<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/NCT03813147</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2019-00215</org_study_id>
    <secondary_id>NCI-2019-00215</secondary_id>
    <secondary_id>ADVL1712</secondary_id>
    <secondary_id>ADVL1712</secondary_id>
    <nct_id>NCT03813147</nct_id>
  </id_info>
  <brief_title>Pevonedistat, Azacitidine, Fludarabine Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome</brief_title>
  <official_title>A Feasibility Trial of MLN4924 (Pevonedistat, TAK 924) Given in Combination With Azacitidine, Fludarabine, and Cytarabine, in Children, Adolescents, and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Children's Oncology Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This phase I trial studies the side effects and how well pevonedistat, azacitidine,&#xD;
      fludarabine phosphate, and cytarabine work in treating patients with acute myeloid leukemia&#xD;
      or myelodysplastic syndrome that has come back (relapsed) or has not responded to treatment&#xD;
      (refractory). Pevonedistat may stop the growth of cancer cells by blocking some of the&#xD;
      enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, fludarabine&#xD;
      phosphate, and cytarabine, work in different ways to stop the growth of cancer cells, either&#xD;
      by killing the cells, by stopping them from dividing, or by stopping them from spreading.&#xD;
      Giving more than one drug (combination chemotherapy) and pevonedistat may work better in&#xD;
      treating patients with acute myeloid leukemia or myelodysplastic syndrome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the tolerability and feasibility of MLN4924 (pevonedistat) added to the 3-drug&#xD;
      backbone of azacitidine (aza), fludarabine phosphate (fludarabine), and cytarabine&#xD;
      re-induction for pediatric patients with recurrent/refractory acute myeloid leukemia (AML)&#xD;
      and myelodysplastic syndrome (MDS).&#xD;
&#xD;
      II. To define and describe the toxicities of MLN4924 (pevonedistat) when given in combination&#xD;
      with azacitidine, fludarabine, and cytarabine to pediatric patients with relapsed/refractory&#xD;
      AML and MDS.&#xD;
&#xD;
      III. To characterize the pharmacokinetics of MLN4924 (pevonedistat) in children with&#xD;
      recurrent or refractory AML and MDS.&#xD;
&#xD;
      SECONDARY OBJECTIVE:&#xD;
&#xD;
      I. To describe the antitumor activity of MLN4924 (pevonedistat) in combination with&#xD;
      azacitidine, fludarabine, and cytarabine within the confines of a feasibility study.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To describe the effect of MLN4924 (pevonedistat) administered on this schedule on&#xD;
      messenger ribonucleic acid (mRNA) transcript levels of genes known to be induced by MLN4924&#xD;
      (pevonedistat) mediated NEDD8 activating enzyme (NAE) inhibition.&#xD;
&#xD;
      II. To describe the effect of MLN4924 (pevonedistat) on NEDDylation of proteins in the NEDD8&#xD;
      pathway that are likely to be affected by NAE inhibition with MLN4924 (pevonedistat).&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of&#xD;
      each cycle. Patients then receive azacitidine intravenously (IV) over 15 minutes once daily&#xD;
      (QD) on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine&#xD;
      phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients&#xD;
      with central nervous system (CNS)2 or CNS3 receive cytarabine intrathecally or methotrexate&#xD;
      intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and&#xD;
      11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable&#xD;
      toxicity. Patients with stable or greater with non-hematologic toxicities probably or&#xD;
      definitely related to pevonedistat may receive an additional cycle of treatment.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 30 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 1, 2019</start_date>
  <completion_date type="Anticipated">October 5, 2023</completion_date>
  <primary_completion_date type="Actual">September 30, 2021</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 of MLN4924 (Pevonedistat)</measure>
    <time_frame>Up to 35 days</time_frame>
    <description>Frequency of patients with dose limiting toxicity in the first cycle of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level among patients in the dose escalation cohort.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Adverse Events Attributable to MLN4924 (Pevonedistat)</measure>
    <time_frame>Up to 70 days</time_frame>
    <description>Frequency of patients with at least one grade 3 adverse event at least possibly attributable to MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Plasma Concentration Versus Time Curve of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</measure>
    <time_frame>Up to 5 days</time_frame>
    <description>Median (Range) of the area under the plasma concentration versus time curve of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Total Plasma Clearance of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</measure>
    <time_frame>Up to 5 days</time_frame>
    <description>Median (Range) of the total plasma clearance of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Elimination Half-life of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</measure>
    <time_frame>Up to 5 days</time_frame>
    <description>Median (Range) of the elimination half-life of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</measure>
    <time_frame>Up to 5 days</time_frame>
    <description>Median (Range) of the maximum concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Time to Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</measure>
    <time_frame>Up to 5 days</time_frame>
    <description>Median (Range) of the maximum time to concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Antitumor Activity of MLN4924 (Pevonedistat)</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Frequency of participants with best overall response by dose level of PR or CR for MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction Per Response Evaluation Criteria for CR (M1 bone marrow (&lt; 5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (ANC &gt; 1000/uL and platelet count &gt; 100,000/uL), CRp (M1 bone marrow (&lt; 5% blasts) and no evidence of circulating blasts or extramedullary disease and with recovery of ANC &gt; 1000/uL and platelet transfusion independence), CRi (M1 bone marrow (&lt;5% blasts) and no evidence of circulating blasts or extramedullary disease and with ANC &lt; 1000/uL or platelet count &lt; 100,000/uL without platelet transfusion independence), or PR (M2 marrow status (&gt; 5% or &lt; 25% blasts cells) and at least 50% decrease in bone marrow blast percent from baseline.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Messenger Ribonucleic Acid (mRNA) Transcript Levels of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</measure>
    <time_frame>Up to 5 days</time_frame>
    <description>Median (IQR) transcript levels of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome</condition>
  <condition>Recurrent Acute Myeloid Leukemia</condition>
