobin less than 10.0 g/dL or less than 6.2 mmol/L&#xD;
             were acceptable if it were corrected by growth factor or transfusion), and platelets&#xD;
             greater than or equal to 100 x 109/L&#xD;
&#xD;
          9. Participants were willing and able to comply with the study protocol for the duration&#xD;
             of the study&#xD;
&#xD;
         10. Written informed consent were obtained prior to any study-specific screening&#xD;
             procedures with the understanding that the participant may withdraw consent at any&#xD;
             time without prejudice&#xD;
&#xD;
         11. Females of childbearing potential with a negative serum beta-Human chorionic&#xD;
             gonadotropin or a negative urine pregnancy test at Visit 1 (Screening) and prior to&#xD;
             starting study drug(s) (Visit 3). Female participants of childbearing potential who&#xD;
             agreed to be abstinent or to use a highly effective method of contraception (eg,&#xD;
             condom + spermicide, condom + diaphragm with spermicide, intrauterine device [IUD], or&#xD;
             have a vasectomised partner) starting prior to starting study drug, throughout the&#xD;
             entire study period and for 30 days after the last dose of study drug. Those women&#xD;
             using hormonal contraceptives must also have used an additional approved method of&#xD;
             contraception (as described previously). Perimenopausal women must be amenorrheic for&#xD;
             at least 12 months to be considered of non-childbearing potential&#xD;
&#xD;
         12. Male participants who were not abstinent or have not undergone a successful vasectomy,&#xD;
             who were partners of women of childbearing potential must have used, or their partners&#xD;
             must have used a highly effective method of contraception (eg, condom + spermicide,&#xD;
             condom + diaphragm with spermicide, IUD) starting prior to starting study drug(s) and&#xD;
             throughout the entire study period and for 30 days after the last dose of study drug.&#xD;
             Those with partners using hormonal contraceptives must also have used an additional&#xD;
             approved method of contraception (as described previously)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Hypersensitivity to halichondrin B and/or halichondrin B chemical derivatives or a&#xD;
             hypersensitivity to rifampicin&#xD;
&#xD;
          2. Prior participation in an eribulin clinical study, even if not previously assigned to&#xD;
             eribulin treatment&#xD;
&#xD;
          3. Preexisting neuropathy greater than Grade 2&#xD;
&#xD;
          4. Any of the following treatments within the specified period before eribulin treatment&#xD;
             starts:&#xD;
&#xD;
               1. chemotherapy, radiation or biological therapy within 2 weeks,&#xD;
&#xD;
               2. hormonal therapy within 1 week with the exception of prostate cancer patients who&#xD;
                  are on medical castration with a gonadotropin-releasing hormone analog,&#xD;
&#xD;
               3. any investigational drug within 4 weeks&#xD;
&#xD;
          5. Any medication, dietary supplements or other compounds or substances known to induce&#xD;
             or inhibit cytochrome P450 3A4 (CYP3A4) activity at the time the study starts&#xD;
&#xD;
          6. Presence of impaired intestinal absorption&#xD;
&#xD;
          7. Significant cardiovascular impairment such as history of congestive heart failure&#xD;
             greater than Grade II (New York Heart Association [NYHA]), unstable angina or&#xD;
             myocardial infarction within the past 6 months, or serious cardiac arrhythmia&#xD;
&#xD;
          8. Clinically significant electrocardiograms (ECGs) abnormality, including a marked&#xD;
             baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval&#xD;
             greater than 500 msec)&#xD;
&#xD;
          9. Known positive human immunodeficiency virus (HIV) status&#xD;
&#xD;
         10. Brain or subdural metastases, unless they had completed local therapy and had&#xD;
             discontinued the use of corticosteroids for this indication for at least 4 weeks&#xD;
             before starting treatment with eribulin&#xD;
&#xD;
         11. Presence of meningeal carcinomatosis&#xD;
&#xD;
         12. Any history of or concomitant medical condition that, in the opinion of the&#xD;
             Investigator, that would have compromise the participant's ability to safely complete&#xD;
             the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Netherlands Cancer Institute</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Utrecht</name>
      <address>
        <city>Utrecht</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>December 21, 2016</study_first_submitted>
  <study_first_submitted_qc>December 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <last_update_submitted>March 13, 2017</last_update_submitted>
  <last_update_submitted_qc>March 13, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 15, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Rifampicin</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Eribulin Mesylate</keyword>
  <keyword>E7389</keyword>
  <keyword>Advanced Solid Tumors</keyword>
  <keyword>Tumors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</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/NCT03002493
org study id: E7389-E044-111
nct id: NCT03002493
lead sponsor: 
has dmc: No
The primary objective of this study was to assess the effect of cytochrome P450 3A4 enzyme
      (CYP3A4) induction by rifampicin on the pharmacokinetics (PK) of eribulin mesylate following
      intravenous (IV) administration in participants with advanced solid tumors. The secondary
      objectives of this study were to assess the safety of eribulin mesylate when co-administered
      with rifampicin and assess the safety and activity of eribulin mesylate as a single agent.
