<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/NCT02255110</url>
  </required_header>
  <id_info>
    <org_study_id>EMR200592-008</org_study_id>
    <nct_id>NCT02255110</nct_id>
  </id_info>
  <brief_title>A Japanese Trial of TH-302 in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma</brief_title>
  <official_title>A Phase II, Single-arm, Japanese Multicenter Trial of TH-302 in Combination With Doxorubicin in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Merck KGaA, Darmstadt, Germany</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Threshold Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Merck KGaA, Darmstadt, Germany</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase 2, single-arm, Japanese multicenter trial to evaluate the safety,&#xD;
      tolerability, and efficacy of TH-302 in combination with doxorubicin in subjects with locally&#xD;
      advanced unresectable or metastatic soft tissue sarcoma (STS).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Sponsor's decision due to negative result of Phase 3 study TH-CR-406/SARC021&#xD;
  </why_stopped>
  <start_date type="Actual">December 10, 2014</start_date>
  <completion_date type="Actual">January 12, 2016</completion_date>
  <primary_completion_date type="Actual">January 12, 2016</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>Progression Free Survival (PFS) by Independent Central Review (Phase II Treatment Period)</measure>
    <time_frame>From first dose of study drug administration until PD or death, evaluated at 6 months</time_frame>
    <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) by Investigator Review (Phase II Treatment Period)</measure>
    <time_frame>From first dose of study drug administration until PD or death, evaluated at 6 months</time_frame>
    <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS) by Investigator and Independent Central Review (Phase II Treatment Period)</measure>
    <time_frame>From first dose of study drug administration until PD or death, evaluated at 3 months and 9 months</time_frame>
    <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS) (Phase II Treatment Period)</measure>
    <time_frame>From first dose of study drug administration until PD or death, assessed up to 12 months</time_frame>
    <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best Overall Response (BOR) by Independent Central Review (Phase II Treatment Period)</measure>
    <time_frame>From first dose of study drug administration until PD or death, assessed up to 12 months</time_frame>
    <description>BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to &lt; 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best Overall Response (BOR) by Investigator (Phase II Treatment Period)</measure>
    <time_frame>From first dose of study drug administration until PD or death, assessed up to 12 months</time_frame>
    <description>BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to &lt; 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (Phase II Treatment Period)</measure>
    <time_frame>From first dose of study drug administration until PD or death, assessed up to 12 months</time_frame>
    <description>Duration of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) is defined as the time from the first assessment of complete response (CR) or partial response (PR) until the date of the first occurrence of progressive disease (PD), or until the date of death. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to less than (&lt;) 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) (Phase II Treatment Period)</measure>
    <time_frame>From first dose of study drug administration until the last subject completes the survival follow-up, assessed up to 12 months</time_frame>
    <description>OS is defined as the time from first dose to death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) (Safety Run-In Phase)</measure>
    <time_frame>From baseline until end of trial, assessed up to Day 210</time_frame>
    <description>An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the stud drug.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Soft Tissue Sarcoma</condition>
  <arm_group>
    <arm_group_label>TH-302 and doxorubicin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TH-302</intervention_name>
    <description>TH-302 will be administered at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Days 1 and 8 of every 21-day cycle until the evidence of significant treatment-related toxicity or progressive disease.</description>
    <arm_group_label>TH-302 and doxorubicin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin</intervention_name>
    <description>Doxorubicin will be administered at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
    <arm_group_label>TH-302 and doxorubicin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female Japanese subjects greater than or equal to (&gt;=) 15 years of age&#xD;
&#xD;
          -  Able to understand the purposes and risks of the trial and has signed or, if&#xD;
             appropriate, the subject's parent or legal guardian has signed a written informed&#xD;
             consent form approved by the Institutional Review Board (IRB) or Independent Ethics&#xD;
             Committee (IEC)&#xD;
&#xD;
          -  Pathologically confirmed diagnosis of STS of the histopathologic types as specified in&#xD;
             the protocol&#xD;
&#xD;
          -  Locally advanced unresectable or metastatic disease with no standard curative therapy&#xD;
             available and for whom treatment with single agent doxorubicin is considered&#xD;
             appropriate&#xD;
&#xD;
          -  Recovered from reversible toxicities of prior therapy&#xD;
&#xD;
          -  Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version&#xD;
             1.1 (at least one target lesion outside of previous radiation fields or progressed&#xD;
             within a previous radiation field)&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          -  Life expectancy of at least 3 months&#xD;