  <condition>Recurrent Myelodysplastic Syndrome</condition>
  <condition>Refractory Acute Myeloid Leukemia</condition>
  <condition>Refractory Myelodysplastic Syndrome</condition>
  <arm_group>
    <arm_group_label>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of each cycle. Patients then receive azacitidine IV over 15 minutes QD on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients with CNS2 or CNS3 receive cytarabine intrathecally or methotrexate intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and 11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable toxicity. Patients with stable or greater with non-hematologic toxicities probably or definitely related to pevonedistat may receive an additional cycle of treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azacitidine</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</arm_group_label>
    <other_name>5 AZC</other_name>
    <other_name>5-AC</other_name>
    <other_name>5-Azacytidine</other_name>
    <other_name>5-AZC</other_name>
    <other_name>Azacytidine</other_name>
    <other_name>Azacytidine, 5-</other_name>
    <other_name>Ladakamycin</other_name>
    <other_name>Mylosar</other_name>
    <other_name>Onureg</other_name>
    <other_name>U-18496</other_name>
    <other_name>Vidaza</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <description>Given intrathecally and IV</description>
    <arm_group_label>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</arm_group_label>
    <other_name>.beta.-Cytosine arabinoside</other_name>
    <other_name>1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone</other_name>
    <other_name>1-.beta.-D-Arabinofuranosylcytosine</other_name>
    <other_name>1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone</other_name>
    <other_name>1-Beta-D-arabinofuranosylcytosine</other_name>
    <other_name>1.beta.-D-Arabinofuranosylcytosine</other_name>
    <other_name>2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-</other_name>
    <other_name>2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-</other_name>
    <other_name>Alexan</other_name>
    <other_name>Ara-C</other_name>
    <other_name>ARA-cell</other_name>
    <other_name>Arabine</other_name>
    <other_name>Arabinofuranosylcytosine</other_name>
    <other_name>Arabinosylcytosine</other_name>
    <other_name>Aracytidine</other_name>
    <other_name>Aracytin</other_name>
    <other_name>Aracytine</other_name>
    <other_name>Beta-Cytosine Arabinoside</other_name>
    <other_name>CHX-3311</other_name>
    <other_name>Cytarabinum</other_name>
    <other_name>Cytarbel</other_name>
    <other_name>Cytosar</other_name>
    <other_name>Cytosine Arabinoside</other_name>
    <other_name>Cytosine-.beta.-arabinoside</other_name>
    <other_name>Cytosine-beta-arabinoside</other_name>
    <other_name>Erpalfa</other_name>
    <other_name>Starasid</other_name>
    <other_name>Tarabine PFS</other_name>
    <other_name>U 19920</other_name>
    <other_name>U-19920</other_name>
    <other_name>Udicil</other_name>
    <other_name>WR-28453</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine Phosphate</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</arm_group_label>
    <other_name>2-F-ara-AMP</other_name>
    <other_name>9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-</other_name>
    <other_name>Beneflur</other_name>
    <other_name>Fludara</other_name>
    <other_name>SH T 586</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>Given intrathecally</description>
    <arm_group_label>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</arm_group_label>
    <other_name>Abitrexate</other_name>
    <other_name>Alpha-Methopterin</other_name>
    <other_name>Amethopterin</other_name>
    <other_name>Brimexate</other_name>
    <other_name>CL 14377</other_name>
    <other_name>CL-14377</other_name>
    <other_name>Emtexate</other_name>
    <other_name>Emthexat</other_name>
    <other_name>Emthexate</other_name>
    <other_name>Farmitrexat</other_name>
    <other_name>Fauldexato</other_name>
    <other_name>Folex</other_name>
    <other_name>Folex PFS</other_name>
    <other_name>Lantarel</other_name>
    <other_name>Ledertrexate</other_name>
    <other_name>Lumexon</other_name>
    <other_name>Maxtrex</other_name>
    <other_name>Medsatrexate</other_name>
    <other_name>Metex</other_name>
    <other_name>Methoblastin</other_name>
    <other_name>Methotrexate LPF</other_name>
    <other_name>Methotrexate Methylaminopterin</other_name>
    <other_name>Methotrexatum</other_name>
    <other_name>Metotrexato</other_name>
    <other_name>Metrotex</other_name>
    <other_name>Mexate</other_name>
    <other_name>Mexate-AQ</other_name>
    <other_name>MTX</other_name>
    <other_name>Novatrex</other_name>
    <other_name>Rheumatrex</other_name>
    <other_name>Texate</other_name>
    <other_name>Tremetex</other_name>
    <other_name>Trexeron</other_name>
    <other_name>Trixilem</other_name>
    <other_name>WR-19039</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pevonedistat</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</arm_group_label>
    <other_name>MLN4924</other_name>
    <other_name>Nedd8-Activating Enzyme Inhibitor MLN4924</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Therapeutic Hydrocortisone</intervention_name>
    <description>Given intrathecally</description>
    <arm_group_label>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</arm_group_label>
    <other_name>Aeroseb-HC</other_name>
    <other_name>Barseb HC</other_name>
    <other_name>Barseb-HC</other_name>
    <other_name>Cetacort</other_name>
    <other_name>Cort-Dome</other_name>
    <other_name>Cortef</other_name>
    <other_name>Cortenema</other_name>
    <other_name>Cortifan</other_name>
    <other_name>Cortisol</other_name>
    <other_name>Cortispray</other_name>
    <other_name>Cortril</other_name>
    <other_name>Dermacort</other_name>
    <other_name>Domolene</other_name>
    <other_name>Eldecort</other_name>
    <other_name>Hautosone</other_name>
    <other_name>Heb-Cort</other_name>
    <other_name>Hydrocortisone</other_name>
    <other_name>Hydrocortone</other_name>
    <other_name>Hytone</other_name>
    <other_name>Komed-HC</other_name>
    <other_name>Nutracort</other_name>
    <other_name>Proctocort</other_name>
    <other_name>Rectoid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have had histologic verification of AML at the original diagnosis.&#xD;
             Patients must have one of the following:&#xD;
&#xD;
               -  Recurrent disease in &gt;= 1st relapse with &gt;= 5% blasts in the bone marrow (M2/M3)&#xD;
                  marrow OR immunophenotypic evidence of disease with &gt;= 0.1% blasts detected by&#xD;
                  flow cytometry, OR evidence of recurrent cytogenetic or molecular abnormalities&#xD;
                  consistent with relapse, with or without extramedullary disease&#xD;
&#xD;
               -  Refractory AML is defined as &gt;= 5% blasts in the bone marrow (M2/M3) after &gt;= 2&#xD;
                  induction attempts (i.e., 2 cycles of chemotherapy)&#xD;
&#xD;
               -  Patients with advanced MDS, including MDS that has progressed to AML, and have&#xD;
                  experienced relapse or are refractory after &gt;= 1 course of induction therapy, are&#xD;
