<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/NCT04498702</url>
  </required_header>
  <id_info>
    <org_study_id>YHCT-1</org_study_id>
    <nct_id>NCT04498702</nct_id>
  </id_info>
  <brief_title>Study of Continuous APL-1202 Treatment in Subjects With High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) Relapsed From Intravesical Chemo/BCG Therapy</brief_title>
  <official_title>A Phase II Single-Arm, Open-Label, Multi-Center Study of Continuous APL-1202 Treatment in Subjects With High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) Relapsed From Intravesical Chemo/BCG Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jiangsu Yahong Meditech Co., Ltd aka Asieris</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Jiangsu Yahong Meditech Co., Ltd aka Asieris</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine the efficacy of oral APL-1202 administered consecutively for 12 weeks in&#xD;
      subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy based on the&#xD;
      recurrence-free rate (RFR) at 12 months after APL-1202 treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This trial was a single-arm, open-label, multi-center clinical study consisting of two&#xD;
      periods: the dose-escalation and treatment period, and the follow-up and maintenance period.&#xD;
&#xD;
      Dose-Escalation and Treatment Period APL-1202 was orally administered TID daily and&#xD;
      continuously for 12 weeks. APL-1202 dose was increased from daily 300, 450, 600 to 750mg or&#xD;
      maximum tolerated dose (MTD).&#xD;
&#xD;
      A modified 3+3 design was employed: The dose was started at 300 mg and increased to 450 mg,&#xD;
      600 mg and 750 mg if there was no dose-limiting toxicity (DLT) in 3 subjects after 4-week&#xD;
      consecutive administration of APL-1202. When the dose-escalation study was in progress, the&#xD;
      doses for any newly enrolled subjects would be the starting dose or the highest dose&#xD;
      confirmed with no DLT by the dose-escalation cohort at the time of enrollment. When the MTD&#xD;
      or the 750 mg daily dose was attained as a safe dose, the dose for all subjects in the study&#xD;
      or subsequently enrolled subjects would be MTD or 750 mg/day.&#xD;
&#xD;
      Follow-up and Maintenance Period APL-1202 was orally administered at the highest safe dose&#xD;
      proven by the dose-escalation cohort, continuously for 3 months; This period was 12 months.&#xD;
      To fit the 3-month cystoscopy follow-up schedule, the maintenance therapy, starting from&#xD;
      3-month off, was given continuously every other 3 months, resulting in 6 months of dosing in&#xD;
      total.&#xD;
&#xD;
      APL-1202 daily administration schedule:&#xD;
&#xD;
      The first dose: within 30 minutes after breakfast; The second dose: within 30 minutes after&#xD;
      lunch, and there should be a 4-hour interval between the first and second doses; The third&#xD;
      dose: taken with a light snack at night before going to bed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 13, 2014</start_date>
  <completion_date type="Actual">January 18, 2017</completion_date>
  <primary_completion_date type="Actual">January 18, 2017</primary_completion_date>
  <phase>Phase 2</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>Recurrence-free rate (RFR) at the end of 12-month follow-up in subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy.</measure>
    <time_frame>12 months</time_frame>
    <description>Recurrence-free rate (RFR) at the end of 12-month follow-up in subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Recurrence-free survival (RFS)</measure>
    <time_frame>12 months</time_frame>
    <description>Recurrence-free survival (RFS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS).</measure>
    <time_frame>12 months</time_frame>
    <description>progression-free survival (PFS).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The safety and tolerability of APL-1202.</measure>
    <time_frame>12 months</time_frame>
    <description>Post-medication safety assessment included laboratory parameters, physical examination, vital signs, performance status score, and AEs. Frequency and severity of AEs were rated in accordance with internationally agreed NCI CTC AE4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Max Concentration - APL-1202 and its metabolites</measure>
    <time_frame>Day 28</time_frame>
    <description>PK measurement expressed as maximum plasma concentration for APL-1202 and metabolites</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Steady state Concentration - APL-1202 and its metabolites</measure>
    <time_frame>Day 28</time_frame>
    <description>PK measurement expressed as Steady state Concentration for plasma APL-1202 and its metabolites</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Area Under Curve - APL-1202 and its metabolites</measure>
    <time_frame>Day 28</time_frame>
    <description>PK measurement expressed as area under curve for plasma APL-1202 and its metabolites</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urinary excreted amounts- APL-1202 and its metabolites</measure>
    <time_frame>Day 28</time_frame>
    <description>PK measurement expressed as Urinary excreted amounts for APL-1202 and its metabolites</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative urinary excreted amounts- APL-1202 and its metabolites</measure>
    <time_frame>Day 28</time_frame>
    <description>PK measurement expressed as Cumulative Urinary excreted amounts for APL-1202 and its metabolites</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative fraction of dose- APL-1202 and its metabolites</measure>
    <time_frame>Day 28</time_frame>
    <description>PK measurement expressed as Cumulative fraction of dose for APL-1202 and its metabolites</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The SNV(single-nucleotide variant) patterns of bladder cancer related genes in pre- and post-treatment plasma ctDNA (circulating tumor DNA) through targeted amplicon sequencing</measure>
    <time_frame>12 months</time_frame>
    <description>Blood ctDNA were extracted from the patients before APL-1202 treatment or after APL-1202 treatment; somatic SNV were detected by targeted amplicon sequencing. Evaluation of RFR (Recurrence-free rate), RFS (Recurrence-free survival), PFS (Progression-free survival) and baseline SNV will be performed using cox regression survival model.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The InDel (insertion-deletion) patterns of bladder cancer related genes in pre- and post-treatment plasma ctDNA (circulating tumor DNA) through targeted amplicon sequencing</measure>
    <time_frame>12 months</time_frame>
    <description>Blood ctDNA were extracted from the patients before APL-1202 treatment or after APL-1202 treatment; somatic InDel were detected by targeted amplicon sequencing. Evaluation of RFR (Recurrence-free rate), RFS (Recurrence-free survival), PFS (Progression-free survival) and baseline InDel will be performed using cox regression survival model.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Non-muscle Invasive Bladder Cancer</condition>
  <arm_group>
    <arm_group_label>APL-1202 treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>APL-1202 treatment</intervention_name>
    <description>A modified 3+3 design was employed: The dose was started at 300 mg and increased to 450 mg, 600 mg and 750 mg if there was no dose-limiting toxicity (DLT) in 3 subjects after 4-week consecutive administration of APL-1202. When the dose-escalation study was in progress, the doses for any newly enrolled subjects would be the starting dose or the highest dose confirmed with no DLT by the dose-escalation cohort at the time of enrollment. When the MTD or the 750 mg daily dose was attained as a safe dose, the dose for all subjects in the study or subsequently enrolled subjects would be MTD or 750 mg/day.</description>
    <arm_group_label>APL-1202 treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Well-informed with this trial and willing to sign the informed consent form;&#xD;
&#xD;
          2. Subjects have been clinically and histologically proven as relapsed high-risk&#xD;
             non-muscle-invasive urothelial carcinoma of the bladder through clinical cystoscopy,&#xD;
             urine cytology and pathological examination within 28 days before the enrollment;&#xD;
             Subjects who met the high-risk definition in EAU Guidelines on Non-Muscle-Invasive&#xD;
             Bladder Cancer (2012 Edition), including those who met the high-risk definition in&#xD;
             current or any previous recurrence or primary diseases; Papillary carcinomas may or&#xD;
             may not include Cis; All papillary carcinoma subjects with no visible tumor after&#xD;
             transurethral resection of bladder tumor (TURBT); May include Cis subjects with&#xD;
             visible tumors remaining after TURBT;&#xD;
&#xD;
          3. Past treatment history:&#xD;
&#xD;
             Chemo-relapsed subgroup: the subjects who should have had intravesical chemotherapy in&#xD;
             the 3 years prior to enrollment, but could not undergo any BCG therapy; BCG-relapsed&#xD;
             subgroup: the subjects who should have had intravesical BCG treatment in the 3 years&#xD;
             prior to enrollment, prior intravesical chemotherapy is allowed;&#xD;
&#xD;
          4. Subjects with treatment failure included:&#xD;
&#xD;
             Subjects with recurrence after at least one intravesical course; BCG-relapsed subjects&#xD;
             might include those intolerable to intravesical BCG therapy; Subjects with tumor grade&#xD;
             progression after intravesical therapy;&#xD;
&#xD;
          5. The subject is willing to provide cystoscopic biopsy specimens for assessment&#xD;
&#xD;
          6. Age ≥ 18 years, male or female;&#xD;
&#xD;
          7. Performance status score (ECOG scale) ≤ 1 (0-1), and did not deteriorate within 7&#xD;
             days;&#xD;
&#xD;
          8. The subject must have normal organ and bone marrow functions within 28 days prior to&#xD;
             enrollment into the study (based on normal range measured by the clinical site):&#xD;
&#xD;
             ANC &gt; 1.0×109 /L; Platelet count &gt; 100×109 /L; Hemoglobin &gt; 9.0 g/dL; ALP &lt; 2.5 times&#xD;
             upper limit of normal range (should be less than 10 times upper limit of normal range&#xD;
             if at the presence of bone metastasis); GFR (calculated using Cockcroft-Gault formula)&#xD;
             ≥ 50 mL/min; INR &lt; 1.5, except subjects who was undergoing Warfarin treatment at the&#xD;
             time of screening.&#xD;
&#xD;
          9. Subjects who were receiving other medications with known or potential effects on the&#xD;
             efficacy or pharmacokinetics of nitroxoline should be assessed and determined by the&#xD;
             principal investigator.&#xD;
&#xD;
         10. Female subjects must be surgically sterilized or menopaused or must agree to take&#xD;
             effective contraceptive measures during the treatment. Male subjects must be&#xD;
             surgically sterilized or must agree to take effective contraceptive measures during&#xD;
             treatment. Subjects must continue to take contraceptive measures for 3 months after&#xD;
             the investigational therapy was completed. Definition of an effective contraceptive&#xD;
             measure should be determined at the discretion of the principal investigator or any&#xD;
             investigator appointed by the principal investigator.&#xD;
&#xD;
         11. Life expectancy is over 12 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. TBIL, ALT or AST exceeded 1.5 times upper limit of the normal range (based on the&#xD;
             normal range determined by the clinical site);&#xD;
&#xD;
          2. Upper tract urothelial carcinoma;&#xD;
&#xD;
          3. Subjects who had systemic chemotherapy on bladder carcinoma in the past;&#xD;
&#xD;
          4. Subject who had undergone any surgical procedure (excluding TURBT or cystoscopy),&#xD;
             radiotherapy or systemic chemotherapy within 4 weeks prior to enrollment;&#xD;
&#xD;
          5. Grade 3 hemorrhage as per NCI CTCAE 4.0 occurred within 4 weeks prior to enrollment;&#xD;
&#xD;
          6. Any of the following conditions occurred within 6 months prior to enrollment:&#xD;
             myocardial infarction, serious/unstable angina, coronary/peripheral artery bypass&#xD;
             graft, symptomatic congestive heart failure, cerebrovascular accident or transient&#xD;
             ischemic attack, or pulmonary embolism;&#xD;
&#xD;
          7. Regardless of antihypertensive medication, systolic blood pressure ≥ 140 mmHg and/or&#xD;
             diastolic blood pressure ≥ 90 mmHg;&#xD;
&#xD;
          8. Subjects having a malignancy history within 2 years, except cured basal cell&#xD;
             carcinoma, squamous cell skin cancer or cervical carcinoma &quot;in situ&quot;;&#xD;
&#xD;
          9. Subjects with any optic nerve disorder or having a history of optic nerve disorders;&#xD;
&#xD;
         10. Subjects with clinically uncontrolled active infections such as acute pneumonia,&#xD;
             immunoactive phase of hepatitis B, etc.;&#xD;
&#xD;
         11. Subjects with dysphagia or any known drug absorption disorder;&#xD;
&#xD;
         12. Subjects with anuria;&#xD;
&#xD;
         13. Subjects with any active digestive disease such as duodenal ulcer and ulcerative&#xD;
             colitis or any other conditions potentially leading to gastrointestinal hemorrhage or&#xD;
             perforation as identified by the investigator;&#xD;
&#xD;
         14. The investigator deemed that a subject might have increased risk for the study or&#xD;
             medication or had any other serious acute or chronic medical conditions potentially&#xD;
             interfering with interpretation and judgment of study results;&#xD;
&#xD;
         15. Any pregnant or breastfeeding woman or any woman with a positive pregnancy test&#xD;
             results prior to the first medication;&#xD;
&#xD;
         16. Subjects having a serious mental disorder with compliance concern in this clinical&#xD;
             study;&#xD;
&#xD;
         17. Subjects participating in any other clinical drug trial in the past 4 weeks.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dingwei Ye, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fudan University</affiliation>
  </overall_official>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 31, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2020</study_first_posted>
  <last_update_submitted>August 12, 2020</last_update_submitted>
  <last_update_submitted_qc>August 12, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2020</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>Urinary Bladder Neoplasms</mesh_term>
    <mesh_term>Non-Muscle Invasive Bladder Neoplasms</mesh_term>
  </condition_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/NCT04498702
org study id: YHCT-1
nct id: NCT04498702
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
To determine the efficacy of oral APL-1202 administered consecutively for 12 weeks in
      subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy based on the
      recurrence-free rate (RFR) at 12 months after APL-1202 treatment.
This trial was a single-arm, open-label, multi-center clinical study consisting of two
      periods: the dose-escalation and treatment period, and the follow-up and maintenance period.

      Dose-Escalation and Treatment Period APL-1202 was orally administered TID daily and
      continuously for 12 weeks. APL-1202 dose was increased from daily 300, 450, 600 to 750mg or
      maximum tolerated dose (MTD).