The study consisted of 3 phases: Pre-Treatment, Treatment, and Extension. Pre-Treatment Phase
      had 2 periods: Screening and Baseline. Treatment Phase consisted of intensive PK assessment
      with eribulin mesylate given IV alone on Day 1 followed by eribulin mesylate given IV on Day
      15 with rifampicin given orally from Days 9 to 20. Extension Phase allowed eribulin mesylate
      treatment to continue for participants without progressive disease or unacceptable toxicity.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Best overall tumor response
time frame: From signing of Informed consent until disease progression, undue toxicity, withdrawal by participant, at the discretion of the investigator or up to approximately 8 Months
measure: Area under the concentration-time curve from zero (pre-dose) extrapolated to infinite time (AUC 0-infinity) for eribulin mesylate +/- rifampicin
time frame: Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 minute (min), and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
measure: Maximum observed plasma concentration (Cmax) for eribulin mesylate +/- rifampicin
time frame: Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
measure: Area under the concentration-time curve from zero (pre-dose) to time of last quantifiable concentration (AUC 0-t) for eribulin mesylate
time frame: Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
measure: Time of maximum observed plasma concentration (Tmax) for eribulin mesylate
time frame: Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
measure: Half-life (t1/2) for eribulin mesylate
time frame: Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
measure: Clearance (CL) for eribulin mesylate
time frame: Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
measure: Volume of distribution at steady state (Vss) for eribulin mesylate
time frame: Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
measure: Number of participants with adverse events (AEs) and serious adverse events (SAEs) as a measure of safety
time frame: From date of administration of first dose up to 30 days after the last dose of study treatment, up to approximately 8 months.
arm group label: Eribulin mesylate + Rifampicin
arm group type: Experimental
intervention type: Drug
intervention name: Eribulin mesylate
description: Treatment phase: During Cycle 1, eribulin mesylate was administered as a 2 to 5 minute (min) intravenous (IV) infusion at 1.4 mg/m2 on Day 1 and Day 15 of 21-day cycle. During subsequent cycles, eribulin mesylate administration as a 2 to 5 min IV infusion at 1.4 mg/m2 on Day 1 and Day 8 of a 21-day cycle.
Extension phase: Eribulin mesylate was administered continuously as a 2 to 5 min IV infusion at 1.4 mg/m2 on Day 1 and Day 8 of 21-day cycles, as long as the Investigator considered eribulin mesylate therapy to be clinically appropriate.
arm group label: Eribulin mesylate + Rifampicin
other name: E7389
intervention type: Drug
intervention name: Eribulin mesylate
arm group label: Eribulin mesylate + Rifampicin
intervention type: Drug
intervention name: Rifampicin
description: Treatment phase: Rifampicin 600 mg was administered orally once a day, from Day 9 to Day 20 of 28-day cycle of Cycle 1.
arm group label: Eribulin mesylate + Rifampicin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Rifampin