<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/NCT02201329</url>
  </required_header>
  <id_info>
    <org_study_id>1230.35</org_study_id>
    <nct_id>NCT02201329</nct_id>
  </id_info>
  <brief_title>Volasertib in Combination With Azacitidine in Japanese Patients With Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia</brief_title>
  <official_title>An Open Label Phase I Trial of Intravenous Volasertib in Combination With Subcutaneous Azacitidine in Japanese Patients With Higher-risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      To identify the maximum tolerated dose or recommended dose for further development of&#xD;
      volasertib in combination with azacitidine in Japanese patients with myelodysplastic&#xD;
      syndromes or chronic myelomonocytic leukemia, and evaluate the safety and tolerability,&#xD;
      pharmacokinetics and the preliminary efficacy of this combination.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">September 2015</completion_date>
  <primary_completion_date type="Actual">January 2015</primary_completion_date>
  <phase>Phase 1</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>Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)</measure>
    <time_frame>Up to 57 days.</time_frame>
    <description>This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLT was defined as any of the following Adverse Events (AEs) considered to be related to the study drug (Volasertib and/or Azacitidine).&#xD;
Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 drug-related non-haematologic toxicity.&#xD;
Drug-related AEs that led to inability to deliver the full dose of the study drugs (Volasertib and/or Azacitidine) according to the assigned dose level within Cycle 1.&#xD;
Absence of haematological recovery (sustained CTCAE grade ≥3 thrombocytopenia &lt;50000/mm^3 and/or neutropenia &lt;1000/mm^3) after completing Cycle 1 and lasting at least until Day 57 (from Day 1 of Cycle 1) despite complete marrow blast clearance on Day 29 (&lt;5% blasts in the bone marrow.&#xD;
Any other drug-related AEs that required treatment delay of ≥4 weeks between the Cycle 1 and Cycle 2 (i.e., Cycle 2 was not started until Day 57 of Cycle 1)).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose of Volasertib</measure>
    <time_frame>Up to 57 days.</time_frame>
    <description>This outcome measure presents MTD of Volasertib in Combination with Azacitidine. The MTD was defined as the highest dose level at which Dose Limiting Toxicities (DLTs) were reported in not more than 1 in 6 evaluable patients during Cycle 1.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR)</measure>
    <time_frame>Up to 9 months.</time_frame>
    <description>This outcome measure presents overall Objective Response (CR+PR+mCR). Response to treatment was evaluated according to the International Working Group (IWG) 2006 criteria. Best response was tabulated from all available data, with each patient being classified into one of the categories defined in CR, PR, mCR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax)</measure>
    <time_frame>-0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration.</time_frame>
    <description>This outcome measure presents maximum measured concentration of Volasertib 200 mg in plasma (Cmax).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)</measure>
    <time_frame>-0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration.</time_frame>
    <description>This outcome measure presents area under the concentration-time curve of Volasertib 200 mg + Azacitidine 75 mg/m^2 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Myelodysplastic Syndromes</condition>
  <condition>Leukemia, Myelomonocytic, Chronic</condition>
  <arm_group>
    <arm_group_label>A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Volasertib escalating doses + azacitidine</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azacitidine</intervention_name>
    <description>Azacitidine (subcutaneous)</description>
    <arm_group_label>A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Volasertib</intervention_name>
    <description>Volasertib escalating doses (intravenous)</description>
    <arm_group_label>A</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. Patients of age &gt;=20 and &lt;=80 years&#xD;
&#xD;
          2. Patients with primary or treatment-related myelodysplastic syndrome (MDS) or chronic&#xD;
             myelomonocytic leukemia (CMML), who are not eligible for hematopoietic stem cell&#xD;
             transplantation based on the investigator's judgment, that meet one of the following&#xD;
             criteria:&#xD;
&#xD;
               -  Intermediate-2 and high-risk MDS according to the International Prognostic&#xD;
                  Scoring System, in the setting of 5-30% bone marrow blasts&#xD;
&#xD;
               -  CMML with &gt;= 10% marrow blasts without myeloproliferative disorder (white blood&#xD;
                  cell count of &lt;13,000/ µL)&#xD;
&#xD;
          3. Patients with no prior azacitidine treatment, or with prior azacitidine treatment that&#xD;
             meet one of the following criteria:&#xD;
&#xD;
               -  Patients failing to achieve haematological improvement, partial remission, marrow&#xD;
                  complete remission or complete remission after 3 cycles of azacitidine or&#xD;
                  progressed at any time after start of azacitidine&#xD;
&#xD;
               -  Patients achieved an initial response and subsequently develop disease&#xD;
                  progression or relapse&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group performance status score 0 or 1 at screening&#xD;
&#xD;
          5. Signed written informed consent consistent with Good Clinical Practice.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Treatment with systemic therapy for MDS, including an investigational drug, within 14&#xD;
             days before the first dose of study treatment, except for lenalidomide within 12 weeks&#xD;
             before the first dose of study treatment, or lack of recovery from any acute&#xD;
             toxicities pertinent to the prior systemic therapy.&#xD;
&#xD;
          2. Prior treatment with volasertib&#xD;
&#xD;
          3. Contraindications for azacitidine treatment according to the manufacturer's product&#xD;
             information&#xD;
&#xD;
          4. Known hypersensitivity to the trial drugs or its excipients&#xD;
&#xD;
          5. Concomitant malignancy currently requiring active therapy (except for&#xD;
             hormonal/anti-hormonal treatment, e.g. in prostate or breast cancer)&#xD;
&#xD;
          6. QTcF prolongation &gt;470 ms or QT prolongation deemed clinically relevant by the&#xD;
             investigator (e.g., congenital long QT syndrome).&#xD;
&#xD;
          7. Total bilirubin &gt;1.5 x upper limit of normal (ULN) not related to Gilbert's syndrome,&#xD;
             hemolysis, or secondary to MDS at screening&#xD;
&#xD;
          8. Aspartate amino transferase or alanine amino transferase &gt;2.5 x ULN&#xD;
&#xD;
          9. Serum creatinine &gt;1.5 x ULN at screening&#xD;
&#xD;
         10. Arterial oxygen pressure &lt;60 torr or arterial oxygen saturation &lt;92% (at room air)&#xD;
&#xD;
         11. Active hepatitis B or hepatitis C, or laboratory evidence of hepatitis with positive&#xD;
             results of hepatitis B surface antigen and/or hepatitis C antibody.&#xD;
&#xD;
         12. Human immunodeficiency virus infection.&#xD;
&#xD;
         13. Severe illness or organ dysfunction involving the heart, lung, kidney, liver or other&#xD;
             organ system, which in the opinion of the investigator would interfere with the&#xD;
             evaluation of the safety of the study treatment including; infection requiring active&#xD;
             treatment, poorly controlled ventricular/atrial tachyarrhythmia, use of heart pacer,&#xD;
             unstable angina pectoris, history of myocardial infarction or severe congestive heart&#xD;
             failure, clinically unstable cardiac or pulmonary disease&#xD;
&#xD;
         14. Any significant concurrent psychiatric disorder or social situation that according to&#xD;
             the investigator's judgment would compromise patient's safety or compliance, interfere&#xD;
             with consent, study participation, or interpretation of study results&#xD;
&#xD;
         15. All male patients and female patients of child bearing potential who are unwilling to&#xD;
             use a medically acceptable method of contraception during the trial and at least 6&#xD;
             months after the end of study treatment (i.e. hormonal contraception, intrauterine&#xD;
             device, condom with spermicide, etc.). Note: females are considered to be of child&#xD;
             bearing potential unless they have been surgically sterilized or are post-menopausal&#xD;
             (complete absence of menses for at least 12 months without other medical reasons).&#xD;
&#xD;
         16. Pregnant or nursing female patients&#xD;
&#xD;
         17. Known or suspected active alcohol or drug abuse&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Boehringer Ingelheim</last_name>
    <role>Study Chair</role>
    <affiliation>Boehringer Ingelheim</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Aichi, Nagoya</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Gunma, Maebashi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Nagasaki, Nagasaki</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Tokyo, Sinagawa-ku</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <link>
    <url>http://trials.boehringer-ingelheim.com</url>
    <description>Related Info</description>
  </link>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>July 25, 2014</study_first_submitted>
  <study_first_submitted_qc>July 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 28, 2014</study_first_posted>
  <results_first_submitted>October 23, 2017</results_first_submitted>
  <results_first_submitted_qc>October 23, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">July 30, 2018</results_first_posted>
  <last_update_submitted>October 23, 2017</last_update_submitted>
  <last_update_submitted_qc>October 23, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">July 30, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Chronic</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Juvenile</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azacitidine</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Volasertib 200 mg</title>
          <description>The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Progressive Dis./Relapse/Clinical Prog.</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.</population>
      <group_list>
        <group group_id="B1">
          <title>Volasertib 200 mg</title>
          <description>The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="5"/>
          </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="73.2" spread="4.6"/>
                  </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="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)</title>
        <description>This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLT was defined as any of the following Adverse Events (AEs) considered to be related to the study drug (Volasertib and/or Azacitidine).&#xD;
Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 drug-related non-haematologic toxicity.&#xD;
Drug-related AEs that led to inability to deliver the full dose of the study drugs (Volasertib and/or Azacitidine) according to the assigned dose level within Cycle 1.&#xD;
Absence of haematological recovery (sustained CTCAE grade ≥3 thrombocytopenia &lt;50000/mm^3 and/or neutropenia &lt;1000/mm^3) after completing Cycle 1 and lasting at least until Day 57 (from Day 1 of Cycle 1) despite complete marrow blast clearance on Day 29 (&lt;5% blasts in the bone marrow.&#xD;
Any other drug-related AEs that required treatment delay of ≥4 weeks between the Cycle 1 and Cycle 2 (i.e., Cycle 2 was not started until Day 57 of Cycle 1)).</description>
        <time_frame>Up to 57 days.</time_frame>
        <population>MTD Set: This patient set included all patients in the treated set who were evaluable for MTD determination.</population>
        <group_list>
          <group group_id="O1">
            <title>Volasertib 200 mg</title>
            <description>The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)</title>
          <description>This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLT was defined as any of the following Adverse Events (AEs) considered to be related to the study drug (Volasertib and/or Azacitidine).&#xD;
Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 drug-related non-haematologic toxicity.&#xD;
Drug-related AEs that led to inability to deliver the full dose of the study drugs (Volasertib and/or Azacitidine) according to the assigned dose level within Cycle 1.&#xD;
Absence of haematological recovery (sustained CTCAE grade ≥3 thrombocytopenia &lt;50000/mm^3 and/or neutropenia &lt;1000/mm^3) after completing Cycle 1 and lasting at least until Day 57 (from Day 1 of Cycle 1) despite complete marrow blast clearance on Day 29 (&lt;5% blasts in the bone marrow.&#xD;
Any other drug-related AEs that required treatment delay of ≥4 weeks between the Cycle 1 and Cycle 2 (i.e., Cycle 2 was not started until Day 57 of Cycle 1)).</description>
          <population>MTD Set: This patient set included all patients in the treated set who were evaluable for MTD determination.</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose of Volasertib</title>
        <description>This outcome measure presents MTD of Volasertib in Combination with Azacitidine. The MTD was defined as the highest dose level at which Dose Limiting Toxicities (DLTs) were reported in not more than 1 in 6 evaluable patients during Cycle 1.</description>
        <time_frame>Up to 57 days.</time_frame>
        <population>MTD Set: This patient set included all patients in the treated set who were evaluable for MTD determination.</population>
        <group_list>
          <group group_id="O1">
            <title>Volasertib 200 mg</title>
            <description>The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose of Volasertib</title>
          <description>This outcome measure presents MTD of Volasertib in Combination with Azacitidine. The MTD was defined as the highest dose level at which Dose Limiting Toxicities (DLTs) were reported in not more than 1 in 6 evaluable patients during Cycle 1.</description>
          <population>MTD Set: This patient set included all patients in the treated set who were evaluable for MTD determination.</population>
          <units>mg</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">On the basis of DLTs, the MTD of Volasertib administered intravenously on Days 1 and 15 in 28-day cycles in combination with Azacitidine was considered to be less than 200 mg.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR)</title>
        <description>This outcome measure presents overall Objective Response (CR+PR+mCR). Response to treatment was evaluated according to the International Working Group (IWG) 2006 criteria. Best response was tabulated from all available data, with each patient being classified into one of the categories defined in CR, PR, mCR.</description>
        <time_frame>Up to 9 months.</time_frame>
        <population>Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.</population>
        <group_list>
          <group group_id="O1">
            <title>Volasertib 200 mg</title>
            <description>The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR)</title>
          <description>This outcome measure presents overall Objective Response (CR+PR+mCR). Response to treatment was evaluated according to the International Working Group (IWG) 2006 criteria. Best response was tabulated from all available data, with each patient being classified into one of the categories defined in CR, PR, mCR.</description>
          <population>Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Objective Response (OR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Complete Remission (CR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Remission (PR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Marrow Complete Remission (mCR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax)</title>
        <description>This outcome measure presents maximum measured concentration of Volasertib 200 mg in plasma (Cmax).</description>
        <time_frame>-0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration.</time_frame>
        <population>Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.</population>
        <group_list>
          <group group_id="O1">
            <title>Volasertib 200 mg</title>
            <description>The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax)</title>
          <description>This outcome measure presents maximum measured concentration of Volasertib 200 mg in plasma (Cmax).</description>
          <population>Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="713" spread="44.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)</title>
        <description>This outcome measure presents area under the concentration-time curve of Volasertib 200 mg + Azacitidine 75 mg/m^2 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞).</description>
        <time_frame>-0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration.</time_frame>
        <population>Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.</population>
        <group_list>
          <group group_id="O1">
            <title>Volasertib 200 mg</title>
            <description>The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)</title>
          <description>This outcome measure presents area under the concentration-time curve of Volasertib 200 mg + Azacitidine 75 mg/m^2 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞).</description>