&#xD;
          -  Acceptable liver function, renal function, hematologic status (without growth factor&#xD;
             support for neutropenia or transfusion dependency), and cardiac function as specified&#xD;
             in the protocol&#xD;
&#xD;
          -  All women of childbearing potential must have a negative serum pregnancy test and all&#xD;
             subjects must agree to use effective means of contraception (surgical sterilization or&#xD;
             the use of barrier contraception with either a condom or diaphragm in conjunction with&#xD;
             spermicidal gel or an intrauterine device, intrauterine device [IUD]) with their&#xD;
             partner from entry into the trial through 6 months after the last dose.&#xD;
             Post-menopausal women must meet the criteria of 12 months of natural (spontaneous)&#xD;
             amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-stimulating&#xD;
             hormone (FSH) levels greater than (&gt;) 35 international units per liter (IU/L)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Low grade tumors according to standard grading systems (for example, American Joint&#xD;
             Committee on Cancer [AJCC] Grade 1 and 2 or Fédération Nationale des Centres de Lutte&#xD;
             Contre le Cancer [FNCLCC] Grade 1)&#xD;
&#xD;
          -  Prior systemic therapy for advanced or metastatic STS (neoadjuvant therapy followed by&#xD;
             surgical resection and adjuvant therapy permitted)&#xD;
&#xD;
          -  Prior STS therapy with ifosfamide or cyclophosphamide or other nitrogen mustards;&#xD;
             prior systemic therapy with an anthracycline or anthracenedione; or prior&#xD;
             mediastinal/cardiac radiotherapy&#xD;
&#xD;
          -  Current use of drugs with known cardiotoxicity or known interactions with doxorubicin&#xD;
&#xD;
          -  Anti-cancer treatment with radiation therapy, neoadjuvant or adjuvant chemotherapy,&#xD;
             targeted therapies, immunotherapy, hormones or other antitumor therapies within 4&#xD;
             weeks prior to trial entry (6 weeks for nitrosoureas or mitomycin C).&#xD;
&#xD;
          -  Significant cardiac dysfunction precluding treatment with doxorubicin as specified in&#xD;
             the protocol&#xD;
&#xD;
          -  Seizure disorders requiring anticonvulsant therapy unless seizure-free for the last&#xD;
             year&#xD;
&#xD;
          -  Known brain metastases (unless previously treated and well controlled for a period of&#xD;
             &gt;=3 months before screening)&#xD;
&#xD;
          -  Previously diagnosed 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 before screening&#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 normal tissue hypoxia&#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;
          -  Prior therapy with a hypoxic cytotoxin&#xD;
&#xD;
          -  Subjects who participated in an investigational drug or device trial within 28 days&#xD;
             prior to trial entry&#xD;
&#xD;
          -  Known infection with human immunodeficiency virus (HIV) or active infection with&#xD;
             hepatitis B or hepatitis C&#xD;
&#xD;
          -  Subjects who have exhibited allergic reactions to a structural compound similar to&#xD;
             TH-302 or the drug product excipients&#xD;
&#xD;
          -  Subjects who are taking medications that prolong QT interval and have a risk of&#xD;
             Torsades de Pointes&#xD;
&#xD;
          -  Subjects with a corrected QT (QTc) interval calculated according to Bazett's formula&#xD;
             of &gt;450 milliseconds (msec) based on a screening electrocardiogram (ECG)&#xD;
&#xD;
          -  Subjects with a history of long QT syndrome&#xD;
&#xD;
          -  Subjects taking a medication that is a moderate or strong inhibitor or inducer of&#xD;
             cytochrome P450 3A4 (CYP3A4)&#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;
&#xD;
          -  Legal incapacity or limited legal capacity&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Responsible</last_name>
    <role>Study Director</role>
    <affiliation>Merck Serono Co., Ltd., Japan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Kashiwa</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Tokyo</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>September 30, 2014</study_first_submitted>
  <study_first_submitted_qc>September 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2014</study_first_posted>
  <results_first_submitted>September 29, 2017</results_first_submitted>
  <results_first_submitted_qc>July 26, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">December 14, 2018</results_first_posted>
  <last_update_submitted>July 26, 2018</last_update_submitted>
  <last_update_submitted_qc>July 26, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 14, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma</keyword>
  <keyword>TH-302</keyword>
  <keyword>Doxorubicin</keyword>
  <keyword>Evofosfamide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sarcoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Doxorubicin</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>First/Last subject (informed consent): 10 December 2014/02 November 2015. Study completion date: 12 January 2016. Clinical data cut-off: 31 March 2016.</recruitment_details>
      <pre_assignment_details>The study was planned to include a combination therapy period (including an initial Safety Run-In Phase followed by Phase II treatment period) and a TH-302 monotherapy period. However, due to early termination, only Safety Run-In Phase was conducted; thus, all the analyses are limited to Safety Run-In Phase.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>TH-302 and Doxorubicin</title>
          <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Safety Analysis Set (SAF) included all subjects who received at least 1 dose of either TH-302 or doxorubicin.</population>
