<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/NCT01721941</url>
  </required_header>
  <id_info>
    <org_study_id>TH302 TACE</org_study_id>
    <nct_id>NCT01721941</nct_id>
  </id_info>
  <brief_title>TH-302 Plus Doxorubicin Delivered by Trans-Arterial Chemoembolization (TACE) in Patients With Hepatocellular Carcinoma</brief_title>
  <official_title>A Phase I Dose Escalation Study of TH-302 Plus Doxorubicin Delivered by Trans-Arterial Chemoembolization (TACE) in Patients With Hepatocellular Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Scripps Clinic Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Threshold Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Scripps Clinic Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this phase I dose escalation study is to determine the maximum&#xD;
      tolerated dose of TH-302 when administered with doxorubicin via trans-arterial&#xD;
      chemo-embolization (TACE) in patients with hepatocellular carcinoma (HCC) who are not&#xD;
      transplant candidates and have unresectable disease. HCC is the second leading cause of&#xD;
      worldwide cancer death and is generally incurable without liver transplant. TACE can convert&#xD;
      about 40% of these patients to transplant candidates. Additionally, in non-transplant HCC&#xD;
      patients, TACE confers statistical improvements in overall survival. Selective HCC arterial&#xD;
      catheterization during TACE allows for the delivery of concentrated drugs to the liver tumor&#xD;
      but the optimal TACE chemotherapy regimen has not yet been determined. TH-302 is a hypoxia&#xD;
      inducible agent that can be activated in the hypoxic environment induced by TACE.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Transarterial chemoembolization (TACE) is the major modality utilized for tumor downstaging&#xD;
      for transplant and for local therapy in non-transplant patients. This procedure allows&#xD;
      delivery of concentrated drugs to the tumor, followed by embolization that eliminates its&#xD;
      blood supply creating an environment of hypoxia. The process induces tumor ischemia, while&#xD;
      achieving a drug concentration in the tumor 10 to 25 times greater than can be achieved by&#xD;
      infusion.&#xD;
&#xD;
      A hypoxic microenvironment is a characteristic of many solid tumors including hepatocellular&#xD;
      cancer, further induced by TACE. The hypoxia-activated prodrug, TH-302, is designed to&#xD;
      selectively physiologically target the hypoxic microenvironment. While doxorubicin and&#xD;
      cisplatin have been used as the drugs in TACE among other agents, none have stood out as the&#xD;
      optimal agent in targeting HCC. Because of the action of TH-302 in hypoxia, this agent has a&#xD;
      mechanistic advantage as a agent in TACE.&#xD;
&#xD;
      The current study is designed to assess the potential therapeutic benefit of adding TH-302 to&#xD;
      the standard doxorubicin based TACE regimen in patients with advanced hepatocellular&#xD;
      carcinomas.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>December 2014</start_date>
  <completion_date type="Anticipated">December 2016</completion_date>
  <primary_completion_date type="Anticipated">December 2015</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</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 of TH-302 use in TACE</measure>
    <time_frame>33 weeks</time_frame>
    <description>Maximum tolerated dose (MTD) of TH-302 when co-administered with doxorubicin via TACE in patients with advanced hepatocellular cancer will be assessed with a Fibonacci (3+3) dose escalation design.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate</measure>
    <time_frame>12 months</time_frame>
    <description>Assess overall response rate using standard RECIST criteria measured by triple phase CT or MRI at least 6 weeks post TACE administration</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Phase I dose level -1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TH-302 25mg; Doxorubicin 50mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase I Dose level 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TH-302 50mg; doxorubicin 50mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase I Dose level 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TH-302 100mg; doxorubicin 50mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase 1 Dose level 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TH-302 150mg; Doxorubicin 50mg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase I Dose level -1</intervention_name>
    <description>The dose of TH-302 will be mixed with doxorubicin 50mg to use as the chemoembolization mixture for transarterial chemoembolization (TACE).</description>
    <arm_group_label>Phase I dose level -1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase I dose level 1</intervention_name>
    <description>The dose of TH-302 will be mixed with doxorubicin 50mg to use as the chemoembolization mixture for transarterial chemoembolization (TACE).</description>
    <arm_group_label>Phase I Dose level 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase I Dose level 2</intervention_name>
    <description>The dose of TH-302 will be mixed with doxorubicin 50mg to use as the chemoembolization mixture for transarterial chemoembolization (TACE).</description>
