<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/NCT02992340</url>
  </required_header>
  <id_info>
    <org_study_id>ASLAN001-007</org_study_id>
    <nct_id>NCT02992340</nct_id>
  </id_info>
  <brief_title>Varlitinib in Combination With Gemcitabine and Cisplatin for Treatment naïve Advanced or Metastatic BTC</brief_title>
  <official_title>A Multicentre, Phase 1B/2 Study of Varlitinib in Combination With Gemcitabine and Cisplatin for Treatment naïve Advanced or Metastatic Biliary Tract Cancer.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ASLAN Pharmaceuticals</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>ASLAN Pharmaceuticals</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study intends to evaluate the following objectives in patients with advanced or&#xD;
      metastatic biliary tract cancer who have not received systemic therapy for&#xD;
      advanced/metastatic disease.&#xD;
&#xD;
      Primary Objectives:&#xD;
&#xD;
      Phase 1B&#xD;
&#xD;
        -  To determine the maximum tolerated dose (MTD), as determined by dose-limiting toxicities&#xD;
           (DLTs), and to characterise the safety profile of Varlitinib in combination with&#xD;
           Gemcitabine and Cisplatin.&#xD;
&#xD;
      Phase 2A&#xD;
&#xD;
        -  To further evaluate the safety and tolerability of Varlitinib in combination with&#xD;
           Gemcitabine and Cisplatin at the recommended phase 2 dose (RP2D).&#xD;
&#xD;
        -  To provide a preliminary assessment of the clinical activity of Varlitinib in&#xD;
           combination with Gemcitabine and Cisplatin at the RP2D as measured by Objective Response&#xD;
           Rate (ORR) and progression-free survival (PFS) (based on RECIST v1.1)&#xD;
&#xD;
      Phase 2B&#xD;
&#xD;
        -  To compare the efficacy of Varlitinib in combination with Gemcitabine and Cisplatin to&#xD;
           placebo in combination with Gemcitabine and Cisplatin as measured by progression-free&#xD;
           survival (based on RECIST v1.1).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In phase 1B part, patients will receive Varlitinib plus Gemcitabine and Cisplatin, and follow&#xD;
      a modified 3+3+3 study dose escalation scheme starting from Varlitinib 200 mg BID. The&#xD;
      primary objective of the phase 1B part is to determine the MTD of Varlitinib when given in&#xD;
      combination with Gemcitabine and Cisplatin, and to characterise the safety profile of the&#xD;
      study treatment regimen.&#xD;
&#xD;
      Based on the determined MTD and clinical information obtained from phase 1B part of the&#xD;
      study, the DSMB will review the safety data and other clinical data, together with the&#xD;
      sponsor, determine the MTD as well as the recommended phase 2 dose (RP2D). The sponsor will&#xD;
      make a decision when to proceed with the phase 2A part of the study.&#xD;
&#xD;
      The phase 2A part of the study is designed as a single arm expansion, enrolling a further 20&#xD;
      patients at the RP2D. The purpose of the phase 2A expansion study is to confirm the safety&#xD;
      and tolerability of the RP2D in a larger number of patients, and to provide preliminary&#xD;
      estimates of the clinical activity of Varlitinib in combination with Gemcitabine and&#xD;
      Cisplatin, prior to embarking on the larger, randomised phase 2B part of the trial.&#xD;
&#xD;
      The phase 2B part will be a two-arm, double-blinded, placebo controlled study. Patients will&#xD;
      be randomised into 2 arms to receive Varlitinib plus Gemcitabine and Cisplatin, or placebo&#xD;
      plus Gemcitabine and Cisplatin. The primary endpoint of the phase 2B part is progression-free&#xD;
      survival (PFS). The randomisation will be stratified by primary tumour location (gall bladder&#xD;
      or non-gall bladder).&#xD;
&#xD;
      Patient screening activities including informed consent and study eligibility verification&#xD;
      will be performed within 21 days prior to first dose of the study medication. Radiological&#xD;
      imaging to assess the disease status will be performed at baseline and every 6 weeks from&#xD;
      Cycle 1 Day 1. Blood samples will be taken during the screening phase, treatment period until&#xD;
      end of treatment. Patients will be required to complete safety follow-up within 28 days after&#xD;
      the last administration of study medication.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Sponsor decided to terminate the study and not proceed to Phase 2.&#xD;
  </why_stopped>
  <start_date type="Actual">December 13, 2016</start_date>
  <completion_date type="Actual">November 24, 2020</completion_date>
  <primary_completion_date type="Actual">June 16, 2020</primary_completion_date>
  <phase>Phase 1/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>Phase 1B: Maximum tolerated dose (MTD) of Varlitinib</measure>
    <time_frame>DLT period is 3 weeks</time_frame>
    <description>To determine the maximum tolerated dose (MTD), as determined by dose-limiting toxicities (DLTs), and to characterise the safety and tolerability profile of Varlitinib as determined by the adverse events in combination with Gemcitabine and Cisplatin.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 1B: Safety and toxicity</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>Determined by the adverse events.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2A: Safety and tolerability</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>Determined by adverse events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2A: Safety and tolerability</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>Determined by safety parameters (including vital signs, ECG parameters, clinical laboratory tests)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2A: Safety and tolerability</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>Other measures of tolerability such as dose interruptions, treatment exposure and dose intensity.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2A: Objective Response Rate (ORR)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>ORR is defined as the number (%) of patients with at least one visit response of CR or PR. Data obtained up until the earlier of progression or the last evaluable assessment prior to starting subsequent therapy, will be included in the assessment of ORR.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2A: Progression Free Survival (PFS)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined in accordance with the RECIST v1.1 criteria and will be derived programmatically.