<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/NCT04457180</url>
  </required_header>
  <id_info>
    <org_study_id>HR-APTN-I-008</org_study_id>
    <nct_id>NCT04457180</nct_id>
  </id_info>
  <brief_title>A Pharmacokinetic Interaction Study Between Apatinib Mesylate and Repaglinide or Bupropion in Advanced Solid Tumor Subjects</brief_title>
  <official_title>A Single Arm, Open and Fixed Sequence Study to Investigate the Pharmacokinetic Effects of Apatinib Mesylate on CYP2C8 Substrate Repaglinide or CYP2B6 Substrate in Advanced Solid Tumor Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jiangsu HengRui Medicine Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Jiangsu HengRui Medicine Co., Ltd.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of the study was to assess investigate the pharmacokinetic effects of&#xD;
      Apatinib Mesylate on CYP2C8 Substrate Repaglinide or CYP2B6 Substrate Bupropion and&#xD;
      metabolite Hydroxy bupropion in Advanced solid tumor subjects.&#xD;
&#xD;
      The secondary objective of the study was to assess the safety of Apatinib or/and Repaglinide&#xD;
      and Bupropion.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 16, 2020</start_date>
  <completion_date type="Actual">June 19, 2021</completion_date>
  <primary_completion_date type="Actual">May 20, 2021</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>Pharmacokinetics parameter: Cmax of digoxin</measure>
    <time_frame>through study completion, an average of 16 days</time_frame>
    <description>Peak Plasma Concentration (Cmax) of digoxin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetics parameter: AUC of digoxin</measure>
    <time_frame>through study completion, an average of 16 days</time_frame>
    <description>Area under the plasma concentration versus time curve (AUC) of digoxin</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics parameter: Tmax of digoxin</measure>
    <time_frame>through study completion, an average of 16 days</time_frame>
    <description>Time of maximum observed concentration (Tmax) of digoxin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics parameter: T1/2 of digoxin</measure>
    <time_frame>through study completion, an average of 16 days</time_frame>
    <description>Half time (T1/2) of digoxin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters CL/F of digoxin</measure>
    <time_frame>through study completion, an average of 16 days</time_frame>
    <description>Total body clearance for extravascular administration (CL/F) of digoxin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics parameter: Vz/F of digoxin</measure>
    <time_frame>through study completion, an average of 16 days</time_frame>
    <description>Volume of distribution (Vz/F) of digoxin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v5.0</measure>
    <time_frame>through study completion, an average of 16 days</time_frame>
    <description>An adverse event is any untoward medical occurrence in a patient or clinical study participant criteria</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Advanced Solid Tumor</condition>
  <arm_group>
    <arm_group_label>treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In phase A, subjects receiving a single dose of Repaglinide orally on day 1 , a single dose of Bupropion orally on day 2 and wash-out for 10 days, then apatinib once daily will be conducted on D5 through D16&#xD;
# In addition, In phase B, subjects receiving a single dose of Repaglinide (in combination with apatinib) orally on day 12 , a single dose of Bupropion (in combination with apatinib) orally on day 13.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apatinib Mesylate</intervention_name>
    <description>Apatinib will be administered daily from on D5 through D16</description>
    <arm_group_label>treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Repaglinide</intervention_name>
    <description>Repaglinide will be administered daily on D1 and D12</description>
    <arm_group_label>treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupropion</intervention_name>
    <description>Bupropion will be administered daily on D2 and D13</description>
    <arm_group_label>treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age: 18-70 years old (Include both values).&#xD;
&#xD;
          2. Patients with histopathologically or cytologically confirmed advanced solid tumor (not&#xD;
             necessary to have measurable lesions).&#xD;
&#xD;
          3. Refractory or intolerant to standard treatment regimens, or no effective standard&#xD;