    <arm_group_label>Phase I Dose level 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase I Dose level 3</intervention_name>
    <description>The dose of TH-302 will be mixed with doxorubicin 50mg to use as the chemoembolization mixture for transarterial chemoembolization (TACE).</description>
    <arm_group_label>Phase 1 Dose level 3</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  At least 18 years of age&#xD;
&#xD;
          -  Ability to understand the purposes and risks of the study and has signed a written&#xD;
             informed consent form approved by the investigator's IRB/Ethics Committee&#xD;
&#xD;
          -  Patients with hepatocellular carcinoma with either:&#xD;
&#xD;
               1. liver limited disease who are not transplant candidates as they fall outside of&#xD;
                  Milan criteria, but may be eligible for transplant after successful downstaging&#xD;
                  with TACE&#xD;
&#xD;
               2. liver limited disease who satisfy Milan criteria, but are at risk of falling out&#xD;
                  of Milan criteria before they receive a liver transplant&#xD;
&#xD;
               3. non-transplantable HCC but with liver limited or metastatic disease that requires&#xD;
                  local TACE therapy&#xD;
&#xD;
          -  Measurable disease by modified RECIST criteria (at least one target lesion outside of&#xD;
             previous radiation fields)&#xD;
&#xD;
          -  ECOG performance status of 2 or less&#xD;
&#xD;
          -  Life expectancy of at least 3 months&#xD;
&#xD;
          -  Childs-Pugh Class A or B&#xD;
&#xD;
          -  HCC amenable to TACE&#xD;
&#xD;
          -  Patent main portal vein (thrombosis of portal vein branch not exclusionary)&#xD;
&#xD;
          -  Acceptable liver function:&#xD;
&#xD;
          -  Bilirubin &lt; 2 mg/dL&#xD;
&#xD;
          -  AST (SGOT) and ALT (SGPT) &lt; 5 x ULN is allowed&#xD;
&#xD;
          -  Acceptable renal function:&#xD;
&#xD;
          -  Serum creatinine &lt; 1.5 ULN&#xD;
&#xD;
          -  Acceptable hematologic status (without hematologic support for TACE #1):&#xD;
&#xD;
          -  ANC &gt; 500 cells/μL&#xD;
&#xD;
          -  Platelet count &gt; 50,000/μL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial&#xD;
             infarction within 6 months prior to Day 1, unstable arrhythmia or symptomatic&#xD;
             peripheral arterial vascular disease&#xD;
&#xD;
          -  Known brain, leptomeningeal or epidural metastases (unless treated and well controlled&#xD;
             for &gt;=3 months)&#xD;
&#xD;
          -  Previously treated malignancies, except for adequately treated non-melanoma skin&#xD;
             cancer, in situ cancer, or other cancer from which the subject has been disease-free&#xD;
             for at least 5 years&#xD;
&#xD;
          -  Severe chronic obstructive or other pulmonary disease with hypoxemia (requires&#xD;
             supplementary oxygen, symptoms due to hypoxemia or oxygen saturation &lt;90% by pulse&#xD;
             oximetry after a 2 minute walk) or in the opinion of the investigator any&#xD;
             physiological state likely to cause systemic or regional hypoxemia&#xD;
&#xD;
          -  Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without&#xD;
             complete recovery&#xD;
&#xD;
          -  Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic&#xD;
             therapy&#xD;
&#xD;
          -  Sorafenib within the previous 4 weeks or the intention to initiate sorafenib while on&#xD;
             study&#xD;
&#xD;
          -  Poor liver function as indicated by serum bilirubin &gt; 2 mg/dL, Child-Pugh Class C,&#xD;
             severe coagulopathy (INR &gt; 2) not correctable with vitamin K, or active hepatic&#xD;
             encephalopathy&#xD;
&#xD;
          -  Main portal vein occlusion&#xD;
&#xD;
          -  Liver rupture or tumor penetration of liver capsule&#xD;
&#xD;
          -  Tumor invasion of biliary system with biliary obstruction&#xD;
&#xD;
          -  Severe cytopenias, including ANC &lt; 500 cells/μL, Hemoglobin &lt; 8 g/dL, or platelets &lt;&#xD;
             50,000/μL&#xD;
&#xD;
          -  Subjects who have exhibited allergic reactions to a structural compound, biological&#xD;
             agent similar to TH-302&#xD;
&#xD;
          -  Females who are pregnant or breast-feeding&#xD;
&#xD;
          -  Concomitant disease or condition that could interfere with the conduct of the study,&#xD;
             or that would, in the opinion of the investigator, pose an unacceptable risk to the&#xD;
             subject in this study&#xD;
&#xD;
          -  Unwillingness or inability to comply with the study protocol for any reason&#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>Darren S Sigal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Scripps Health</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Alain Perez</last_name>
    <phone>858-554-9379</phone>
    <email>Perez.Alain@scrippshealth.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Scripps Clinic</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92037</zip>
        <country>United States</country>
      </address>
    </facility>
    <contact>
      <last_name>Alain Perez</last_name>
      <phone>858-554-8937</phone>
