<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/NCT02191878</url>
  </required_header>
  <id_info>
    <org_study_id>TKM-HCC-001</org_study_id>
    <nct_id>NCT02191878</nct_id>
  </id_info>
  <brief_title>Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Intravenous TKM-080301 in Subjects With Advanced Hepatocellular Carcinoma</brief_title>
  <official_title>Open-Label, Multi-Center, Phase 1, Dose Escalation Study With Phase 2 Expansion Cohort to Determine the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Intravenous TKM-080301 in Subjects With Advanced Hepatocellular Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Arbutus Biopharma Corporation</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Arbutus Biopharma Corporation</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is an open-label, multi-center, phase 1, dose escalation study with a phase 2&#xD;
      expansion cohort to determine the safety, pharmacokinetics and preliminary anti-tumor&#xD;
      activity of intravenous TKM-080301 in subjects with advanced hepatocellular carcinoma (HCC).&#xD;
&#xD;
      This study is being done to:&#xD;
&#xD;
        -  Test the safety and tolerability of TKM-080301 in subjects with advanced hepatocellular&#xD;
           carcinoma&#xD;
&#xD;
        -  Find the highest dose of TKM-080301 that can be given without causing side effects,&#xD;
           called the maximum tolerated dose (MTD).&#xD;
&#xD;
        -  Provide a preliminary assessment of anti-tumor activity of TKM-080301&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design: Open label, multi-center, 3 + 3 dose-escalation study with an expansion cohort&#xD;
      at the maximum tolerated dose (MTD) to investigate safety, tolerability, PK, and preliminary&#xD;
      anti-tumor activity of TKM 080301 in subjects with HCC.&#xD;
&#xD;
      Sequential cohorts of 3 to 6 subjects will receive escalating doses of TKM 080301 according&#xD;
      to a pre-specified dose escalation scheme. Assessment of dose-limiting toxicities (DLTs) will&#xD;
      be made during Cycle 1 to determine the maximum tolerated dose (MTD). Once the MTD level is&#xD;
      established, approximately 20 subjects will be enrolled in an expansion cohort to further&#xD;
      confirm the safety and tolerability of TKM-080301 at the MTD.&#xD;
&#xD;
      Study Population: A minimum of 9 and up to approximately 18 adult male or female subjects&#xD;
      with histologically or cytologically confirmed metastatic or locally advanced inoperable HCC&#xD;
      and a life expectancy of 3 months or more are planned in the dose escalation phase.&#xD;
      Approximately 20 subjects are planned in the expansion cohort.&#xD;
&#xD;
      Study Treatment: TKM-080301 will be administered by intravenous (IV) infusion, once weekly&#xD;
      for 3 consecutive weeks followed by a 1 week rest period. This 28-day treatment period&#xD;
      constitutes 1 cycle.&#xD;
&#xD;
      Subjects who demonstrate clinical benefit without progression per RECIST 1.1 guidelines may&#xD;
      receive treatment beyond 6 cycles if the Investigator considers it is in the best interest of&#xD;
      the subject, and only with the approval of the Medical Monitor. Subjects would then continue&#xD;
      TKM 080301 therapy until withdrawal of consent, disease progression or unacceptable toxicity&#xD;
      occurs.&#xD;
&#xD;
      Pharmacokinetics (PK) Subjects will undergo blood sample collection for PK analysis during&#xD;
      cycles 1 and 2.&#xD;
&#xD;
      Study Duration: Each treatment cycle will have duration of 28 days and each subject will&#xD;
      typically receive up to 6 cycles of treatment. The total duration of the study is expected to&#xD;
      be approximately 28 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2014</start_date>
  <completion_date type="Actual">July 2016</completion_date>
  <primary_completion_date type="Actual">May 2016</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>Maximum tolerated dose (MTD)</measure>
    <time_frame>Up to 6 months after initial dose.</time_frame>
    <description>Laboratory assessments</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Preliminary assessment of anti-tumor activity by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)</measure>
    <time_frame>Upon every 2 cycles of treatment for up to 6 months</time_frame>
    <description>Obtain preliminary assessment of anti-tumor activity by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate at maximum tolerated dose (MTD) in Expansion Cohort</measure>
    <time_frame>Upon completion of treatment of expansion cohort; up to 6 months after last participant is dosed.</time_frame>
    <description>Assessed after completion of Phase 2.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Assessment of Pharmacodynamic Effect</measure>
    <time_frame>Upon completion of cycle 1 and cycle 2 treatment; 1 and 2 months after last participant is dosed in expansion cohort.</time_frame>
    <description>Assessment of target mRNA reduction in participants consenting to pre- and post-treatment tumor biopsies.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>Hepatocellular Carcinoma</condition>
  <condition>Hepatoma</condition>
  <condition>Liver Cancer, Adult</condition>
  <condition>Liver Cell Carcinoma, Adult</condition>
  <arm_group>