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2B: Progression Free Survival (PFS)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>PFS is defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined in accordance with the RECIST v1.1 criteria and will be derived programmatically based on data from the Independent Central Review (ICR) of radiological data.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)(Phase 1B)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>ORR is defined as the number (%) of patients with at least one visit response of CR or PR. Data obtained up until the earlier of progression or the last evaluable assessment prior to starting subsequent therapy, will be included in the assessment of ORR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (Phase 2B)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>ORR is defined as the number (%) of patients with at least one visit response of CR or PR. Data obtained up until progression or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate (DCR) (Phase 1B, Phase 2A and Phase 2B)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>DCR is defined as the number (%) of patients with at least one visit response of CR or PR, or with stable disease for a minimum of twelve weeks (- 5 days) from randomisation (Phase 2B) or starting treatment (Phase 1B and Phase 2A). For Phase 2B, data obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of DCR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DoR) (Phase 1B, Phase 2A and Phase 2B)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>DoR is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) (Phase 2A and Phase 2B only)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>OS is defined as time from the start of treatment (Phase 2A) or randomisation (Phase 2B) until death by any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of AEs (Phase 2B)</measure>
    <time_frame>Through study duration, estimated 3 years</time_frame>
    <description>Changes from baseline in safety parameters (including vital signs, ECG parameters, clinical laboratory tests) as categorized in accordance to CTCAE v4.03</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 1B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Maximum plasma concentration (Cmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 1B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Time to Cmax (tmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 1B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Area under the plasma concentration-time curve from 0 to 6 hours (AUC0-6), and area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 1B)</measure>
    <time_frame>Cycle 2 Day 1</time_frame>
    <description>Pre-dose concentration (Ctrough)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 1B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Accumulation ratio of AUC0-6 (Day 22) compared to AUC0-6 (Day 1) (RacAUC0-6), accumulation ratio of AUC0-12 (Day 22) compared to AUC0-12 (Day 1) (RacAUC0-12)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 1B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Accumulation ratio of Cmax (Day 22) compared to Cmax (Day 1) (RacCmax).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 1B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Accumulation ratio of Cmax (Day 22) compared to Cmax (Day 1) (RacCmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Maximum plasma concentration (Cmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Time to Cmax (tmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Area under the plasma concentration-time curve from 0 to 6 hours (AUC0-6), and area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 2B)</measure>
    <time_frame>Cycle 2 Day 1</time_frame>
    <description>Pre-dose concentration (Ctrough)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Accumulation ratio of AUC0-6 (Day 22) compared to AUC0-6 (Day 1) (RacAUC0-6), accumulation ratio of AUC0-12 (Day 22) compared to AUC0-12 (Day 1) (RacAUC0-12)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Varlitinib (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Accumulation ratio of Cmax (Day 22) compared to Cmax (Day 1) (RacCmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Maximum plasma concentration (Cmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Time to Cmax (tmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Last measurable concentration (Clast)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Terminal half-life (t1/2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Mean residence time (MRT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Volume of distribution at the terminal phase (Vz) and volume of distribution at the steady-state (Vss)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Plasma clearance (Cl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Area under the plasma concentration-time curve from 0 to t (AUC0-t), and area under the plasma concentration-time curve from 0 to infinite (AUC0-inf)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Accumulation ratio of AUC0-inf (Day 22) compared to AUC0-inf (Day 1) (RacAUC0-inf)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)</measure>
    <time_frame>Cycle 1 Day 1 and Cycle 2 Day 1</time_frame>
    <description>Accumulation ratio of Cmax (Day 22) compared to Cmax (Day 1) (RacCmax)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">204</enrollment>
  <condition>Biliary Tract Cancer</condition>
  <arm_group>
    <arm_group_label>Phase 1B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Varlitinib (starting dose at 200 mg BID) Cisplatin Gemcitabine</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Varlitinib</intervention_name>
    <description>Per oral (PO) Varlitinib BID (starting dose at 200 mg BID)</description>
    <arm_group_label>Phase 1B</arm_group_label>
    <other_name>ASLAN001</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>On D1 and D8, every 3 weeks. Cisplatin (25 mg per square meter of body surface area) in 1 litre of 0.9% saline with 20 mmol of potassium chloride and 8 mmol of magnesium sulfate intravenous (IV) infusion for 2 hours, followed by 500 mL of 0.9% saline over 30 minutes before the administration of Gemcitabine</description>
    <arm_group_label>Phase 1B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>On D1 and D8, every 3 weeks. Gemcitabine (1000 mg per square meter of body surface area) as a 30-minute infusion.</description>
    <arm_group_label>Phase 1B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient of respective country's legal age or older at the time of written informed&#xD;
             consent.&#xD;
&#xD;
          2. Patient must be able to understand and willing to provide informed consent for&#xD;
             participation in the study and donation of tumour tissue (archival or fresh) for&#xD;
             evaluation of relevant exploratory endpoints.&#xD;
&#xD;
          3. Patient must have histologically or cytologically confirmed advanced (unresectable) or&#xD;
             metastatic biliary tract cancer, including intrahepatic or extrahepatic&#xD;
             cholangiocarcinoma, gallbladder cancer, or carcinoma of the Ampulla of Vater, with no&#xD;
             prior systemic therapy for advanced/metastatic disease. This includes clinical&#xD;
             diagnosis of biliary tract cancer with histological confirmation of adenocarcinoma.&#xD;
&#xD;
          4. For phase 1B and 2A only: Presence of radiologically measured disease with at least&#xD;
             one, not previously irradiated, measurable lesion according to RECIST v.1.1.&#xD;
&#xD;
          5. No evidence of clinically significant biliary duct obstruction, unless obstruction is&#xD;
             controlled by local treatment or, in whom the biliary tree can be decompressed by&#xD;
             endoscopic or percutaneous stenting with subsequent reduction in bilirubin to below or&#xD;
             equal to 1.5 x upper level of normal (ULN).&#xD;
&#xD;
          6. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.&#xD;
&#xD;
          7. Patient with adequate organ and haematological function prior to first dose of study&#xD;
             medication:&#xD;
&#xD;
             a. Haematological function, as follows: i. Absolute neutrophil count (ANC) ≥ 1.5 x&#xD;
             109/L ii. Platelet count ≥ 100 x 109/L iii. Haemoglobin level ≥ 10 g/dl b. Renal&#xD;
             functions, as follows: i. Serum creatinine ≤ 1.5x ULN or eGFR &gt; 60 ml/min/1.73m2 c.&#xD;
             Hepatic function, as follows: i. Total bilirubin ≤ 1.5 x ULN ii. AST and ALT ≤ 5 x ULN&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with radiation or local treatment 6 weeks prior to screening for the target&#xD;
             lesion(s).&#xD;
&#xD;
          2. Patients with major surgical procedures within 21 days prior to screening.&#xD;
&#xD;
          3. Patients with known brain metastases.&#xD;
&#xD;
          4. Patients with malabsorption syndrome, diseases significantly affecting&#xD;
             gastrointestinal function, resection of the stomach or small bowel, or difficulty in&#xD;
             swallowing and retaining oral medications which in the opinion of the Investigator&#xD;
             could jeopardize the validity of the study results. Any extent of stomach resection&#xD;
             will be excluded.&#xD;
&#xD;
          5. Pre-existing peripheral sensory neuropathy ≥ grade 2 according to CTCAE (v.4.03).&#xD;
&#xD;
          6. Patients with an uncontrolled intercurrent illness including, but not limited to,&#xD;
             ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, diabetes,&#xD;
             hypertension, or psychiatric illness/social situations that would limit compliance&#xD;
             with study requirements.&#xD;
&#xD;
          7. Patients with any history of other malignancy unless in remission for more than 1 year&#xD;
             prior to screening (Non-melanoma skin carcinoma and carcinoma-in-situ of uterine&#xD;
             cervix treated with curative intent is not exclusionary).&#xD;
&#xD;
          8. Patients with a known history of HIV, decompensated cirrhosis, HCV infection, and for&#xD;
             phase 1B: HBV infection with detectable HBV deoxyribonucleic acid (DNA) or abnormal&#xD;
             transaminase; for phase 2A &amp; 2B: HBV infection with HBV DNA exceeding 2000 IU/mL.&#xD;
&#xD;
          9. Any history or presence of clinically significant cardiovascular, respiratory,&#xD;
             hepatic, renal, haematologic, gastrointestinal, endocrine, immunologic, dermatologic,&#xD;
             neurologic or psychiatric disease or any other condition, which, in the opinion of the&#xD;
             investigator, could jeopardise the safety of the patient or the validity of the study&#xD;
             results.&#xD;
&#xD;
         10. Patients with known history of drug addiction within last 1 year.&#xD;
&#xD;
         11. Patients who may need continuous treatment with proton pump inhibitors or strong&#xD;
             CYP3A4 inhibitors during the study period.&#xD;
&#xD;
         12. Female patients who are pregnant or breast-feeding.&#xD;
&#xD;
         13. Patients who have received any investigational drug (or have used an investigational&#xD;
             device) within the last 14 days before receiving the first dose of study medication.&#xD;
&#xD;
         14. Patients who have received immunotherapy for cancer, including but not limited to&#xD;
             immune checkpoint inhibitors, monoclonal antibody, cancer vaccine, and cell therapy.&#xD;
&#xD;
         15. Patient with unresolved or unstable serious toxicity (≥ CTCAE 4.03 Grade 2) from prior&#xD;
             administration of another investigational drug and/or prior cancer treatment.&#xD;
&#xD;
         16. Have a history of (non-infectious) pneumonitis that required steroids or current&#xD;
             pneumonitis, or have a history of interstitial lung disease or current interstitial&#xD;
             lung disease.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>ASLAN Pharmaceuticals ASLAN Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>contact@aslanpharma.com</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Singapore</city>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
    <country>Singapore</country>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>December 8, 2016</study_first_submitted>
  <study_first_submitted_qc>December 10, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 14, 2016</study_first_posted>
  <last_update_submitted>January 12, 2021</last_update_submitted>
  <last_update_submitted_qc>January 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 14, 2021</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>Biliary Tract Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</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/NCT02992340
org study id: ASLAN001-007
nct id: NCT02992340
lead sponsor: 
has dmc: Yes
The study intends to evaluate the following objectives in patients with advanced or
      metastatic biliary tract cancer who have not received systemic therapy for
      advanced/metastatic disease.

      Primary Objectives:

      Phase 1B

        -  To determine the maximum tolerated dose (MTD), as determined by dose-limiting toxicities
           (DLTs), and to characterise the safety profile of Varlitinib in combination with
           Gemcitabine and Cisplatin.

      Phase 2A

        -  To further evaluate the safety and tolerability of Varlitinib in combination with
           Gemcitabine and Cisplatin at the recommended phase 2 dose (RP2D).

        -  To provide a preliminary assessment of the clinical activity of Varlitinib in
           combination with Gemcitabine and Cisplatin at the RP2D as measured by Objective Response
           Rate (ORR) and progression-free survival (PFS) (based on RECIST v1.1)

      Phase 2B

        -  To compare the efficacy of Varlitinib in combination with Gemcitabine and Cisplatin to
           placebo in combination with Gemcitabine and Cisplatin as measured by progression-free
           survival (based on RECIST v1.1).
In phase 1B part, patients will receive Varlitinib plus Gemcitabine and Cisplatin, and follow
      a modified 3+3+3 study dose escalation scheme starting from Varlitinib 200 mg BID. The
      primary objective of the phase 1B part is to determine the MTD of Varlitinib when given in
      combination with Gemcitabine and Cisplatin, and to characterise the safety profile of the
      study treatment regimen.

      Based on the determined MTD and clinical information obtained from phase 1B part of the
      study, the DSMB will review the safety data and other clinical data, together with the
      sponsor, determine the MTD as well as the recommended phase 2 dose (RP2D). The sponsor will
      make a decision when to proceed with the phase 2A part of the study.

      The phase 2A part of the study is designed as a single arm expansion, enrolling a further 20
      patients at the RP2D. The purpose of the phase 2A expansion study is to confirm the safety
      and tolerability of the RP2D in a larger number of patients, and to provide preliminary
      estimates of the clinical activity of Varlitinib in combination with Gemcitabine and
      Cisplatin, prior to embarking on the larger, randomised phase 2B part of the trial.

      The phase 2B part will be a two-arm, double-blinded, placebo controlled study. Patients will
      be randomised into 2 arms to receive Varlitinib plus Gemcitabine and Cisplatin, or placebo
      plus Gemcitabine and Cisplatin. The primary endpoint of the phase 2B part is progression-free
      survival (PFS). The randomisation will be stratified by primary tumour location (gall bladder
      or non-gall bladder).

      Patient screening activities including informed consent and study eligibility verification
      will be performed within 21 days prior to first dose of the study medication. Radiological
      imaging to assess the disease status will be performed at baseline and every 6 weeks from
      Cycle 1 Day 1. Blood samples will be taken during the screening phase, treatment period until
      end of treatment. Patients will be required to complete safety follow-up within 28 days after
      the last administration of study medication.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase 1B: Maximum tolerated dose (MTD) of Varlitinib
time frame: DLT period is 3 weeks
description: To determine the maximum tolerated dose (MTD), as determined by dose-limiting toxicities (DLTs), and to characterise the safety and tolerability profile of Varlitinib as determined by the adverse events in combination with Gemcitabine and Cisplatin.
measure: Phase 1B: Safety and toxicity
time frame: Through study duration, estimated 3 years
description: Determined by the adverse events.
measure: Phase 2A: Safety and tolerability
time frame: Through study duration, estimated 3 years
description: Determined by adverse events
measure: Phase 2A: Safety and tolerability
time frame: Through study duration, estimated 3 years
description: Determined by safety parameters (including vital signs, ECG parameters, clinical laboratory tests)
measure: Phase 2A: Safety and tolerability
time frame: Through study duration, estimated 3 years
description: Other measures of tolerability such as dose interruptions, treatment exposure and dose intensity.
measure: Phase 2A: Objective Response Rate (ORR)
time frame: Through study duration, estimated 3 years
description: ORR is defined as the number (%) of patients with at least one visit response of CR or PR. Data obtained up until the earlier of progression or the last evaluable assessment prior to starting subsequent therapy, will be included in the assessment of ORR.
measure: Phase 2A: Progression Free Survival (PFS)
time frame: Through study duration, estimated 3 years
description: PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined in accordance with the RECIST v1.1 criteria and will be derived programmatically.
measure: Phase 2B: Progression Free Survival (PFS)
time frame: Through study duration, estimated 3 years
description: PFS is defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined in accordance with the RECIST v1.1 criteria and will be derived programmatically based on data from the Independent Central Review (ICR) of radiological data.
measure: Objective Response Rate (ORR)(Phase 1B)
time frame: Through study duration, estimated 3 years
description: ORR is defined as the number (%) of patients with at least one visit response of CR or PR. Data obtained up until the earlier of progression or the last evaluable assessment prior to starting subsequent therapy, will be included in the assessment of ORR.
measure: Objective Response Rate (Phase 2B)
time frame: Through study duration, estimated 3 years
description: ORR is defined as the number (%) of patients with at least one visit response of CR or PR. Data obtained up until progression or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR.
measure: Disease control rate (DCR) (Phase 1B, Phase 2A and Phase 2B)
time frame: Through study duration, estimated 3 years
description: DCR is defined as the number (%) of patients with at least one visit response of CR or PR, or with stable disease for a minimum of twelve weeks (- 5 days) from randomisation (Phase 2B) or starting treatment (Phase 1B and Phase 2A). For Phase 2B, data obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of DCR.
measure: Duration of response (DoR) (Phase 1B, Phase 2A and Phase 2B)
time frame: Through study duration, estimated 3 years
description: DoR is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression.
measure: Overall Survival (OS) (Phase 2A and Phase 2B only)
time frame: Through study duration, estimated 3 years
description: OS is defined as time from the start of treatment (Phase 2A) or randomisation (Phase 2B) until death by any cause.
measure: Incidence of AEs (Phase 2B)
time frame: Through study duration, estimated 3 years
description: Changes from baseline in safety parameters (including vital signs, ECG parameters, clinical laboratory tests) as categorized in accordance to CTCAE v4.03
measure: Pharmacokinetics of Varlitinib (Phase 1B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Maximum plasma concentration (Cmax)
measure: Pharmacokinetics of Varlitinib (Phase 1B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Time to Cmax (tmax)
measure: Pharmacokinetics of Varlitinib (Phase 1B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Area under the plasma concentration-time curve from 0 to 6 hours (AUC0-6), and area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12).
measure: Pharmacokinetics of Varlitinib (Phase 1B)
time frame: Cycle 2 Day 1
description: Pre-dose concentration (Ctrough)
measure: Pharmacokinetics of Varlitinib (Phase 1B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Accumulation ratio of AUC0-6 (Day 22) compared to AUC0-6 (Day 1) (RacAUC0-6), accumulation ratio of AUC0-12 (Day 22) compared to AUC0-12 (Day 1) (RacAUC0-12)
measure: Pharmacokinetics of Varlitinib (Phase 1B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Accumulation ratio of Cmax (Day 22) compared to Cmax (Day 1) (RacCmax).
measure: Pharmacokinetics of Varlitinib (Phase 1B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Accumulation ratio of Cmax (Day 22) compared to Cmax (Day 1) (RacCmax)
measure: Pharmacokinetics of Varlitinib (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Maximum plasma concentration (Cmax)
measure: Pharmacokinetics of Varlitinib (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Time to Cmax (tmax)
measure: Pharmacokinetics of Varlitinib (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Area under the plasma concentration-time curve from 0 to 6 hours (AUC0-6), and area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12)
measure: Pharmacokinetics of Varlitinib (Phase 2B)
time frame: Cycle 2 Day 1
description: Pre-dose concentration (Ctrough)
measure: Pharmacokinetics of Varlitinib (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Accumulation ratio of AUC0-6 (Day 22) compared to AUC0-6 (Day 1) (RacAUC0-6), accumulation ratio of AUC0-12 (Day 22) compared to AUC0-12 (Day 1) (RacAUC0-12)
measure: Pharmacokinetics of Varlitinib (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Accumulation ratio of Cmax (Day 22) compared to Cmax (Day 1) (RacCmax)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Maximum plasma concentration (Cmax)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Time to Cmax (tmax)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Last measurable concentration (Clast)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Terminal half-life (t1/2)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Mean residence time (MRT)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Volume of distribution at the terminal phase (Vz) and volume of distribution at the steady-state (Vss)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Plasma clearance (Cl)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Area under the plasma concentration-time curve from 0 to t (AUC0-t), and area under the plasma concentration-time curve from 0 to infinite (AUC0-inf)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Accumulation ratio of AUC0-inf (Day 22) compared to AUC0-inf (Day 1) (RacAUC0-inf)
measure: Pharmacokinetics of Gemcitabine, dFdU (gemcitabine metabolite) and Cisplatin (Phase 2B)
time frame: Cycle 1 Day 1 and Cycle 2 Day 1
description: Accumulation ratio of Cmax (Day 22) compared to Cmax (Day 1) (RacCmax)
arm group label: Phase 1B
arm group type: Experimental
description: Varlitinib (starting dose at 200 mg BID) Cisplatin Gemcitabine
intervention type: Drug
intervention name: Varlitinib
description: Per oral (PO) Varlitinib BID (starting dose at 200 mg BID)
arm group label: Phase 1B
other name: ASLAN001
intervention type: Drug
intervention name: Cisplatin
description: On D1 and D8, every 3 weeks. Cisplatin (25 mg per square meter of body surface area) in 1 litre of 0.9% saline with 20 mmol of potassium chloride and 8 mmol of magnesium sulfate intravenous (IV) infusion for 2 hours, followed by 500 mL of 0.9% saline over 30 minutes before the administration of Gemcitabine
arm group label: Phase 1B
intervention type: Drug
intervention name: Gemcitabine
description: On D1 and D8, every 3 weeks. Gemcitabine (1000 mg per square meter of body surface area) as a 30-minute infusion.
arm group label: Phase 1B
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: ASLAN Pharmaceuticals ASLAN Pharmaceuticals
role: Study Director
affiliation: contact@aslanpharma.com
facility: 
facility: 
facility: 
country: Korea, Republic of
country: Singapore
country: Taiwan
responsible party type: Sponsor
mesh term: Biliary Tract Neoplasms
mesh term: Gemcitabine
sharing ipd: No