      <email>Perez.Alain@scrippshealth.org</email>
    </contact>
    <investigator>
      <last_name>Darren S Sigal, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>October 8, 2012</study_first_submitted>
  <study_first_submitted_qc>November 2, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 6, 2012</study_first_posted>
  <last_update_submitted>July 3, 2014</last_update_submitted>
  <last_update_submitted_qc>July 3, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 4, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>hepatocellular carcinoma</keyword>
  <keyword>HCC</keyword>
  <keyword>liver cancer</keyword>
  <keyword>hepatoma</keyword>
  <keyword>TACE</keyword>
  <keyword>transarterial chemoembolization</keyword>
  <keyword>TH302</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>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01721941
org study id: TH302 TACE
nct id: NCT01721941
lead sponsor: 
collaborator: 
has dmc: Yes
The primary objective of this phase I dose escalation study is to determine the maximum
      tolerated dose of TH-302 when administered with doxorubicin via trans-arterial
      chemo-embolization (TACE) in patients with hepatocellular carcinoma (HCC) who are not
      transplant candidates and have unresectable disease. HCC is the second leading cause of
      worldwide cancer death and is generally incurable without liver transplant. TACE can convert
      about 40% of these patients to transplant candidates. Additionally, in non-transplant HCC
      patients, TACE confers statistical improvements in overall survival. Selective HCC arterial
      catheterization during TACE allows for the delivery of concentrated drugs to the liver tumor
      but the optimal TACE chemotherapy regimen has not yet been determined. TH-302 is a hypoxia
      inducible agent that can be activated in the hypoxic environment induced by TACE.
Transarterial chemoembolization (TACE) is the major modality utilized for tumor downstaging
      for transplant and for local therapy in non-transplant patients. This procedure allows
      delivery of concentrated drugs to the tumor, followed by embolization that eliminates its
      blood supply creating an environment of hypoxia. The process induces tumor ischemia, while
      achieving a drug concentration in the tumor 10 to 25 times greater than can be achieved by
      infusion.

      A hypoxic microenvironment is a characteristic of many solid tumors including hepatocellular
      cancer, further induced by TACE. The hypoxia-activated prodrug, TH-302, is designed to
      selectively physiologically target the hypoxic microenvironment. While doxorubicin and
      cisplatin have been used as the drugs in TACE among other agents, none have stood out as the
      optimal agent in targeting HCC. Because of the action of TH-302 in hypoxia, this agent has a
      mechanistic advantage as a agent in TACE.

      The current study is designed to assess the potential therapeutic benefit of adding TH-302 to
      the standard doxorubicin based TACE regimen in patients with advanced hepatocellular
      carcinomas.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of TH-302 use in TACE
time frame: 33 weeks
description: Maximum tolerated dose (MTD) of TH-302 when co-administered with doxorubicin via TACE in patients with advanced hepatocellular cancer will be assessed with a Fibonacci (3+3) dose escalation design.
measure: Objective response rate
time frame: 12 months
description: Assess overall response rate using standard RECIST criteria measured by triple phase CT or MRI at least 6 weeks post TACE administration
arm group label: Phase I dose level -1
arm group type: Experimental
description: TH-302 25mg; Doxorubicin 50mg
arm group label: Phase I Dose level 1
arm group type: Experimental
description: TH-302 50mg; doxorubicin 50mg
arm group label: Phase I Dose level 2
arm group type: Experimental
description: TH-302 100mg; doxorubicin 50mg
arm group label: Phase 1 Dose level 3
arm group type: Experimental
description: TH-302 150mg; Doxorubicin 50mg
intervention type: Drug
intervention name: Phase I Dose level -1
description: The dose of TH-302 will be mixed with doxorubicin 50mg to use as the chemoembolization mixture for transarterial chemoembolization (TACE).
arm group label: Phase I dose level -1
intervention type: Drug
intervention name: Phase I dose level 1
description: The dose of TH-302 will be mixed with doxorubicin 50mg to use as the chemoembolization mixture for transarterial chemoembolization (TACE).
arm group label: Phase I Dose level 1
intervention type: Drug
intervention name: Phase I Dose level 2
description: The dose of TH-302 will be mixed with doxorubicin 50mg to use as the chemoembolization mixture for transarterial chemoembolization (TACE).
arm group label: Phase I Dose level 2
intervention type: Drug
intervention name: Phase I Dose level 3
description: The dose of TH-302 will be mixed with doxorubicin 50mg to use as the chemoembolization mixture for transarterial chemoembolization (TACE).
arm group label: Phase 1 Dose level 3
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Darren S Sigal, MD
role: Principal Investigator
affiliation: Scripps Health
last name: Alain Perez
phone: 858-554-9379
email: Perez.Alain@scrippshealth.org
facility: 
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular