<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/NCT03814005</url>
  </required_header>
  <id_info>
    <org_study_id>Pevonedistat-1016</org_study_id>
    <secondary_id>U1111-1220-1396</secondary_id>
    <secondary_id>2018-004049-17</secondary_id>
    <nct_id>NCT03814005</nct_id>
  </id_info>
  <brief_title>A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems</brief_title>
  <official_title>A Phase 1/1b Study of Pevonedistat in Combination With Select Standard of Care Agents in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myelogenous Leukemia, or Advanced Solid Tumors With Severe Renal Impairment or Mild or Moderate Hepatic Impairment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Takeda</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Takeda</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pevonedistat is a medicine to treat people with blood cancers or solid tumors.&#xD;
&#xD;
      The main aim of the study is to learn about the levels of pevonedistat in the blood of&#xD;
      participants with blood cancers or solid tumors, who also have severe kidney problems or mild&#xD;
      to moderate liver problems. The information from this study will be used to work out the best&#xD;
      dose of pevonedistat to give people with these conditions in future studies. At the first&#xD;
      visit, the study doctor will check who can take part in the study.&#xD;
&#xD;
      This study is in 2 parts: A and B.&#xD;
&#xD;
      Part A Participants will be placed into 1 of 4 treatment groups depending on how severe their&#xD;
      kidney and liver problems are. All participants will receive 1 dose of pevonedistat as a slow&#xD;
      injection in their vein (infusion). Then, the study doctors will check the levels of&#xD;
      pevonedistat in the blood of the participants for 3 days after the infusion. They will also&#xD;
      check if the participants have any side effects from pevonedistat.&#xD;
&#xD;
      Participants will be asked to continue to Part B. Those who don't want to continue will visit&#xD;
      the clinic 30 days later for a final check-up.&#xD;
&#xD;
      Part B Participants who agree to participate into Part B will receive an infusion of&#xD;
      pevonedistat on specific days during a 21-day or 28-day cycle. The cycle time will depend on&#xD;
      what type of cancer the participants have. Participants will also be treated with standard of&#xD;
      care medicines for their kidney and liver problems during this time. In the first cycle, the&#xD;
      study doctors will also check the levels of pevonedistat in the blood and urine of&#xD;
      participants for 3 days after the infusion. Participants will continue with cycles of&#xD;
      treatment together with standard of care medicines until their condition gets worse or they&#xD;
      have too many side effects from the treatment.&#xD;
&#xD;
      When treatment has finished, participants will visit the clinic 10 days later for a final&#xD;
      check-up.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The drug being tested in this study is called pevonedistat. The study will characterize the&#xD;
      PK of pevonedistat, assess the safety, and determine the dose of pevonedistat, in combination&#xD;
      with azacitidine, docetaxel OR paclitaxel plus carboplatin in participants with higher-risk&#xD;
      myelodysplastic syndromes (HRMDS), myelodysplastic syndromes (MDS), chronic myelomonocytic&#xD;
      leukemia (CMML), acute myelogenous leukemia (AML), or advanced solid tumors who also have&#xD;
      severe renal impairment or mild or moderate hepatic impairment.&#xD;
&#xD;
      The study will enroll approximately 42 participants. Participants with solid tumors or&#xD;
      hematologic malignancies will be assigned to one of the four treatment groups on the basis of&#xD;
      their renal and hepatic function:&#xD;
&#xD;
        -  Control Arm (Normal Renal and Hepatic Function)&#xD;
&#xD;
        -  Renal Arm (Severe Renal Impairment)&#xD;
&#xD;
        -  Mild Hepatic Arm (Mild Hepatic Impairment)&#xD;
&#xD;
        -  Moderate Hepatic Arm (Moderate Hepatic Impairment)&#xD;
&#xD;
      The study will be conducted in 2 parts: Part A and Part B. Part A will include single dose&#xD;
      administration of pevonedistat. Eligible participants from Part A who will opt to continue&#xD;
      treatment in Part B will be treated with pevonedistat in combination with standard of care&#xD;
      (SOC) agents (azacitidine, docetaxel OR paclitaxel plus carboplatin) in Part B.&#xD;
&#xD;
      Intrapatient dose escalation of pevonedistat and SOC agents will be based on the safety data&#xD;
      from Cycle 1 of Part B as mentioned below:&#xD;
&#xD;
        -  In renal arm (severe renal impairment ) based on the safety data from Cycle 1 of Part B,&#xD;
           pevonedistat may be increased to 15 mg/m^2 on Days 1, 3, and 5 of Cycle 2 Part B and in&#xD;
           subsequent Cycles, to a maximum dose of 25 mg/m^2. Participants may be eligible for&#xD;
           intrapatient dose escalation to paclitaxel 175 mg/m^2 in Cycle 2 or beyond if the lower&#xD;
           dose is well tolerated. Intrapatient dose escalation of carboplatin to AUC5 will be&#xD;
           allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.&#xD;
&#xD;
        -  In mild hepatic arm (mild hepatic impairment), the starting dose for pevonedistat and&#xD;
           azacitidine in combination are not escalated in the cohort. Intrapatient dose escalation&#xD;
           of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is&#xD;
           safe and tolerable.&#xD;
&#xD;
        -  In moderate hepatic arm (moderate hepatic impairment) based on the safety data from&#xD;
           Cycle 1 of Part B, pevonedistat may be increased to 15 mg/m^2 on Days 1, 3, and 5 of&#xD;
           Cycle 2 Part B and in subsequent Cycles, to a maximum dose of 20 mg/m^2. Intrapatient&#xD;
           dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1&#xD;
           of Part B is safe and tolerable.&#xD;
&#xD;
      This multi-center trial will be conducted in the United States and Spain. The overall time to&#xD;
      participate in this study is approximately 3.5 years. Participants will attend end of the&#xD;
      study visit 30 days after the last dose of study drug or before the start of subsequent&#xD;
      therapy, if that occurs sooner for safety follow up.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 10, 2019</start_date>
  <completion_date type="Actual">April 19, 2022</completion_date>
  <primary_completion_date type="Actual">March 19, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part A, AUC∞: Area Under the Plasma Concentration-time Curve from Time Zero to Infinity for Pevonedistat Following a Single Dose</measure>
    <time_frame>Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Part A, AUClast: Area Under the Plasma Concentration-time Curve from Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose</measure>
    <time_frame>Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose</measure>
    <time_frame>Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose</measure>
    <time_frame>Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle (C ) 1 Day (D) 3 pre-dose and at multiple time points (up to 48 hours) post-dose (C length =28 D [hematologic malignancies], and =21 D [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts A and B, fu: Fraction of Unbound Drug in Plasma for Pevonedistat</measure>
    <time_frame>Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle (C) 1 Day (D) 3 pre-dose and at multiple time points (up to 48 hours) post-dose (C length =28 D [hematologic malignancies], and =21 D [solid tumors]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length is equal to [=] 28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length = 28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, AUCτ: Area under the Concentration-time Curve from Time Zero to the end of the Dosing Interval for Pevonedistat and Azacitidine Following Multiple Dose</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts A and B, CL: Total Clearance for Pevonedistat</measure>
    <time_frame>Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle (C) 1 Day (D) 3 pre-dose and at multiple time points (up to 48 hours) post-dose (C length =28 D [hematologic malignancies], and =21 D [solid tumors]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, CL/F: Apparent Clearance for Azacitidine</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, CLR: Renal Clearance for Pevonedistat</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, CLR: Renal Clearance for Azacitidine</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat</measure>
    <time_frame>Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle (C) 1 Day (D) 3 pre-dose and at multiple time points (up to 48 hours) post-dose (C length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Vss: Apparent Volume of Distribution of Azacitidine</measure>
    <time_frame>Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Percentage of AML Participants with Complete Response (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR)</measure>
    <time_frame>Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 3.5 years) (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
    <description>Disease response in AML are based on international working group (IWG) for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in AML. For AML participants, all CR includes both CR and CRi. CR: morphologic leukemia-free state with absolute neutrophil count (ANC) of greater than (&gt;) 1000 per microliter (/mcL) and platelets of greater than or equal to (&gt;=) 100,000/mcL, and no residual evidence of extramedullary leukemia. CRi: After chemotherapy, some participants fulfill all criteria for CR except for residual neutropenia (less than [&lt;] 1000/mcL) or thrombocytopenia (&lt;100,000/mcL). PR: requires all hematologic values for a CR but with a decrease of at least 50 percent (%) in the percentage of blasts to 5% to 25% in the bone marrow aspirate. A value of less than or equal to (&lt;=) 5% blasts may also be considered a PR if Auer rods are present.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Percentage of MDS and CMML Participants with CR, PR or Hematologic Improvement (HI)</measure>
    <time_frame>Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 3.5 years) (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
    <description>Disease response in MDS and CMML will be based on best overall response (CR+PR+HI) as determined by investigator using revised IWG response criteria for MDS and CMML.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Percentage of AML Participants with Overall Response</measure>
    <time_frame>Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 3.5 years) (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
    <description>Overall response (CR + PR) will be determined by using the revised IWG response criteria. For AML participants, all CR includes both CR and CRi.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Duration of CR, PR and HI</measure>
    <time_frame>From first documentation of response up to disease progression ( up to 3.5 years)</time_frame>
    <description>Duration of response in participants with disease response (CR+PR+HI) for hematologic malignancies is time between first documentation of response and disease progression. Duration of response will be determined by the investigator using the revised IWG response criteria. The duration of response in participants with disease response (CR+PR) for solid tumors is time between the first documentation of response and the first documentation of progressive disease (PD) or death if no prior PD is documented. Duration of response will be determined by investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B, Percentage of Solid Tumors Participants with CR or PR</measure>
    <time_frame>Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 3.5 years) (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])</time_frame>
    <description>Disease response in solid tumors will be based on best overall response (CR+PR) as determined by investigator using the RECIST version 1.1 criteria. CR: disappearance of all target lesions with any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to &lt;10 millimeter (mm) and disappearance of all nontarget lesions and normalization of tumor marker level with all lymph nodes must be nonpathological in size (&lt;10 mm short axis); PR: At least a 30% decrease from baseline in the sum of diameters of target lesions, taking as reference the baseline sum of diameters and Persistence of one or more nontarget lesion(s) or/and maintenance of tumor marker level above the normal limits.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Myelodysplastic Syndromes</condition>
  <condition>Leukemia, Myelomonocytic, Chronic</condition>
  <condition>Leukemia, Myeloid, Acute</condition>
  <condition>Renal Insufficiency</condition>
  <condition>Liver Disease</condition>
  <condition>Neoplasms</condition>
  <arm_group>
    <arm_group_label>Control Arm (Normal Renal and Hepatic Function)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pevonedistat 20 milligram per square meter (mg/m^2), infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Renal Arm (Severe Renal Impairment)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pevonedistat 20 mg/m^2, infusion, intravenously, once, on Day1 of Part A in participants with hematologic malignancies or solid tumors, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day1 through Day7 or Day1 through Day5, and on Days 8-9 in combination with pevonedistat 15 mg/m^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies and docetaxel 75 mg/m^2 OR carboplatin AUC4, infusion, intravenously, once along with paclitaxel 135 mg/m^2, infusion, intravenously, once on Day 1 in combination with pevonedistat 15 mg/m^2, infusion, intravenously, on Days 3 and 5 in each 21-day treatment cycle in participants with solid tumors until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Mild Hepatic Arm (Mild Hepatic Impairment)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pevonedistat 20 mg/m^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies or solid tumors, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies, and carboplatin AUC4, infusion, intravenously, once along with paclitaxel 135 mg/m^2, infusion, intravenously, once on Day 1 in combination with pevonedistat 20 mg/m^2, infusion, intravenously, on Days 3 and 5 in each 21-day treatment cycle in participants with solid tumors until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Moderate Hepatic Arm (Moderate Hepatic Impairment)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pevonedistat 20 mg/m^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies or solid tumors, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 10 mg/m^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies, and carboplatin AUC4, infusion, intravenously, once along with paclitaxel 90 mg/m^2, infusion, intravenously, once on Day 1 in combination with pevonedistat 10 mg/m^2, infusion, intravenously, on Days 3 and 5 in each 21-day treatment cycle in participants with solid tumors until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azacitidine</intervention_name>
    <description>Azacitidine subcutaneous or intravenous injection.</description>
    <arm_group_label>Control Arm (Normal Renal and Hepatic Function)</arm_group_label>
    <arm_group_label>Mild Hepatic Arm (Mild Hepatic Impairment)</arm_group_label>
    <arm_group_label>Moderate Hepatic Arm (Moderate Hepatic Impairment)</arm_group_label>
    <arm_group_label>Renal Arm (Severe Renal Impairment)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pevonedistat</intervention_name>
    <description>Pevonedistat intravenous infusion.</description>
    <arm_group_label>Control Arm (Normal Renal and Hepatic Function)</arm_group_label>
    <arm_group_label>Mild Hepatic Arm (Mild Hepatic Impairment)</arm_group_label>
    <arm_group_label>Moderate Hepatic Arm (Moderate Hepatic Impairment)</arm_group_label>
    <arm_group_label>Renal Arm (Severe Renal Impairment)</arm_group_label>
    <other_name>TAK-924 and MLN4924</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Docetaxel</intervention_name>
    <description>Docetaxel intravenous infusion.</description>
    <arm_group_label>Renal Arm (Severe Renal Impairment)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paclitaxel</intervention_name>
    <description>Paclitaxel intravenous infusion.</description>
    <arm_group_label>Mild Hepatic Arm (Mild Hepatic Impairment)</arm_group_label>
    <arm_group_label>Moderate Hepatic Arm (Moderate Hepatic Impairment)</arm_group_label>
    <arm_group_label>Renal Arm (Severe Renal Impairment)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Carboplatin intravenous infusion.</description>
    <arm_group_label>Mild Hepatic Arm (Mild Hepatic Impairment)</arm_group_label>
    <arm_group_label>Moderate Hepatic Arm (Moderate Hepatic Impairment)</arm_group_label>
    <arm_group_label>Renal Arm (Severe Renal Impairment)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All participants:&#xD;
&#xD;
          1. Has expected survival of at least 3 months from the date of enrollment in the study.&#xD;
&#xD;
          2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.&#xD;
&#xD;
          3. Has recovered (that is, Grade &lt;=1 toxicity) from the reversible effects of prior&#xD;
             anticancer therapy.&#xD;
&#xD;
          4. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) &lt;=1.5 * upper&#xD;
             limit of the normal range (ULN) at screening or within 7 days before the first dose of&#xD;
             study drug.&#xD;
&#xD;
          5. Suitable venous access for the study-required blood sampling (that is, PK sampling).&#xD;
&#xD;
             For hematologic malignancies:&#xD;
&#xD;
          6. Previously untreated hematologic malignancies not suitable for induction therapy.&#xD;
&#xD;
          7. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with&#xD;
             white blood cell [WBC] &lt;13,000 /mcL) at the study entry, based on one of the&#xD;
             following:&#xD;
&#xD;
             French-American-British (FAB) Classifications:&#xD;
&#xD;
               -  Refractory anemia with excess blasts (RAEB), defined as having 5% to 20%&#xD;
                  myeloblasts in the bone marrow.&#xD;
&#xD;
               -  CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in&#xD;
                  the blood.&#xD;
&#xD;
             OR&#xD;
&#xD;
             World Health Organization (WHO) Classifications:&#xD;
&#xD;
               -  RAEB-1, defined as having 5% to 9% myeloblasts in the bone marrow.&#xD;
&#xD;
               -  RAEB-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to&#xD;
                  19% blasts in the blood.&#xD;
&#xD;
               -  CMML-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to&#xD;
                  19% blasts in the blood.&#xD;
&#xD;
               -  CMML-1 (although CMML-1 is defined as having &lt;10% myeloblasts in the bone marrow&#xD;
                  and/or &lt;5% blasts in the blood, these participants may enroll only if bone marrow&#xD;
                  blasts &gt;=5%).&#xD;
&#xD;
          8. With MDS or CMML and must also have one of the following Prognostic Risk Categories,&#xD;
             based on the Revised International Prognostic Scoring System (IPSS-R):&#xD;
&#xD;
               -  Very high (&gt;6 points).&#xD;
&#xD;
               -  High (&gt;4.5-6 points).&#xD;
&#xD;
               -  Intermediate (&gt;3-4.5 points): a participant determined to be in the Intermediate&#xD;
                  Prognostic Risk Category is only allowable in the setting of &gt;=5% bone marrow&#xD;
                  myeloblasts.&#xD;
&#xD;
          9. With WHO-defined AML at study entry, including leukemia secondary to prior&#xD;
             chemotherapy or resulting from an antecedent hematologic disorder, have failed to&#xD;
             achieve CR or have relapsed after prior therapy and are not candidates for potentially&#xD;
             curative treatment.&#xD;
&#xD;
         10. With relapsed or refractory MDS, have previously been treated with an hypomethylating&#xD;
             agent.&#xD;
&#xD;
         11. Laboratory value requirements per study arms are:&#xD;
&#xD;
               -  Estimated glomerular filtration rate (eGFR) (milliliter per minute per 1.73&#xD;
                  square meter [mL/min/1.73^m]) &gt;=90 (Control arm), &lt;30 (Renal arm) , &gt;=60 (Mild&#xD;
                  and Moderate hepatic arm).&#xD;
&#xD;
               -  Total Bilirubin &lt;= ULN (Control arm), &lt;= ULN (Renal arm), ULN &lt;Bilirubin &lt;=1.5 *&#xD;
                  ULN (not secondary to transfusions) (Mild hepatic arm) and 1.5 * ULN &lt;bilirubin&#xD;
                  &lt;=3.0 * ULN (not secondary to transfusions) (Moderate hepatic arm).&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) &lt;= ULN (Control arm), &lt;=2.5 * ULN (Renal arm) and&#xD;
                  any value (for mild and moderate hepatic arm).&#xD;
&#xD;
             For advanced solid tumors:&#xD;
&#xD;
         12. Have a histologically or cytologically confirmed metastatic or locally advanced solid&#xD;
             tumor that is appropriate for treatment with pevonedistat in combination with either&#xD;
             docetaxel or carboplatin plus paclitaxel in Part B of this study, or have progressed&#xD;
             despite standard therapy, or whom conventional therapy is not considered effective.&#xD;
&#xD;
         13. Computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the chest,&#xD;
             abdomen, and pelvis within 28 days of the first dose of the study drug.&#xD;
&#xD;
         14. Laboratory value requirements per study arms are:&#xD;
&#xD;
               -  eGFR (mL/min/1.73m^2) &lt;30 (Renal arm) and &gt;=60 (mild and moderate hepatic arm).&#xD;
&#xD;
               -  Total bilirubin &lt;=ULN (Renal arm), ULN &lt;bilirubin &lt;=1.5 * ULN (Mild hepatic arm)&#xD;
                  and 1.5 * ULN &lt;bilirubin &lt;=3.0 * ULN (Moderate hepatic arm).&#xD;
&#xD;
               -  ALT &lt;=1.5 * ULN (for participants who receive pevonedistat plus docetaxel only)&#xD;
                  or &lt;=2.5 * ULN (for participants who receive pevonedistat plus carboplatin plus&#xD;
                  paclitaxel only) (Renal arm) and any value (Mild and Moderate hepatic arm).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        All participants:-&#xD;
&#xD;
          1. With end-stage renal disease requiring hemodialysis.&#xD;
&#xD;
          2. Has Gilbert syndrome.&#xD;
&#xD;
          3. Has active uncontrolled infection or severe infectious disease, such as severe&#xD;
             pneumonia, meningitis, or septicemia. Prophylactic treatment with antibiotics is&#xD;
             allowed.&#xD;
&#xD;
          4. Has life-threatening illness unrelated to cancer.&#xD;
&#xD;
          5. Known human immunodeficiency virus (HIV) seropositive.&#xD;
&#xD;
          6. Treatment with strong cytochrome P450 (CYP)3A inducers within 14 days before the first&#xD;
             dose of pevonedistat.&#xD;
&#xD;
          7. Has left ventricular ejection fraction (LVEF) &lt;50% within 6 months prior to study&#xD;
             enrollment. If a result within this time frame is unavailable, LVEF must be determined&#xD;
             by echocardiography or multigated acquisition scan at screening.&#xD;
&#xD;
          8. Has severe uncontrolled ventricular arrhythmias or torsade de pointes;&#xD;
             electrocardiographic evidence of acute ischemia or active conduction system&#xD;
             abnormalities; or clinically significant arrhythmia (as an example, well-controlled&#xD;
             atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation&#xD;
             would be an exclusion).&#xD;
&#xD;
          9. Has severe symptomatic pulmonary hypertension requiring pharmacologic therapy or&#xD;
             participants with chronic respiratory disease that requires continuous oxygen.&#xD;
&#xD;
             For hematologic malignancies:&#xD;
&#xD;
         10. Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone&#xD;
             marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or&#xD;
             bone marrow, or by other accepted analysis.&#xD;
&#xD;
         11. With AML with a WBC count &gt;=50,000/mcL. Participants who are cytoreduced with&#xD;
             leukapheresis or with hydroxyurea may be enrolled if they otherwise meet the&#xD;
             eligibility criteria.&#xD;
&#xD;
         12. With either clinical evidence of or history of central nervous system (CNS)&#xD;
             involvement by AML.&#xD;
&#xD;
         13. With hematologic malignancies, PT or aPTT &gt;1.5 * ULN or active uncontrolled&#xD;
             coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with&#xD;
             warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are&#xD;
             excluded from enrollment.&#xD;
&#xD;
             For advanced solid tumors:&#xD;
&#xD;
         14. Has prior treatment with radiation therapy involving &gt;=25% of the hematopoietically&#xD;
             active bone marrow.&#xD;
&#xD;
         15. Has CNS metastasis, except for participants who have received prior treatment&#xD;
             (radiation or resection) and have stable CNS disease (example: stable MRI, no steroid&#xD;
             requirement).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Takeda</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of North Carolina at Chapel Hill</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27514</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ICO lHospitalet Hospital Duran i Reynals</name>
      <address>
        <city>LHospitalet de Llobregat</city>
        <state>Barcelona</state>
        <zip>8908</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Vall d'Hebron - PPDS</name>
      <address>
        <city>Barcelona</city>
        <zip>8035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de San Pedro de Alcantara</name>
      <address>
        <city>Caceres</city>
        <zip>10003</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>C.H. Regional Reina Sofia</name>
      <address>
        <city>Cordoba</city>
        <zip>14004</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complejo Asistencial Universitario de Salamanca H. Clinico</name>
      <address>
        <city>Salamanca</city>
        <zip>37007</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen del Rocio - PPDS</name>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicaltrials.takeda.com/study-detail/5f6b603a4db2bf003ab4a2d1</url>
    <description>To obtain more information on the study, click here/on this link</description>
  </link>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>January 21, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <last_update_submitted>December 7, 2022</last_update_submitted>
  <last_update_submitted_qc>December 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Drug therapy</keyword>
  <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, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Chronic</mesh_term>
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Renal Insufficiency</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Docetaxel</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Azacitidine</mesh_term>
    <mesh_term>Pevonedistat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_access_criteria>IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.</ipd_access_criteria>
    <ipd_url>https://vivli.org/ourmember/takeda/</ipd_url>
  </patient_data>
  <pending_results>
    <submitted>April 18, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03814005
org study id: Pevonedistat-1016
secondary id: U1111-1220-1396
secondary id: 2018-004049-17
nct id: NCT03814005
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Pevonedistat is a medicine to treat people with blood cancers or solid tumors.

      The main aim of the study is to learn about the levels of pevonedistat in the blood of
      participants with blood cancers or solid tumors, who also have severe kidney problems or mild
      to moderate liver problems. The information from this study will be used to work out the best
      dose of pevonedistat to give people with these conditions in future studies. At the first
      visit, the study doctor will check who can take part in the study.

      This study is in 2 parts: A and B.

      Part A Participants will be placed into 1 of 4 treatment groups depending on how severe their
      kidney and liver problems are. All participants will receive 1 dose of pevonedistat as a slow
      injection in their vein (infusion). Then, the study doctors will check the levels of
      pevonedistat in the blood of the participants for 3 days after the infusion. They will also
      check if the participants have any side effects from pevonedistat.

      Participants will be asked to continue to Part B. Those who don't want to continue will visit
      the clinic 30 days later for a final check-up.

      Part B Participants who agree to participate into Part B will receive an infusion of
      pevonedistat on specific days during a 21-day or 28-day cycle. The cycle time will depend on
      what type of cancer the participants have. Participants will also be treated with standard of
      care medicines for their kidney and liver problems during this time. In the first cycle, the
      study doctors will also check the levels of pevonedistat in the blood and urine of
      participants for 3 days after the infusion. Participants will continue with cycles of
      treatment together with standard of care medicines until their condition gets worse or they
      have too many side effects from the treatment.

      When treatment has finished, participants will visit the clinic 10 days later for a final
      check-up.
The drug being tested in this study is called pevonedistat. The study will characterize the
      PK of pevonedistat, assess the safety, and determine the dose of pevonedistat, in combination
      with azacitidine, docetaxel OR paclitaxel plus carboplatin in participants with higher-risk
      myelodysplastic syndromes (HRMDS), myelodysplastic syndromes (MDS), chronic myelomonocytic
      leukemia (CMML), acute myelogenous leukemia (AML), or advanced solid tumors who also have
      severe renal impairment or mild or moderate hepatic impairment.

      The study will enroll approximately 42 participants. Participants with solid tumors or
      hematologic malignancies will be assigned to one of the four treatment groups on the basis of
      their renal and hepatic function:

        -  Control Arm (Normal Renal and Hepatic Function)

        -  Renal Arm (Severe Renal Impairment)

        -  Mild Hepatic Arm (Mild Hepatic Impairment)

        -  Moderate Hepatic Arm (Moderate Hepatic Impairment)

      The study will be conducted in 2 parts: Part A and Part B. Part A will include single dose
      administration of pevonedistat. Eligible participants from Part A who will opt to continue
      treatment in Part B will be treated with pevonedistat in combination with standard of care
      (SOC) agents (azacitidine, docetaxel OR paclitaxel plus carboplatin) in Part B.

      Intrapatient dose escalation of pevonedistat and SOC agents will be based on the safety data
      from Cycle 1 of Part B as mentioned below:

        -  In renal arm (severe renal impairment ) based on the safety data from Cycle 1 of Part B,
           pevonedistat may be increased to 15 mg/m^2 on Days 1, 3, and 5 of Cycle 2 Part B and in
           subsequent Cycles, to a maximum dose of 25 mg/m^2. Participants may be eligible for
           intrapatient dose escalation to paclitaxel 175 mg/m^2 in Cycle 2 or beyond if the lower
           dose is well tolerated. Intrapatient dose escalation of carboplatin to AUC5 will be
           allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.

        -  In mild hepatic arm (mild hepatic impairment), the starting dose for pevonedistat and
           azacitidine in combination are not escalated in the cohort. Intrapatient dose escalation
           of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is
           safe and tolerable.

        -  In moderate hepatic arm (moderate hepatic impairment) based on the safety data from
           Cycle 1 of Part B, pevonedistat may be increased to 15 mg/m^2 on Days 1, 3, and 5 of
           Cycle 2 Part B and in subsequent Cycles, to a maximum dose of 20 mg/m^2. Intrapatient
           dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1
           of Part B is safe and tolerable.

      This multi-center trial will be conducted in the United States and Spain. The overall time to
      participate in this study is approximately 3.5 years. Participants will attend end of the
      study visit 30 days after the last dose of study drug or before the start of subsequent
      therapy, if that occurs sooner for safety follow up.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Other
masking: None (Open Label)
measure: Part A, AUC∞: Area Under the Plasma Concentration-time Curve from Time Zero to Infinity for Pevonedistat Following a Single Dose
time frame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Part A, AUClast: Area Under the Plasma Concentration-time Curve from Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose
time frame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose
time frame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose
time frame: Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle (C ) 1 Day (D) 3 pre-dose and at multiple time points (up to 48 hours) post-dose (C length =28 D [hematologic malignancies], and =21 D [solid tumors])
measure: Part B, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors]
measure: Parts A and B, fu: Fraction of Unbound Drug in Plasma for Pevonedistat
time frame: Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle (C) 1 Day (D) 3 pre-dose and at multiple time points (up to 48 hours) post-dose (C length =28 D [hematologic malignancies], and =21 D [solid tumors]
measure: Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length is equal to [=] 28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length = 28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Part B, AUCτ: Area under the Concentration-time Curve from Time Zero to the end of the Dosing Interval for Pevonedistat and Azacitidine Following Multiple Dose
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Parts A and B, CL: Total Clearance for Pevonedistat
time frame: Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle (C) 1 Day (D) 3 pre-dose and at multiple time points (up to 48 hours) post-dose (C length =28 D [hematologic malignancies], and =21 D [solid tumors]
measure: Part B, CL/F: Apparent Clearance for Azacitidine
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Part B, CLR: Renal Clearance for Pevonedistat
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Part B, CLR: Renal Clearance for Azacitidine
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat
time frame: Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle (C) 1 Day (D) 3 pre-dose and at multiple time points (up to 48 hours) post-dose (C length =28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Part B, Vss: Apparent Volume of Distribution of Azacitidine
time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
measure: Part B, Percentage of AML Participants with Complete Response (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR)
time frame: Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 3.5 years) (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
description: Disease response in AML are based on international working group (IWG) for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in AML. For AML participants, all CR includes both CR and CRi. CR: morphologic leukemia-free state with absolute neutrophil count (ANC) of greater than (>) 1000 per microliter (/mcL) and platelets of greater than or equal to (>=) 100,000/mcL, and no residual evidence of extramedullary leukemia. CRi: After chemotherapy, some participants fulfill all criteria for CR except for residual neutropenia (less than [<] 1000/mcL) or thrombocytopenia (<100,000/mcL). PR: requires all hematologic values for a CR but with a decrease of at least 50 percent (%) in the percentage of blasts to 5% to 25% in the bone marrow aspirate. A value of less than or equal to (<=) 5% blasts may also be considered a PR if Auer rods are present.
measure: Part B, Percentage of MDS and CMML Participants with CR, PR or Hematologic Improvement (HI)
time frame: Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 3.5 years) (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
description: Disease response in MDS and CMML will be based on best overall response (CR+PR+HI) as determined by investigator using revised IWG response criteria for MDS and CMML.
measure: Part B, Percentage of AML Participants with Overall Response
time frame: Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 3.5 years) (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
description: Overall response (CR + PR) will be determined by using the revised IWG response criteria. For AML participants, all CR includes both CR and CRi.
measure: Part B, Duration of CR, PR and HI
time frame: From first documentation of response up to disease progression ( up to 3.5 years)
description: Duration of response in participants with disease response (CR+PR+HI) for hematologic malignancies is time between first documentation of response and disease progression. Duration of response will be determined by the investigator using the revised IWG response criteria. The duration of response in participants with disease response (CR+PR) for solid tumors is time between the first documentation of response and the first documentation of progressive disease (PD) or death if no prior PD is documented. Duration of response will be determined by investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.
measure: Part B, Percentage of Solid Tumors Participants with CR or PR
time frame: Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 3.5 years) (Cycle length =28 days [hematologic malignancies], and =21 days [solid tumors])
description: Disease response in solid tumors will be based on best overall response (CR+PR) as determined by investigator using the RECIST version 1.1 criteria. CR: disappearance of all target lesions with any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 millimeter (mm) and disappearance of all nontarget lesions and normalization of tumor marker level with all lymph nodes must be nonpathological in size (<10 mm short axis); PR: At least a 30% decrease from baseline in the sum of diameters of target lesions, taking as reference the baseline sum of diameters and Persistence of one or more nontarget lesion(s) or/and maintenance of tumor marker level above the normal limits.
arm group label: Control Arm (Normal Renal and Hepatic Function)
arm group type: Experimental
description: Pevonedistat 20 milligram per square meter (mg/m^2), infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.
arm group label: Renal Arm (Severe Renal Impairment)
arm group type: Experimental
description: Pevonedistat 20 mg/m^2, infusion, intravenously, once, on Day1 of Part A in participants with hematologic malignancies or solid tumors, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day1 through Day7 or Day1 through Day5, and on Days 8-9 in combination with pevonedistat 15 mg/m^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies and docetaxel 75 mg/m^2 OR carboplatin AUC4, infusion, intravenously, once along with paclitaxel 135 mg/m^2, infusion, intravenously, once on Day 1 in combination with pevonedistat 15 mg/m^2, infusion, intravenously, on Days 3 and 5 in each 21-day treatment cycle in participants with solid tumors until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.
arm group label: Mild Hepatic Arm (Mild Hepatic Impairment)
arm group type: Experimental
description: Pevonedistat 20 mg/m^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies or solid tumors, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies, and carboplatin AUC4, infusion, intravenously, once along with paclitaxel 135 mg/m^2, infusion, intravenously, once on Day 1 in combination with pevonedistat 20 mg/m^2, infusion, intravenously, on Days 3 and 5 in each 21-day treatment cycle in participants with solid tumors until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.
arm group label: Moderate Hepatic Arm (Moderate Hepatic Impairment)
arm group type: Experimental
description: Pevonedistat 20 mg/m^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies or solid tumors, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 10 mg/m^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies, and carboplatin AUC4, infusion, intravenously, once along with paclitaxel 90 mg/m^2, infusion, intravenously, once on Day 1 in combination with pevonedistat 10 mg/m^2, infusion, intravenously, on Days 3 and 5 in each 21-day treatment cycle in participants with solid tumors until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.
intervention type: Drug
intervention name: Azacitidine
description: Azacitidine subcutaneous or intravenous injection.
arm group label: Control Arm (Normal Renal and Hepatic Function)
arm group label: Mild Hepatic Arm (Mild Hepatic Impairment)
arm group label: Moderate Hepatic Arm (Moderate Hepatic Impairment)
arm group label: Renal Arm (Severe Renal Impairment)
intervention type: Drug
intervention name: Pevonedistat
description: Pevonedistat intravenous infusion.
arm group label: Control Arm (Normal Renal and Hepatic Function)
arm group label: Mild Hepatic Arm (Mild Hepatic Impairment)
arm group label: Moderate Hepatic Arm (Moderate Hepatic Impairment)
arm group label: Renal Arm (Severe Renal Impairment)
other name: TAK-924 and MLN4924
intervention type: Drug
intervention name: Docetaxel
description: Docetaxel intravenous infusion.
arm group label: Renal Arm (Severe Renal Impairment)
intervention type: Drug
intervention name: Paclitaxel
description: Paclitaxel intravenous infusion.
arm group label: Mild Hepatic Arm (Mild Hepatic Impairment)
arm group label: Moderate Hepatic Arm (Moderate Hepatic Impairment)
arm group label: Renal Arm (Severe Renal Impairment)
intervention type: Drug
intervention name: Carboplatin
description: Carboplatin intravenous infusion.
arm group label: Mild Hepatic Arm (Mild Hepatic Impairment)
arm group label: Moderate Hepatic Arm (Moderate Hepatic Impairment)
arm group label: Renal Arm (Severe Renal Impairment)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Study Director
role: Study Director
affiliation: Takeda
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
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facility: 
country: Spain
country: United States
url: https://clinicaltrials.takeda.com/study-detail/5f6b603a4db2bf003ab4a2d1
description: To obtain more information on the study, click here/on this link
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Preleukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Leukemia, Myelomonocytic, Chronic
mesh term: Liver Diseases
mesh term: Renal Insufficiency
mesh term: Myelodysplastic Syndromes
mesh term: Paclitaxel
mesh term: Docetaxel
mesh term: Carboplatin
mesh term: Azacitidine
mesh term: Pevonedistat
sharing ipd: Yes
ipd description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd access criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
ipd url: https://vivli.org/ourmember/takeda/
submitted: April 18, 2023