                  eligible&#xD;
&#xD;
          -  Karnofsky &gt;= 50% for patients &gt; 16 years of age and Lansky &gt;= 50 for patients =&lt; 16&#xD;
             years of age&#xD;
&#xD;
          -  Patients must have fully recovered from the acute toxic effects of all prior&#xD;
             anti-cancer therapy and must meet the following minimum duration from prior&#xD;
             anti-cancer directed therapy prior to enrollment. If after the required timeframe, the&#xD;
             numerical eligibility criteria are met, e.g., blood count criteria, the patient is&#xD;
             considered to have recovered adequately&#xD;
&#xD;
               -  Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive&#xD;
&#xD;
                    -  &gt;= 14 days must have elapsed after the completion of other cytotoxic&#xD;
                       therapy, with the exception of hydroxyurea, for patients not receiving&#xD;
                       standard maintenance therapy. Additionally, patients must have recovered&#xD;
                       from all acute toxic effects of prior therapy&#xD;
&#xD;
                         -  NOTE: Cytoreduction with hydroxyurea must be discontinued &gt;= 24 hours&#xD;
                            prior to the start of protocol therapy&#xD;
&#xD;
               -  Anti-cancer agents not known to be myelosuppressive (e.g. not associated with&#xD;
                  reduced platelet or absolute neutrophil [ANC] counts): &gt;= 7 days after the last&#xD;
                  dose of agent&#xD;
&#xD;
               -  Antibodies: &gt;= 21 days must have elapsed from infusion of last dose of antibody,&#xD;
                  and toxicity related to prior antibody therapy must be recovered to grade =&lt; 1&#xD;
&#xD;
               -  Hematopoietic growth factors: &gt;= 14 days after the last dose of a long-acting&#xD;
                  growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For&#xD;
                  agents that have known adverse events occurring beyond 7 days after&#xD;
                  administration, this period must be extended beyond the time during which adverse&#xD;
                  events are known to occur. The duration of this interval must be discussed with&#xD;
                  the study chair and the study-assigned research coordinator&#xD;
&#xD;
               -  Interleukins, interferons and cytokines (other than hematopoietic growth&#xD;
                  factors): &gt;= 21 days after the completion of interleukins, interferon or&#xD;
                  cytokines (other than hematopoietic growth factors)&#xD;
&#xD;
               -  Stem cell Infusions (with or without traumatic brain injury [TBI]):&#xD;
&#xD;
                    -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem&#xD;
                       cell infusion including donor leukocyte infusion (DLI) or boost infusion: &gt;=&#xD;
                       84 days after infusion and no evidence of graft versus host disease (GVHD)&#xD;
&#xD;
                    -  Autologous stem cell infusion including boost infusion: &gt;= 42 days&#xD;
&#xD;
               -  Cellular Therapy: &gt;= 30 days after the completion of any type of cellular therapy&#xD;
                  (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)&#xD;
&#xD;
               -  Radiation therapy (XRT)/external beam irradiation including protons: &gt;= 14 days&#xD;
                  after local XRT; &gt;= 42 days after TBI, craniospinal XRT or if radiation to &gt;= 50%&#xD;
                  of the pelvis; &gt;= 42 days if other substantial brain metastases (BM) radiation&#xD;
&#xD;
               -  Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131 iodine&#xD;
                  [I]-metaiodobenzylguanidine [MIBG]): &gt;= 42 days after systemically administered&#xD;
                  radiopharmaceutical therapy&#xD;
&#xD;
               -  Patients must not have received prior exposure to MLN4924 (pevonedistat)&#xD;
&#xD;
          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) &gt;= 60&#xD;
             ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:&#xD;
&#xD;
               -  1 month to &lt; 6 months; 0.4 (male and female)&#xD;
&#xD;
               -  6 months to &lt; 1 year; 0.5 (male and female)&#xD;
&#xD;
               -  1 to &lt; 2 years; 0.6 (male and female)&#xD;
&#xD;
               -  2 to &lt; 6 years; 0.8 (male and female)&#xD;
&#xD;
               -  6 to &lt; 10 years; 1 (male and female)&#xD;
&#xD;
               -  10 to &lt; 13 years; 1.2 (male and female)&#xD;
&#xD;
               -  13 to &lt; 16 years; 1.5 (male) and 1.4 (female)&#xD;
&#xD;
               -  &gt;= 16 years; 1.7 (male) and 1.4 (female)&#xD;
&#xD;
          -  Bilirubin (sum of conjugated + unconjugated) =&lt; upper limit of normal (ULN) for age&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =&lt; 2.5 x ULN. For&#xD;
             the purpose of this study, the ULN for serum glutamate pyruvate transaminase (SGPT) is&#xD;
             45 U/L&#xD;
&#xD;
          -  Shortening fraction of &gt;= 27% by echocardiogram, or&#xD;
&#xD;
          -  Ejection fraction of &gt;= 50% by echocardiogram or radionuclide angiogram&#xD;
&#xD;
          -  No ventricular or supraventricular arrhythmia on electrocardiogram (EKG)&#xD;
&#xD;
          -  Prolonged rate corrected QT (QTc) interval &lt; 500 msec&#xD;
&#xD;
          -  Pulse oximetry &gt; 94% on room air if there is clinical indication for determination&#xD;
             (e.g. dyspnea at rest)&#xD;
&#xD;
          -  International normalized ratio (INR) =&lt; 1.5&#xD;
&#xD;
          -  Hemoglobin &gt; 8.0 g/dL (may receive red blood cell [RBC] transfusions)&#xD;
&#xD;
          -  All patients and/or their parents or legally authorized representatives must sign a&#xD;
             written informed consent. Assent, when appropriate, will be obtained according to&#xD;
             institutional guidelines&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast-feeding women will not be entered on this study due to risks of&#xD;
             fetal and teratogenic adverse events as seen in animal/human studies, OR because there&#xD;
             is yet no available information regarding human fetal or teratogenic toxicities.&#xD;
             Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of&#xD;
             reproductive potential may not participate unless they have agreed to use 1 highly&#xD;
             effective and 1 additional effective (barrier) method of contraception at the same&#xD;
             time for the duration of study therapy and for 4 months after the completion of&#xD;
             MLN4924 (pevonedistat) administration. True abstinence, when this is in line with the&#xD;
             preferred and usual lifestyle of the subject, is acceptable. Periodic abstinence&#xD;
             (e.g., calendar, ovulation, symptothermal, post-ovulation methods), withdrawal,&#xD;
             spermicides only, and lactational amenorrhea are not acceptable methods of&#xD;
             contraception&#xD;
&#xD;
          -  Investigational drugs: Patients who are currently receiving another investigational&#xD;
             drug are not eligible&#xD;
&#xD;
          -  Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are&#xD;
             not eligible (except hydroxyurea, which may be continued until 24 hours prior to start&#xD;
             of protocol therapy)&#xD;
&#xD;
          -  Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus&#xD;
             or other systemic agents to prevent graft-versus-host disease post bone marrow&#xD;
             transplant are not eligible for this trial. Topical immunosuppressive agents (e.g.&#xD;
             topical steroids) are allowed. Physiologic replacement of hydrocortisone is allowed&#xD;
&#xD;
          -  Patients who are taking drugs that are strong CYP3A4 inducers and cannot be switched&#xD;
             to alternative drugs 14 days prior to enrollment are not eligible. Strong inducers of&#xD;
             CYP34 are not permitted during the study&#xD;
&#xD;
          -  Patients with known hepatitis B surface antigen seropositive or known or suspected&#xD;
             active hepatitis C infection are not eligible. NOTE: Patients who have isolated&#xD;
             positive hepatitis B core antibody (i.e. in the setting of negative hepatitis B&#xD;
             surface antigen and negative hepatitis B surface antibody) must have an undetectable&#xD;
             hepatitis B viral load. Patients who have positive hepatitis C antibody may be&#xD;
             included if they have an undetectable hepatitis C viral load&#xD;
&#xD;
          -  Patients with known hepatic cirrhosis or severe pre-existing hepatic impairment are&#xD;
             not eligible&#xD;
&#xD;
          -  Patients with uncontrolled high blood pressure (i.e., &gt;= 99% for age) are not eligible&#xD;
&#xD;
          -  Patients with any of the following diagnoses:&#xD;
&#xD;
               -  Acute promyelocytic leukemia&#xD;
&#xD;
               -  Down syndrome&#xD;
&#xD;
               -  Juvenile myelomonocytic leukemia&#xD;
&#xD;
          -  Patients who have a documented active uncontrolled infection are not eligible&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition as the study agent&#xD;
&#xD;
          -  Patients with human immunodeficiency virus (HIV) are not eligible unless they meet all&#xD;
             of the following criteria:&#xD;
&#xD;
               -  CD4 count &gt; 350 cell/mm^3&#xD;
&#xD;
               -  Undetectable viral load&#xD;
&#xD;
               -  Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents&#xD;
&#xD;
               -  No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic&#xD;
                  infections&#xD;
&#xD;
          -  Female patients who intend to donate eggs (ova) during the course of this study or 4&#xD;
             months after receiving their last dose of study drug(s) are not eligible&#xD;
&#xD;
          -  Male patients who intend to donate sperm during the course of this study or 4 months&#xD;
             after receiving their last dose of study drug(s) are not eligible&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Katherine G Tarlock</last_name>
    <role>Principal Investigator</role>
    <affiliation>COG Phase I Consortium</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Orange County</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF Medical Center-Mission Bay</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's National Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Healthcare of Atlanta - Egleston</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lurie Children's Hospital-Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Riley Hospital for Children</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>C S Mott Children's Hospital</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota/Masonic Cancer Center</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Pittsburgh of UPMC</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Jude Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Children's Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 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>
  <results_first_submitted>November 29, 2022</results_first_submitted>
  <results_first_submitted_qc>February 6, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">March 3, 2023</results_first_posted>
  <last_update_submitted>March 9, 2023</last_update_submitted>
  <last_update_submitted_qc>March 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 10, 2023</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>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Hydrocortisone</mesh_term>
    <mesh_term>Hydrocortisone 17-butyrate 21-propionate</mesh_term>
    <mesh_term>Hydrocortisone acetate</mesh_term>
    <mesh_term>Hydrocortisone hemisuccinate</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
    <mesh_term>Fludarabine phosphate</mesh_term>
    <mesh_term>Azacitidine</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Enzyme Inhibitors</mesh_term>
    <mesh_term>Pevonedistat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page</ipd_description>
    <ipd_url>https://grants.nih.gov/policy/sharing.htm</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 27, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/47/NCT03813147/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>All patients were treated at the 20 mg/m2 dosing. An initial 6 patients were treated in this stratum to ensure this dose was feasible with the backbone therapy and then an additional 6 patients were treated in the PK stratum at this same dose to gain additional PK data.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Stratum 1 With 20 mg/m^2</title>
          <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
        </group>
        <group group_id="P2">
          <title>PK With 20 mg/m^2</title>
          <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Stratum 1 With 20 mg/m^2</title>
          <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
        </group>
        <group group_id="B2">
          <title>PK With 20 mg/m^2</title>
          <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
            <count group_id="B2" value="6"/>
            <count group_id="B3" value="12"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9.5" lower_limit="3" upper_limit="17"/>
                    <measurement group_id="B2" value="16.5" lower_limit="1" upper_limit="21"/>
                    <measurement group_id="B3" value="13" lower_limit="1" upper_limit="21"/>
                  </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="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" 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 of MLN4924 (Pevonedistat)</title>
        <description>Frequency of patients with dose limiting toxicity in the first cycle of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level among patients in the dose escalation cohort.</description>
        <time_frame>Up to 35 days</time_frame>
        <population>All eligible patients</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum 1 With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
          <group group_id="O2">
            <title>PK With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Dose Limiting Toxicities of MLN4924 (Pevonedistat)</title>
          <description>Frequency of patients with dose limiting toxicity in the first cycle of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level among patients in the dose escalation cohort.</description>
          <population>All eligible patients</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Adverse Events Attributable to MLN4924 (Pevonedistat)</title>
        <description>Frequency of patients with at least one grade 3 adverse event at least possibly attributable to MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level.</description>
        <time_frame>Up to 70 days</time_frame>
        <population>All eligible patients</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum 1 With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
          <group group_id="O2">
            <title>PK With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events Attributable to MLN4924 (Pevonedistat)</title>
          <description>Frequency of patients with at least one grade 3 adverse event at least possibly attributable to MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level.</description>
          <population>All eligible patients</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Plasma Concentration Versus Time Curve of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
        <description>Median (Range) of the area under the plasma concentration versus time curve of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
        <time_frame>Up to 5 days</time_frame>
        <population>All eligible patients</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum 1 With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
          <group group_id="O2">
            <title>PK With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Plasma Concentration Versus Time Curve of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
          <description>Median (Range) of the area under the plasma concentration versus time curve of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
          <population>All eligible patients</population>
          <units>hr*ng/mL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1004.9" lower_limit="637.8" upper_limit="1381.4"/>
                    <measurement group_id="O2" value="1047.4" lower_limit="727.6" upper_limit="1362.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Total Plasma Clearance of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
        <description>Median (Range) of the total plasma clearance of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
        <time_frame>Up to 5 days</time_frame>
        <population>All eligible patients</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum 1 With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
          <group group_id="O2">
            <title>PK With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
        </group_list>
        <measure>
          <title>Total Plasma Clearance of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
          <description>Median (Range) of the total plasma clearance of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
          <population>All eligible patients</population>
          <units>L/h/m^2</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.1" lower_limit="14.4" upper_limit="31.4"/>
                    <measurement group_id="O2" value="19.2" lower_limit="14.8" upper_limit="27.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Elimination Half-life of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
        <description>Median (Range) of the elimination half-life of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
        <time_frame>Up to 5 days</time_frame>
        <population>All eligible patients</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum 1 With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
          <group group_id="O2">
            <title>PK With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
        </group_list>
        <measure>
          <title>Elimination Half-life of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
          <description>Median (Range) of the elimination half-life of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
          <population>All eligible patients</population>
          <units>Hour</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.7" lower_limit="1.9" upper_limit="5.2"/>
                    <measurement group_id="O2" value="5.5" lower_limit="3.8" upper_limit="6.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
        <description>Median (Range) of the maximum concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
        <time_frame>Up to 5 days</time_frame>
        <population>All eligible patients</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum 1 With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
          <group group_id="O2">
            <title>PK With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
          <description>Median (Range) of the maximum concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
          <population>All eligible patients</population>
          <units>ng/mL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="248.5" lower_limit="168.0" upper_limit="362.0"/>
                    <measurement group_id="O2" value="213" lower_limit="132.0" upper_limit="400.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Time to Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
        <description>Median (Range) of the maximum time to concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
        <time_frame>Up to 5 days</time_frame>
        <population>All eligible patients</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum 1 With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
          <group group_id="O2">
            <title>PK With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Time to Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
          <description>Median (Range) of the maximum time to concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.</description>
          <population>All eligible patients</population>
          <units>Hour</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.2" lower_limit="1.0" upper_limit="1.2"/>
                    <measurement group_id="O2" value="1.1" lower_limit="1.0" upper_limit="1.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Antitumor Activity of MLN4924 (Pevonedistat)</title>
        <description>Frequency of participants with best overall response by dose level of PR or CR for MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction Per Response Evaluation Criteria for CR (M1 bone marrow (&lt; 5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (ANC &gt; 1000/uL and platelet count &gt; 100,000/uL), CRp (M1 bone marrow (&lt; 5% blasts) and no evidence of circulating blasts or extramedullary disease and with recovery of ANC &gt; 1000/uL and platelet transfusion independence), CRi (M1 bone marrow (&lt;5% blasts) and no evidence of circulating blasts or extramedullary disease and with ANC &lt; 1000/uL or platelet count &lt; 100,000/uL without platelet transfusion independence), or PR (M2 marrow status (&gt; 5% or &lt; 25% blasts cells) and at least 50% decrease in bone marrow blast percent from baseline.</description>
        <time_frame>Up to 1 year</time_frame>
        <population>All eligible patients</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum 1 With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
          <group group_id="O2">
            <title>PK With 20 mg/m^2</title>
            <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Antitumor Activity of MLN4924 (Pevonedistat)</title>
          <description>Frequency of participants with best overall response by dose level of PR or CR for MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction Per Response Evaluation Criteria for CR (M1 bone marrow (&lt; 5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (ANC &gt; 1000/uL and platelet count &gt; 100,000/uL), CRp (M1 bone marrow (&lt; 5% blasts) and no evidence of circulating blasts or extramedullary disease and with recovery of ANC &gt; 1000/uL and platelet transfusion independence), CRi (M1 bone marrow (&lt;5% blasts) and no evidence of circulating blasts or extramedullary disease and with ANC &lt; 1000/uL or platelet count &lt; 100,000/uL without platelet transfusion independence), or PR (M2 marrow status (&gt; 5% or &lt; 25% blasts cells) and at least 50% decrease in bone marrow blast percent from baseline.</description>
          <population>All eligible patients</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Messenger Ribonucleic Acid (mRNA) Transcript Levels of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS</title>
        <description>Median (IQR) transcript levels of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level.</description>
        <time_frame>Up to 5 days</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 1 year</time_frame>
      <desc>Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the &quot;AE Other&quot; table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.</desc>
      <group_list>
        <group group_id="E1">
          <title>Stratum 1 With 20 mg/m^2</title>
          <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
        </group>
        <group group_id="E2">
          <title>PK With 20 mg/m^2</title>
          <description>Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Heart failure</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Left ventricular systolic dysfunction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dental caries</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lower gastrointestinal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatic failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Obesity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumor pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pulmonary edema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <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="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hemolysis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lymph node pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Conduction disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Mitral valve disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pericardial effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pulmonary valve disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tricuspid valve disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Eye disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Floaters</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Scleral disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vitreous hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cheilitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fecal incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gastroparesis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gingival pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lip pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Oral hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Stomach pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tooth discoloration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Upper gastrointestinal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Edema trunk</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neck edema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatobiliary disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Autoimmune disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Immune system disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Phlebitis infective</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vascular access complication</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cholesterol high</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT corrected interval prolonged</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hemoglobin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>INR increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Investigations - Other,</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Acidosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Obesity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Joint range of motion decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other,</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Facial nerve disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Movements involuntary</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Psychiatric disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Urinary urgency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Menorrhagia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Atelectasis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pulmonary edema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Sleep apnea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hirsutism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain of skin</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Purpura</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other,</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hematoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Results Reporting Coordinator</name_or_title>
      <organization>Children's Oncology Group</organization>
      <phone>16264470064</phone>
      <email>resultsreportingcoordinator@childrensoncologygroup.org</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/NCT03813147
org study id: NCI-2019-00215
secondary id: NCI-2019-00215
secondary id: ADVL1712
secondary id: ADVL1712
nct id: NCT03813147
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the side effects and how well pevonedistat, azacitidine,
      fludarabine phosphate, and cytarabine work in treating patients with acute myeloid leukemia
      or myelodysplastic syndrome that has come back (relapsed) or has not responded to treatment
      (refractory). Pevonedistat may stop the growth of cancer cells by blocking some of the
      enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, fludarabine
      phosphate, and cytarabine, work in different ways to stop the growth of cancer cells, either
      by killing the cells, by stopping them from dividing, or by stopping them from spreading.
      Giving more than one drug (combination chemotherapy) and pevonedistat may work better in
      treating patients with acute myeloid leukemia or myelodysplastic syndrome.
PRIMARY OBJECTIVES:

      I. To evaluate the tolerability and feasibility of MLN4924 (pevonedistat) added to the 3-drug
      backbone of azacitidine (aza), fludarabine phosphate (fludarabine), and cytarabine
      re-induction for pediatric patients with recurrent/refractory acute myeloid leukemia (AML)
      and myelodysplastic syndrome (MDS).

      II. To define and describe the toxicities of MLN4924 (pevonedistat) when given in combination
      with azacitidine, fludarabine, and cytarabine to pediatric patients with relapsed/refractory
      AML and MDS.

      III. To characterize the pharmacokinetics of MLN4924 (pevonedistat) in children with
      recurrent or refractory AML and MDS.

      SECONDARY OBJECTIVE:

      I. To describe the antitumor activity of MLN4924 (pevonedistat) in combination with
      azacitidine, fludarabine, and cytarabine within the confines of a feasibility study.

      EXPLORATORY OBJECTIVES:

      I. To describe the effect of MLN4924 (pevonedistat) administered on this schedule on
      messenger ribonucleic acid (mRNA) transcript levels of genes known to be induced by MLN4924
      (pevonedistat) mediated NEDD8 activating enzyme (NAE) inhibition.

      II. To describe the effect of MLN4924 (pevonedistat) on NEDDylation of proteins in the NEDD8
      pathway that are likely to be affected by NAE inhibition with MLN4924 (pevonedistat).

      OUTLINE:

      Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of
      each cycle. Patients then receive azacitidine intravenously (IV) over 15 minutes once daily
      (QD) on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine
      phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients
      with central nervous system (CNS)2 or CNS3 receive cytarabine intrathecally or methotrexate
      intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and
      11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable
      toxicity. Patients with stable or greater with non-hematologic toxicities probably or
      definitely related to pevonedistat may receive an additional cycle of treatment.

      After completion of study treatment, patients are followed up for 30 days.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Dose Limiting Toxicities of MLN4924 (Pevonedistat)
time frame: Up to 35 days
description: Frequency of patients with dose limiting toxicity in the first cycle of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level among patients in the dose escalation cohort.
measure: Number of Participants With Adverse Events Attributable to MLN4924 (Pevonedistat)
time frame: Up to 70 days
description: Frequency of patients with at least one grade 3 adverse event at least possibly attributable to MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level.
measure: Area Under the Plasma Concentration Versus Time Curve of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS
time frame: Up to 5 days
description: Median (Range) of the area under the plasma concentration versus time curve of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.
measure: Total Plasma Clearance of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS
time frame: Up to 5 days
description: Median (Range) of the total plasma clearance of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.
measure: Elimination Half-life of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS
time frame: Up to 5 days
description: Median (Range) of the elimination half-life of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.
measure: Maximum Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS
time frame: Up to 5 days
description: Median (Range) of the maximum concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.
measure: Maximum Time to Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS
time frame: Up to 5 days
description: Median (Range) of the maximum time to concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.
measure: Number of Participants With Antitumor Activity of MLN4924 (Pevonedistat)
time frame: Up to 1 year
description: Frequency of participants with best overall response by dose level of PR or CR for MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction Per Response Evaluation Criteria for CR (M1 bone marrow (< 5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (ANC > 1000/uL and platelet count > 100,000/uL), CRp (M1 bone marrow (< 5% blasts) and no evidence of circulating blasts or extramedullary disease and with recovery of ANC > 1000/uL and platelet transfusion independence), CRi (M1 bone marrow (<5% blasts) and no evidence of circulating blasts or extramedullary disease and with ANC < 1000/uL or platelet count < 100,000/uL without platelet transfusion independence), or PR (M2 marrow status (> 5% or < 25% blasts cells) and at least 50% decrease in bone marrow blast percent from baseline.
measure: Messenger Ribonucleic Acid (mRNA) Transcript Levels of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS
time frame: Up to 5 days
description: Median (IQR) transcript levels of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level.
arm group label: Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)
arm group type: Experimental
description: Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of each cycle. Patients then receive azacitidine IV over 15 minutes QD on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients with CNS2 or CNS3 receive cytarabine intrathecally or methotrexate intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and 11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable toxicity. Patients with stable or greater with non-hematologic toxicities probably or definitely related to pevonedistat may receive an additional cycle of treatment.
intervention type: Drug
intervention name: Azacitidine
description: Given IV
arm group label: Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)
other name: 5 AZC
other name: 5-AC
other name: 5-Azacytidine
other name: 5-AZC
other name: Azacytidine
other name: Azacytidine, 5-
other name: Ladakamycin
other name: Mylosar
other name: Onureg
other name: U-18496
other name: Vidaza
intervention type: Drug
intervention name: Cytarabine
description: Given intrathecally and IV
arm group label: Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)
other name: .beta.-Cytosine arabinoside
other name: 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
other name: 1-.beta.-D-Arabinofuranosylcytosine
other name: 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
other name: 1-Beta-D-arabinofuranosylcytosine
other name: 1.beta.-D-Arabinofuranosylcytosine
other name: 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
other name: 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
other name: Alexan
other name: Ara-C
other name: ARA-cell
other name: Arabine
other name: Arabinofuranosylcytosine
other name: Arabinosylcytosine
other name: Aracytidine
other name: Aracytin
other name: Aracytine
other name: Beta-Cytosine Arabinoside
other name: CHX-3311
other name: Cytarabinum
other name: Cytarbel
other name: Cytosar
other name: Cytosine Arabinoside
other name: Cytosine-.beta.-arabinoside
other name: Cytosine-beta-arabinoside
other name: Erpalfa
other name: Starasid
other name: Tarabine PFS
other name: U 19920
other name: U-19920
other name: Udicil
other name: WR-28453
intervention type: Drug
intervention name: Fludarabine Phosphate
description: Given IV
arm group label: Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)
other name: 2-F-ara-AMP
other name: 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
other name: Beneflur
other name: Fludara
other name: SH T 586
intervention type: Drug
intervention name: Methotrexate
description: Given intrathecally
arm group label: Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)
other name: Abitrexate
other name: Alpha-Methopterin
other name: Amethopterin
other name: Brimexate
other name: CL 14377
other name: CL-14377
other name: Emtexate
other name: Emthexat
other name: Emthexate
other name: Farmitrexat
other name: Fauldexato
other name: Folex
other name: Folex PFS
other name: Lantarel
other name: Ledertrexate
other name: Lumexon
other name: Maxtrex
other name: Medsatrexate
other name: Metex
other name: Methoblastin
other name: Methotrexate LPF
other name: Methotrexate Methylaminopterin
other name: Methotrexatum
other name: Metotrexato
other name: Metrotex
other name: Mexate
other name: Mexate-AQ
other name: MTX
other name: Novatrex
other name: Rheumatrex
other name: Texate
other name: Tremetex
other name: Trexeron
other name: Trixilem
other name: WR-19039
intervention type: Drug
intervention name: Pevonedistat
description: Given IV
arm group label: Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)
other name: MLN4924
other name: Nedd8-Activating Enzyme Inhibitor MLN4924
intervention type: Drug
intervention name: Therapeutic Hydrocortisone
description: Given intrathecally
arm group label: Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)
other name: Aeroseb-HC
other name: Barseb HC
other name: Barseb-HC
other name: Cetacort
other name: Cort-Dome
other name: Cortef
other name: Cortenema
other name: Cortifan
other name: Cortisol
other name: Cortispray
other name: Cortril
other name: Dermacort
other name: Domolene
other name: Eldecort
other name: Hautosone
other name: Heb-Cort
other name: Hydrocortisone
other name: Hydrocortone
other name: Hytone
other name: Komed-HC
other name: Nutracort
other name: Proctocort
other name: Rectoid
criteria: 
gender: All
minimum age: 1 Month
maximum age: 21 Years
healthy volunteers: No
last name: Katherine G Tarlock
role: Principal Investigator
affiliation: COG Phase I Consortium
facility: 
facility: 
facility: 
facility: 
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facility: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
mesh term: Syndrome
mesh term: Recurrence
mesh term: Cytarabine
mesh term: Hydrocortisone
mesh term: Hydrocortisone 17-butyrate 21-propionate
mesh term: Hydrocortisone acetate
mesh term: Hydrocortisone hemisuccinate
mesh term: Methotrexate
mesh term: Fludarabine phosphate
mesh term: Azacitidine
mesh term: Fludarabine
mesh term: Enzyme Inhibitors
mesh term: Pevonedistat
sharing ipd: Yes
ipd description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
ipd url: https://grants.nih.gov/policy/sharing.htm
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 