      <group_list>
        <group group_id="B1">
          <title>TH-302 and Doxorubicin</title>
          <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="52.7" spread="10.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression Free Survival (PFS) by Independent Central Review (Phase II Treatment Period)</title>
        <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
        <time_frame>From first dose of study drug administration until PD or death, evaluated at 6 months</time_frame>
        <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) by Independent Central Review (Phase II Treatment Period)</title>
          <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
          <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS) by Investigator Review (Phase II Treatment Period)</title>
        <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
        <time_frame>From first dose of study drug administration until PD or death, evaluated at 6 months</time_frame>
        <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) by Investigator Review (Phase II Treatment Period)</title>
          <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
          <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS) by Investigator and Independent Central Review (Phase II Treatment Period)</title>
        <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
        <time_frame>From first dose of study drug administration until PD or death, evaluated at 3 months and 9 months</time_frame>
        <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS) by Investigator and Independent Central Review (Phase II Treatment Period)</title>
          <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
          <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS) (Phase II Treatment Period)</title>
        <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
        <time_frame>From first dose of study drug administration until PD or death, assessed up to 12 months</time_frame>
        <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS) (Phase II Treatment Period)</title>
          <description>PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
          <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Best Overall Response (BOR) by Independent Central Review (Phase II Treatment Period)</title>
        <description>BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to &lt; 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions.</description>
        <time_frame>From first dose of study drug administration until PD or death, assessed up to 12 months</time_frame>
        <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Best Overall Response (BOR) by Independent Central Review (Phase II Treatment Period)</title>
          <description>BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to &lt; 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions.</description>
          <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Best Overall Response (BOR) by Investigator (Phase II Treatment Period)</title>
        <description>BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to &lt; 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions.</description>
        <time_frame>From first dose of study drug administration until PD or death, assessed up to 12 months</time_frame>
        <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Best Overall Response (BOR) by Investigator (Phase II Treatment Period)</title>
          <description>BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to &lt; 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions.</description>
          <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response (Phase II Treatment Period)</title>
        <description>Duration of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) is defined as the time from the first assessment of complete response (CR) or partial response (PR) until the date of the first occurrence of progressive disease (PD), or until the date of death. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to less than (&lt;) 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
        <time_frame>From first dose of study drug administration until PD or death, assessed up to 12 months</time_frame>
        <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response (Phase II Treatment Period)</title>
          <description>Duration of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) is defined as the time from the first assessment of complete response (CR) or partial response (PR) until the date of the first occurrence of progressive disease (PD), or until the date of death. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to less than (&lt;) 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.</description>
          <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS) (Phase II Treatment Period)</title>
        <description>OS is defined as the time from first dose to death due to any cause.</description>
        <time_frame>From first dose of study drug administration until the last subject completes the survival follow-up, assessed up to 12 months</time_frame>
        <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS) (Phase II Treatment Period)</title>
          <description>OS is defined as the time from first dose to death due to any cause.</description>
          <population>As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) (Safety Run-In Phase)</title>
        <description>An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the stud drug.</description>
        <time_frame>From baseline until end of trial, assessed up to Day 210</time_frame>
        <population>The SAF Analysis Set included all subjects who received at least 1 dose of either TH-302 or doxorubicin.</population>
        <group_list>
          <group group_id="O1">
            <title>TH-302 and Doxorubicin</title>
            <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) (Safety Run-In Phase)</title>
          <description>An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the stud drug.</description>
          <population>The SAF Analysis Set included all subjects who received at least 1 dose of either TH-302 or doxorubicin.</population>
          <units>Subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Baseline up to Day 210 (Safety Run-In Phase)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>TH-302 and Doxorubicin</title>
          <description>Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumour haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Infusion site reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lymph gland infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Incorrect dosage administered</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>C-reactive protein increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT prolonged</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypophosphataemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumour pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dysphonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysaesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
    </certain_agreements>
    <limitations_and_caveats>This study was terminated early following the discontinuation of TH-302 clinical development program. Only 6 subjects were enrolled and treated in the Safety Run-In Phase; thus, the statistical analyses are limited to the Safety Run-In Phase.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Merck KGaA Communication Center</name_or_title>
      <organization>Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany</organization>
      <phone>+49-6151-72-5200</phone>
      <email>service@merckgroup.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02255110
org study id: EMR200592-008
nct id: NCT02255110
lead sponsor: 
collaborator: 
has dmc: No
This is a Phase 2, single-arm, Japanese multicenter trial to evaluate the safety,
      tolerability, and efficacy of TH-302 in combination with doxorubicin in subjects with locally
      advanced unresectable or metastatic soft tissue sarcoma (STS).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival (PFS) by Independent Central Review (Phase II Treatment Period)
time frame: From first dose of study drug administration until PD or death, evaluated at 6 months
description: PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
measure: Progression Free Survival (PFS) by Investigator Review (Phase II Treatment Period)
time frame: From first dose of study drug administration until PD or death, evaluated at 6 months
description: PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
measure: Progression-free Survival (PFS) by Investigator and Independent Central Review (Phase II Treatment Period)
time frame: From first dose of study drug administration until PD or death, evaluated at 3 months and 9 months
description: PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
measure: Progression-free Survival (PFS) (Phase II Treatment Period)
time frame: From first dose of study drug administration until PD or death, assessed up to 12 months
description: PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
measure: Best Overall Response (BOR) by Independent Central Review (Phase II Treatment Period)
time frame: From first dose of study drug administration until PD or death, assessed up to 12 months
description: BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions.
measure: Best Overall Response (BOR) by Investigator (Phase II Treatment Period)
time frame: From first dose of study drug administration until PD or death, assessed up to 12 months
description: BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions.
measure: Duration of Response (Phase II Treatment Period)
time frame: From first dose of study drug administration until PD or death, assessed up to 12 months
description: Duration of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) is defined as the time from the first assessment of complete response (CR) or partial response (PR) until the date of the first occurrence of progressive disease (PD), or until the date of death. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to less than (<) 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
measure: Overall Survival (OS) (Phase II Treatment Period)
time frame: From first dose of study drug administration until the last subject completes the survival follow-up, assessed up to 12 months
description: OS is defined as the time from first dose to death due to any cause.
measure: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) (Safety Run-In Phase)
time frame: From baseline until end of trial, assessed up to Day 210
description: An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the stud drug.
arm group label: TH-302 and doxorubicin
arm group type: Experimental
intervention type: Drug
intervention name: TH-302
description: TH-302 will be administered at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Days 1 and 8 of every 21-day cycle until the evidence of significant treatment-related toxicity or progressive disease.
arm group label: TH-302 and doxorubicin
intervention type: Drug
intervention name: Doxorubicin
description: Doxorubicin will be administered at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.
arm group label: TH-302 and doxorubicin
criteria: 
gender: All
minimum age: 15 Years
maximum age: N/A
healthy volunteers: No
last name: Medical Responsible
role: Study Director
affiliation: Merck Serono Co., Ltd., Japan
facility: 
facility: 
country: Japan
responsible party type: Sponsor
mesh term: Sarcoma
mesh term: Doxorubicin
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This study was terminated early following the discontinuation of TH-302 clinical development program. Only 6 subjects were enrolled and treated in the Safety Run-In Phase; thus, the statistical analyses are limited to the Safety Run-In Phase.
point of contact: 