    <arm_group_label>Phase 1 Escalation / Phase 2 Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1 - dose escalation with intravenous infusion of TKM-080301 to determine MTD.&#xD;
Phase 2 - dose expansion at the MTD.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TKM-080301</intervention_name>
    <description>TKM-080301 intravenous infusion</description>
    <arm_group_label>Phase 1 Escalation / Phase 2 Expansion</arm_group_label>
    <other_name>PLK1-HCC</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  Child-Pugh class of A&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5.0 × ULN&#xD;
&#xD;
          -  Total bilirubin ≤3.0 mg/dL&#xD;
&#xD;
          -  Platelets ≥75,000 /mL&#xD;
&#xD;
          -  International Normalized Ratio (INR) ≤1.7&#xD;
&#xD;
          -  Subjects must meet the protocol-defined criteria for both hepatitis B virus (HBV) and&#xD;
             hepatitis C virus (HCV) status&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  History of significant cardiovascular disease will be excluded&#xD;
&#xD;
          -  History of liver transplant.&#xD;
&#xD;
          -  Diagnosis of fibrolamellar HCC or tumors of mixed histology.&#xD;
&#xD;
          -  Subjects known to be positive for Human immunodeficiency virus (HIV) infection.&#xD;
&#xD;
          -  Known central nervous system (CNS) or brain metastases.&#xD;
&#xD;
          -  Poorly controlled ascites and/or requirement for therapeutic paracentesis more&#xD;
             frequently than once every 3 months.&#xD;
&#xD;
          -  Symptomatic encephalopathy within 3 months prior to the first dose of TKM-080301&#xD;
             and/or requirement for medication for encephalopathy.&#xD;
&#xD;
          -  Esophageal variceal bleeding within 2 weeks prior to the first dose of TKM-080301.&#xD;
&#xD;
          -  Asthma or chronic obstructive pulmonary disease (COPD) requiring daily medication.&#xD;
&#xD;
          -  Prior therapy with nitrosoureas or mitomycin within 6 weeks prior to the first dose of&#xD;
             TKM-080301.&#xD;
&#xD;
          -  Prior therapy with any biologic chemotherapeutic or investigational drug within 5&#xD;
             half-lives or 3 weeks, whichever is longer prior to the first dose of TKM 080301.&#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>Mark Kowalski, M.D., Ph.D.</last_name>
    <role>Study Director</role>
    <affiliation>Tekmira Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Arizona Clinical Research Center</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85715</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kansas City Research Institute</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64131</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mary Crowley Cancer Research Centers</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess Margaret Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Mary Hospital</name>
      <address>
        <city>Hong Kong</city>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <state>Gyeonggi-do</state>
        <zip>110744</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Samsung Medical Center</name>
      <address>
        <city>Seoul</city>
        <state>Gyeonggi-do</state>
        <zip>135-710</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASAN Medical Center</name>
      <address>
        <city>Seoul</city>
        <state>Gyeonggi-do</state>
        <zip>138-736</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Severence Hospital, Yonsei, University Health System</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National University Hospital</name>
      <address>
        <city>Singapore</city>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Taiwan University Hospital</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Taipei Medical University Hospital, Shuang-Ho Hospital</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Taipei Veterans General Hospital</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>China</country>
    <country>Korea, Republic of</country>
    <country>Singapore</country>
    <country>Taiwan</country>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>July 9, 2014</study_first_submitted>
  <study_first_submitted_qc>July 14, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 16, 2014</study_first_posted>
  <disposition_first_submitted>January 14, 2019</disposition_first_submitted>
  <disposition_first_submitted_qc>January 14, 2019</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">January 16, 2019</disposition_first_posted>
  <last_update_submitted>January 14, 2019</last_update_submitted>
  <last_update_submitted_qc>January 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Liver Cancer</keyword>
  <keyword>Liver Neoplasms</keyword>
  <keyword>Liver Epithelial Neoplasms</keyword>
  <keyword>Liver Cancer, malignant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
    <mesh_term>Liver Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>TKM-080301</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT02191878
org study id: TKM-HCC-001
nct id: NCT02191878
lead sponsor: 
has dmc: No
This study is an open-label, multi-center, phase 1, dose escalation study with a phase 2
      expansion cohort to determine the safety, pharmacokinetics and preliminary anti-tumor
      activity of intravenous TKM-080301 in subjects with advanced hepatocellular carcinoma (HCC).

