<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/NCT03770260</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2018-03121</org_study_id>
    <secondary_id>NCI-2018-03121</secondary_id>
    <secondary_id>10249</secondary_id>
    <secondary_id>10249</secondary_id>
    <secondary_id>UM1CA186691</secondary_id>
    <nct_id>NCT03770260</nct_id>
  </id_info>
  <brief_title>Ixazomib and Pevonedistat in Treating Patients With Multiple Myeloma That Has Come Back or Does Not Respond to Treatment</brief_title>
  <official_title>MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory Multiple Myeloma Patients: A Phase 1b Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase Ib trial studies side effects and best dose of pevonedistat when given together&#xD;
      with ixazomib in treating patients with multiple myeloma that has come back or does not&#xD;
      respond to treatment. Pevonedistat and ixazomib may stop the growth of tumor cells by&#xD;
      blocking some of the enzymes needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of MLN4924&#xD;
      (pevonedistat) in combination with MLN9708 (ixazomib citrate [ixazomib]) in relapsed and/or&#xD;
      refractory multiple myeloma (RRMM) patients after more than one previous line of treatment.&#xD;
      (Dose-escalation phase) II. Describe the safety profile and tolerability of the combination&#xD;
      of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in the proteasome inhibitor (PI)-sensitive&#xD;
      and PI-refractory populations. (Dose-expansion phase) III. Determine the anti-tumor activity&#xD;
      and overall response rates (ORR) in patients with RRMM with the use of MLN9708 (ixazomib) and&#xD;
      MLN4924 (pevonedistat) in combination. (Dose-expansion phase)&#xD;
&#xD;
      SECONDARY OBJECTIVE:&#xD;
&#xD;
      I. Attain pharmacokinetic (PK) characterization of MLN4924 (pevonedistat) in combination with&#xD;
      MLN9708 (ixazomib) for the purpose of understanding concentration-effect relationships of&#xD;
      both agents. (Dose-escalation phase)&#xD;
&#xD;
      EXPLORATORY OBJECTIVE:&#xD;
&#xD;
      I. To correlate and predict disease response using the following tests: NAD(P)H dehydrogenase&#xD;
      (quinone) 1 (NQO1) and cystine/glutamate transporter (SLC7A11) (nuclear factor&#xD;
      [erythroid-derived 2]-like 2 [NRF2] target genes): evaluated on whole blood as markers of&#xD;
      MLN4924 (pevonedistat) activity.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of pevonedistat.&#xD;
&#xD;
      Patients receive ixazomib citrate orally (PO) once daily (QD) on days 1, 8, and 15 of each&#xD;
      cycle and pevonedistat intravenously (IV) over 60 minutes on days 1, 8, and 15 of each cycle.&#xD;
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days, then every 2-3&#xD;
      months for up to 2 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 23, 2019</start_date>
  <completion_date type="Anticipated">February 22, 2024</completion_date>
  <primary_completion_date type="Actual">September 12, 2022</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 Experiencing a Dose Limiting Toxicity (Dose Escalation)</measure>
    <time_frame>At Day 28</time_frame>
    <description>Number of participants experiencing a dose limiting toxicity to determine the maximum tolerated dose (MTD)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants Experiencing a Grade 3-5 Adverse Event (Dose Expansion)</measure>
    <time_frame>Up to 2 years after Treatment</time_frame>
    <description>Number of participants who experienced a grade 3-5 adverse event in the dose expansion group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Response Rate (Dose Expansion)</measure>
    <time_frame>Up to 2 Years after Treatment</time_frame>
    <description>To determine the overall responses in patients receiving pevonedistat and ixazomib</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Characterize the Pharmacokinetics (PK) of Pevonedistat and Ixazomib (Dose Escalation)</measure>
    <time_frame>Up to 3 months</time_frame>
    <description>To understand the concentration-effect relationship of both agents when taken together</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Recurrent Multiple Myeloma</condition>
  <condition>Refractory Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Treatment (ixazomib citrate, pevonedistat)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive ixazomib citrate PO QD on days 1, 8, and 15 of each cycle and pevonedistat IV over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ixazomib Citrate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (ixazomib citrate, pevonedistat)</arm_group_label>
    <other_name>MLN-9708</other_name>
    <other_name>MLN9708</other_name>
    <other_name>Ninlaro</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pevonedistat</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (ixazomib citrate, pevonedistat)</arm_group_label>
    <other_name>MLN4924</other_name>
    <other_name>Nedd8-Activating Enzyme Inhibitor MLN4924</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have RRMM with measurable disease, as defined by at least one of the&#xD;
             following:&#xD;
&#xD;
               -  Serum monoclonal protein &gt;= 0.5 g/dL&#xD;
&#xD;