             treatment regimens available, or the patients refused to use standard treatment plan.&#xD;
&#xD;
          4. ECOG PS score: 0-1.&#xD;
&#xD;
          5. Expected survival ≥ 3 months.&#xD;
&#xD;
          6. Subjects have recovered from other treatments, at least 6 weeks since the last use of&#xD;
             nitrosourea or mitomycin; at least 4 weeks since the last use of small molecule&#xD;
             targeted therapy; at least 8 weeks since the last use of biological macromolecular&#xD;
             therapy; at least 4 weeks since radiotherapy or surgery; at least 4 weeks since the&#xD;
             last use of other cytotoxic or cytostatic drugs.&#xD;
&#xD;
          7. Major organs must function normally, meeting the following criteria: (1) Hematology&#xD;
             (no blood transfusion or blood products within the last 14 days, not corrected with&#xD;
             G-CSF or other hematopoietic colony-stimulating factors):&#xD;
&#xD;
             a. HB≥100 g/L; b. ANC≥1.5×109/L; c. PLT≥90×109/L; (2) Blood biochemistry: d. TBIL≤&#xD;
             1.25×ULN; e. ALT and AST≤2.5×ULN; f. ALP≤2.5×ULN; g. Serum Cr ≤ 1.5 × ULN or&#xD;
             endogenous CrCl &gt; 60 mL/min (Cockcroft-Gault formula); h. Albumin &gt; 30 g/L.&#xD;
&#xD;
          8. Sign the ICF voluntarily, have good compliance, corporate with follow-up visits, and&#xD;
             follow the study requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Gastric cancer; tumors with risk of bleeding which researchers evaluated.&#xD;
&#xD;
          2. Active brain metastasis (medically uncontrolled);&#xD;
&#xD;
          3. Symptomatic third space fluid that cannot be controlled by drainage or other methods;&#xD;
&#xD;
          4. Dysphagia, chronic diarrhea, or other factors affecting drug intake and absorption;&#xD;
&#xD;
          5. Uncontrolled hypertension;&#xD;
&#xD;
          6. Heart rate &lt; 60, Grade II or greater myocardial ischemia or myocardial infarction,&#xD;
             uncontrolled arrhythmias (QTc interval ≥ 450 ms in males and ≥ 470 ms in females);&#xD;
&#xD;
          7. Contraindications to Repaglinide and Bupropion;&#xD;
&#xD;
          8. NYHA Class III-IV cardiac insufficiency or left ventricular ejection fraction (LVEF) &lt;&#xD;
             50% by echocardiography;&#xD;
&#xD;
          9. Abnormal coagulation function (INR &gt; 1.5 or prothrombin time (PT) &gt; ULN + 4 s or APTT&#xD;
             &gt; 1.5 ULN), bleeding tendency or who are currently receiving thrombolytics;&#xD;
&#xD;
         10. Arterial/venous thrombosis within 6 months prior to the first dose;&#xD;
&#xD;
         11. Hemorrhage and thrombophilia;&#xD;
&#xD;
         12. Major surgery or with severe traumatic injury, fracture, or ulcer within 4 weeks prior&#xD;
             to the first dose;&#xD;
&#xD;
         13. Abdominal fistula, gastrointestinal perforation or abdominal abscess within 6 months&#xD;
             prior to the first dose;&#xD;
&#xD;
         14. Urine protein ≥ ++ and 24 h urine protein ≥ 1.0 g as indicated by urinalysis;&#xD;
&#xD;
         15. Treatment with steroids for more than 50 days, or requires chronic steroid use;&#xD;
&#xD;
         16. Use of study drugs in other clinical trials within 4 weeks prior to the first dose;&#xD;
&#xD;
         17. Use of drugs affected gastric acid secretion or inhibitors of cytochrome enzyme&#xD;
             CYP2C8、CYP2B6、CYP2D6、CYP3A or transporter OATP1B1, or traditional Chinese medicine&#xD;
             within 2 weeks prior to the first dose; use of inducers of metabolic enzymes CYP2C8,&#xD;
             CYP2B6, CYP2D6, or CYP3A within 4 weeks prior to the first dose;&#xD;
&#xD;
         18. Unable to hold drugs that may prolong QT interval during the study (such as&#xD;
             antiarrhythmics);&#xD;
&#xD;
         19. Habitual alcohol consumption or smoking, tested positive for alcohol screening, and&#xD;
             unable to abstain from smoking and alcohol during the trial;&#xD;
&#xD;
         20. Other factors affecting drug absorption, distribution, metabolism, excretion within 48&#xD;
             hours；&#xD;
&#xD;
         21. Active hepatitis B (positive HBsAg and HBV-DNA≥104 or 2000IU/ml) or C (Hepatitis C&#xD;
             antibodies are positive and HCV-RNA is above the detection limit of the analytical&#xD;
             method);&#xD;
&#xD;
         22. Active infection requiring antimicrobial therapies (such as antibacterials,&#xD;
             antivirals, or antifungals);&#xD;
&#xD;
         23. Immunodeficiency, including positive results of HIV test or other acquired or&#xD;
             congenital immunodeficiencies, or a history of organ transplantation;&#xD;
&#xD;
         24. Allergic constitution, or known allergies to drug components used in this study;&#xD;
&#xD;
         25. Pregnant or lactating women;&#xD;
&#xD;
         26. Other factors that may affect the progress or the conclusion of the study, as&#xD;
             determined by the investigator.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>pan yueyin, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>The First Affiliated Hospital of University of Science and Technology of China</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The First Affiliated Hospital of University of Science and Technology of China</name>
      <address>
        <city>Hefei</city>
        <state>Anhui</state>
        <zip>201203</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>June 30, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>October 24, 2022</last_update_submitted>
  <last_update_submitted_qc>October 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 26, 2022</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>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Repaglinide</mesh_term>
    <mesh_term>Apatinib</mesh_term>
    <mesh_term>Bupropion</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04457180
org study id: HR-APTN-I-008
nct id: NCT04457180
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The primary objective of the study was to assess investigate the pharmacokinetic effects of
      Apatinib Mesylate on CYP2C8 Substrate Repaglinide or CYP2B6 Substrate Bupropion and
      metabolite Hydroxy bupropion in Advanced solid tumor subjects.

      The secondary objective of the study was to assess the safety of Apatinib or/and Repaglinide
      and Bupropion.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pharmacokinetics parameter: Cmax of digoxin
time frame: through study completion, an average of 16 days
description: Peak Plasma Concentration (Cmax) of digoxin
measure: Pharmacokinetics parameter: AUC of digoxin
time frame: through study completion, an average of 16 days
description: Area under the plasma concentration versus time curve (AUC) of digoxin
measure: Pharmacokinetics parameter: Tmax of digoxin
time frame: through study completion, an average of 16 days
description: Time of maximum observed concentration (Tmax) of digoxin
measure: Pharmacokinetics parameter: T1/2 of digoxin
time frame: through study completion, an average of 16 days
description: Half time (T1/2) of digoxin
measure: Pharmacokinetic parameters CL/F of digoxin
time frame: through study completion, an average of 16 days
description: Total body clearance for extravascular administration (CL/F) of digoxin
measure: Pharmacokinetics parameter: Vz/F of digoxin
time frame: through study completion, an average of 16 days
description: Volume of distribution (Vz/F) of digoxin
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
time frame: through study completion, an average of 16 days
description: An adverse event is any untoward medical occurrence in a patient or clinical study participant criteria
arm group label: treatment
arm group type: Experimental
description: In phase A, subjects receiving a single dose of Repaglinide orally on day 1 , a single dose of Bupropion orally on day 2 and wash-out for 10 days, then apatinib once daily will be conducted on D5 through D16
# In addition, In phase B, subjects receiving a single dose of Repaglinide (in combination with apatinib) orally on day 12 , a single dose of Bupropion (in combination with apatinib) orally on day 13.
intervention type: Drug
intervention name: Apatinib Mesylate
description: Apatinib will be administered daily from on D5 through D16
arm group label: treatment
intervention type: Drug
intervention name: Repaglinide
description: Repaglinide will be administered daily on D1 and D12
arm group label: treatment
intervention type: Drug
intervention name: Bupropion
description: Bupropion will be administered daily on D2 and D13
arm group label: treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: pan yueyin, Ph.D.
role: Principal Investigator
affiliation: The First Affiliated Hospital of University of Science and Technology of China
facility: 
country: China
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Repaglinide
mesh term: Apatinib
mesh term: Bupropion
sharing ipd: Undecided