      This study is being done to:

        -  Test the safety and tolerability of TKM-080301 in subjects with advanced hepatocellular
           carcinoma

        -  Find the highest dose of TKM-080301 that can be given without causing side effects,
           called the maximum tolerated dose (MTD).

        -  Provide a preliminary assessment of anti-tumor activity of TKM-080301
Study design: Open label, multi-center, 3 + 3 dose-escalation study with an expansion cohort
      at the maximum tolerated dose (MTD) to investigate safety, tolerability, PK, and preliminary
      anti-tumor activity of TKM 080301 in subjects with HCC.

      Sequential cohorts of 3 to 6 subjects will receive escalating doses of TKM 080301 according
      to a pre-specified dose escalation scheme. Assessment of dose-limiting toxicities (DLTs) will
      be made during Cycle 1 to determine the maximum tolerated dose (MTD). Once the MTD level is
      established, approximately 20 subjects will be enrolled in an expansion cohort to further
      confirm the safety and tolerability of TKM-080301 at the MTD.

      Study Population: A minimum of 9 and up to approximately 18 adult male or female subjects
      with histologically or cytologically confirmed metastatic or locally advanced inoperable HCC
      and a life expectancy of 3 months or more are planned in the dose escalation phase.
      Approximately 20 subjects are planned in the expansion cohort.

      Study Treatment: TKM-080301 will be administered by intravenous (IV) infusion, once weekly
      for 3 consecutive weeks followed by a 1 week rest period. This 28-day treatment period
      constitutes 1 cycle.

      Subjects who demonstrate clinical benefit without progression per RECIST 1.1 guidelines may
      receive treatment beyond 6 cycles if the Investigator considers it is in the best interest of
      the subject, and only with the approval of the Medical Monitor. Subjects would then continue
      TKM 080301 therapy until withdrawal of consent, disease progression or unacceptable toxicity
      occurs.

      Pharmacokinetics (PK) Subjects will undergo blood sample collection for PK analysis during
      cycles 1 and 2.

      Study Duration: Each treatment cycle will have duration of 28 days and each subject will
      typically receive up to 6 cycles of treatment. The total duration of the study is expected to
      be approximately 28 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD)
time frame: Up to 6 months after initial dose.
description: Laboratory assessments
measure: Preliminary assessment of anti-tumor activity by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
time frame: Upon every 2 cycles of treatment for up to 6 months
description: Obtain preliminary assessment of anti-tumor activity by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
measure: Clinical Benefit Rate at maximum tolerated dose (MTD) in Expansion Cohort
time frame: Upon completion of treatment of expansion cohort; up to 6 months after last participant is dosed.
description: Assessed after completion of Phase 2.
measure: Assessment of Pharmacodynamic Effect
time frame: Upon completion of cycle 1 and cycle 2 treatment; 1 and 2 months after last participant is dosed in expansion cohort.
description: Assessment of target mRNA reduction in participants consenting to pre- and post-treatment tumor biopsies.
arm group label: Phase 1 Escalation / Phase 2 Expansion
arm group type: Experimental
description: Phase 1 - dose escalation with intravenous infusion of TKM-080301 to determine MTD.
Phase 2 - dose expansion at the MTD.
intervention type: Drug
intervention name: TKM-080301
description: TKM-080301 intravenous infusion
arm group label: Phase 1 Escalation / Phase 2 Expansion
other name: PLK1-HCC
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark Kowalski, M.D., Ph.D.
role: Study Director
affiliation: Tekmira Pharmaceuticals
facility: 
facility: 
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country: Canada
country: China
country: Korea, Republic of
country: Singapore
country: Taiwan
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Liver Neoplasms
mesh term: TKM-080301