      A modified 3+3 design was employed: The dose was started at 300 mg and increased to 450 mg,
      600 mg and 750 mg if there was no dose-limiting toxicity (DLT) in 3 subjects after 4-week
      consecutive administration of APL-1202. When the dose-escalation study was in progress, the
      doses for any newly enrolled subjects would be the starting dose or the highest dose
      confirmed with no DLT by the dose-escalation cohort at the time of enrollment. When the MTD
      or the 750 mg daily dose was attained as a safe dose, the dose for all subjects in the study
      or subsequently enrolled subjects would be MTD or 750 mg/day.

      Follow-up and Maintenance Period APL-1202 was orally administered at the highest safe dose
      proven by the dose-escalation cohort, continuously for 3 months; This period was 12 months.
      To fit the 3-month cystoscopy follow-up schedule, the maintenance therapy, starting from
      3-month off, was given continuously every other 3 months, resulting in 6 months of dosing in
      total.

      APL-1202 daily administration schedule:

      The first dose: within 30 minutes after breakfast; The second dose: within 30 minutes after
      lunch, and there should be a 4-hour interval between the first and second doses; The third
      dose: taken with a light snack at night before going to bed.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recurrence-free rate (RFR) at the end of 12-month follow-up in subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy.
time frame: 12 months
description: Recurrence-free rate (RFR) at the end of 12-month follow-up in subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy.
measure: Recurrence-free survival (RFS)
time frame: 12 months
description: Recurrence-free survival (RFS)
measure: Progression-free survival (PFS).
time frame: 12 months
description: progression-free survival (PFS).
measure: The safety and tolerability of APL-1202.
time frame: 12 months
description: Post-medication safety assessment included laboratory parameters, physical examination, vital signs, performance status score, and AEs. Frequency and severity of AEs were rated in accordance with internationally agreed NCI CTC AE4.0.
measure: Plasma Max Concentration - APL-1202 and its metabolites
time frame: Day 28
description: PK measurement expressed as maximum plasma concentration for APL-1202 and metabolites
measure: Plasma Steady state Concentration - APL-1202 and its metabolites
time frame: Day 28
description: PK measurement expressed as Steady state Concentration for plasma APL-1202 and its metabolites
measure: Plasma Area Under Curve - APL-1202 and its metabolites
time frame: Day 28
description: PK measurement expressed as area under curve for plasma APL-1202 and its metabolites
measure: Urinary excreted amounts- APL-1202 and its metabolites
time frame: Day 28
description: PK measurement expressed as Urinary excreted amounts for APL-1202 and its metabolites
measure: Cumulative urinary excreted amounts- APL-1202 and its metabolites
time frame: Day 28
description: PK measurement expressed as Cumulative Urinary excreted amounts for APL-1202 and its metabolites
measure: Cumulative fraction of dose- APL-1202 and its metabolites
time frame: Day 28
description: PK measurement expressed as Cumulative fraction of dose for APL-1202 and its metabolites
measure: The SNV(single-nucleotide variant) patterns of bladder cancer related genes in pre- and post-treatment plasma ctDNA (circulating tumor DNA) through targeted amplicon sequencing
time frame: 12 months
description: Blood ctDNA were extracted from the patients before APL-1202 treatment or after APL-1202 treatment; somatic SNV were detected by targeted amplicon sequencing. Evaluation of RFR (Recurrence-free rate), RFS (Recurrence-free survival), PFS (Progression-free survival) and baseline SNV will be performed using cox regression survival model.
measure: The InDel (insertion-deletion) patterns of bladder cancer related genes in pre- and post-treatment plasma ctDNA (circulating tumor DNA) through targeted amplicon sequencing
time frame: 12 months
description: Blood ctDNA were extracted from the patients before APL-1202 treatment or after APL-1202 treatment; somatic InDel were detected by targeted amplicon sequencing. Evaluation of RFR (Recurrence-free rate), RFS (Recurrence-free survival), PFS (Progression-free survival) and baseline InDel will be performed using cox regression survival model.
arm group label: APL-1202 treatment
arm group type: Experimental
intervention type: Drug
intervention name: APL-1202 treatment
description: A modified 3+3 design was employed: The dose was started at 300 mg and increased to 450 mg, 600 mg and 750 mg if there was no dose-limiting toxicity (DLT) in 3 subjects after 4-week consecutive administration of APL-1202. When the dose-escalation study was in progress, the doses for any newly enrolled subjects would be the starting dose or the highest dose confirmed with no DLT by the dose-escalation cohort at the time of enrollment. When the MTD or the 750 mg daily dose was attained as a safe dose, the dose for all subjects in the study or subsequently enrolled subjects would be MTD or 750 mg/day.
arm group label: APL-1202 treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dingwei Ye, MD,PhD
role: Principal Investigator
affiliation: Fudan University
responsible party type: Sponsor
mesh term: Urinary Bladder Neoplasms
mesh term: Non-Muscle Invasive Bladder Neoplasms
sharing ipd: No