          <population>Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4190" spread="25.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Volasertib 200 mg</title>
          <description>The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 18.1</default_vocab>
        <default_assessment>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="2" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Disseminated intravascular coagulation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypersensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pyelonephritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 18.1</default_vocab>
        <default_assessment>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="5" subjects_at_risk="5"/>
              </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="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Arrhythmia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eyelids pruritus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Enterocolitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Tongue coated</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Peripheral swelling</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatic function abnormal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypersensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Blood creatine phosphokinase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Haemoglobin decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
              </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="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Iron overload</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </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="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal impairment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Drug eruption</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Purpura</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </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>
      <restrictive_agreement>Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Boehringer Ingelheim Call Center</name_or_title>
      <organization>Boehringer Ingelheim</organization>
      <phone>1-800-243-0127</phone>
      <email>clintriage.rdg@boehringer-ingelheim.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/NCT02201329
org study id: 1230.35
nct id: NCT02201329
lead sponsor: 
To identify the maximum tolerated dose or recommended dose for further development of
      volasertib in combination with azacitidine in Japanese patients with myelodysplastic
      syndromes or chronic myelomonocytic leukemia, and evaluate the safety and tolerability,
      pharmacokinetics and the preliminary efficacy of this combination.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
time frame: Up to 57 days.
description: This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLT was defined as any of the following Adverse Events (AEs) considered to be related to the study drug (Volasertib and/or Azacitidine).
Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 drug-related non-haematologic toxicity.
Drug-related AEs that led to inability to deliver the full dose of the study drugs (Volasertib and/or Azacitidine) according to the assigned dose level within Cycle 1.
Absence of haematological recovery (sustained CTCAE grade ≥3 thrombocytopenia <50000/mm^3 and/or neutropenia <1000/mm^3) after completing Cycle 1 and lasting at least until Day 57 (from Day 1 of Cycle 1) despite complete marrow blast clearance on Day 29 (<5% blasts in the bone marrow.
Any other drug-related AEs that required treatment delay of ≥4 weeks between the Cycle 1 and Cycle 2 (i.e., Cycle 2 was not started until Day 57 of Cycle 1)).
measure: Maximum Tolerated Dose of Volasertib
time frame: Up to 57 days.
description: This outcome measure presents MTD of Volasertib in Combination with Azacitidine. The MTD was defined as the highest dose level at which Dose Limiting Toxicities (DLTs) were reported in not more than 1 in 6 evaluable patients during Cycle 1.
measure: Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR)
time frame: Up to 9 months.
description: This outcome measure presents overall Objective Response (CR+PR+mCR). Response to treatment was evaluated according to the International Working Group (IWG) 2006 criteria. Best response was tabulated from all available data, with each patient being classified into one of the categories defined in CR, PR, mCR.
measure: Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax)
time frame: -0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration.
description: This outcome measure presents maximum measured concentration of Volasertib 200 mg in plasma (Cmax).
measure: Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
time frame: -0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration.
description: This outcome measure presents area under the concentration-time curve of Volasertib 200 mg + Azacitidine 75 mg/m^2 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞).
arm group label: A
arm group type: Experimental
description: Volasertib escalating doses + azacitidine
intervention type: Drug
intervention name: Azacitidine
description: Azacitidine (subcutaneous)
arm group label: A
intervention type: Drug
intervention name: Volasertib
description: Volasertib escalating doses (intravenous)
arm group label: A
criteria: 
gender: All
minimum age: 20 Years
maximum age: 80 Years
healthy volunteers: No
last name: Boehringer Ingelheim
role: Study Chair
affiliation: Boehringer Ingelheim
facility: 
facility: 
facility: 
facility: 
country: Japan
url: http://trials.boehringer-ingelheim.com
description: Related Info
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Preleukemia
mesh term: Leukemia, Myelomonocytic, Chronic
mesh term: Leukemia, Myelomonocytic, Juvenile
mesh term: Myelodysplastic Syndromes
mesh term: Syndrome
mesh term: Azacitidine
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 