               -  Urinary monoclonal protein excretion of &gt;= 200 mg/24 hours&#xD;
&#xD;
               -  Kappa or lambda light chain level &gt;= 10 mg/dL with an abnormal free light chain&#xD;
                  ratio&#xD;
&#xD;
          -  At least two prior lines of therapy and all patients should have at least been exposed&#xD;
             to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38&#xD;
             antibody.&#xD;
&#xD;
               -  For proteasome-sensitive expansion cohort: Patients with MM who relapsed or are&#xD;
                  refractory to a prior line of therapy not including a proteasome inhibitor&#xD;
&#xD;
               -  For proteasome-relapsed/refractory expansion cohort: Patients with MM who have&#xD;
                  relapsed after prior PI exposure or are PI-refractory, defined as nonresponsive&#xD;
                  to treatment or progresses within 60 days of last exposure to a PI&#xD;
&#xD;
          -  Age &gt;= 18 years&#xD;
&#xD;
               -  Because no dosing or adverse event (AE) data are currently available on the use&#xD;
                  of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib) in patients &lt; 18&#xD;
                  years of age, and as this disease is exceptionally uncommon in this age group,&#xD;
                  children are excluded from this study&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,000/mcL&#xD;
&#xD;
          -  Platelets &gt;= 75,000/mcL&#xD;
&#xD;
          -  Bilirubin =&lt; institutional upper limit of normal (ULN).&#xD;
&#xD;
               -  Patients with Gilbert's syndrome may enroll if direct bilirubin =&lt; 1.5 x ULN&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 3.0 x institutional ULN&#xD;
&#xD;
          -  Creatinine clearance (CrCl) by Cockcroft-Gault &gt;= 30 mL/min&#xD;
&#xD;
          -  Known human immunodeficiency virus (HIV) positive patients who meet the following&#xD;
             criteria will be considered eligible:&#xD;
&#xD;
               -  CD 4 count &gt; 350 cells/mm^3&#xD;
&#xD;
               -  Undetectable viral load&#xD;
&#xD;
               -  Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents&#xD;
                  (e.g. excluding ritonavir)&#xD;
&#xD;
               -  No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic&#xD;
                  infections&#xD;
&#xD;
          -  The effects of MLN4924 (pevonedistat) and MLN9708 (ixazomib) on the developing human&#xD;
             fetus are unknown. For this reason and because NAE inhibitory agents are known to be&#xD;
             teratogenic, women of child-bearing potential and men must meet the following&#xD;
             criteria:&#xD;
&#xD;
               -  Female patients who are:&#xD;
&#xD;
                    -  Postmenopausal for at least one year before the screening visit, OR&#xD;
&#xD;
                    -  Surgically sterile, OR&#xD;
&#xD;
                    -  If of childbearing potential, agree to practice 1 highly effective method&#xD;
                       and 1 additional (barrier) method of contraception, at the same time, from&#xD;
                       the time of signing the informed consent until 4 months after the last dose&#xD;
                       of the ixazomib and pevonedistat (female and male condoms should not be used&#xD;
                       together), or agree to abstain from heterosexual intercourse, when this is&#xD;
                       in line with the preferred and usual lifestyle of the subject (Periodic&#xD;
                       abstinence [e.g,, calendar, ovulation, symptothermal, postovulation methods]&#xD;
                       withdrawal, spermicides only, and lactational amenorrhea are not acceptable&#xD;
                       methods of contraception)&#xD;
&#xD;
               -  Male patients, even if surgically sterilized, who:&#xD;
&#xD;
                    -  Agree to practice effective barrier contraception during the entire time&#xD;
                       enrolled on study through 4 months after completion of ixazomib and&#xD;
                       pevonedistat administration (female and male condoms should not be used&#xD;
                       together), OR&#xD;
&#xD;
                    -  Agree to abstain from heterosexual intercourse, when this is in line with&#xD;
                       the preferred and usual lifestyle of the subject. (Periodic abstinence&#xD;
                       [e.g., calendar, ovulation, symptothermal, postovulation methods for the&#xD;
                       female partner] withdrawal, spermicides only, and lactational amenorrhea are&#xD;
                       not acceptable methods of contraception)&#xD;
&#xD;
               -  Should a woman become pregnant or suspect she is pregnant while she or her&#xD;
                  partner is participating in this study, she should inform her treating physician&#xD;
                  immediately&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
             Participants with impaired decision-making capacity (IDMC) who have a&#xD;
             legally-authorized representative (LAR) and/or family member available will also be&#xD;
             eligible&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diagnosed or treated for another malignancy within 2 years before randomization or&#xD;
             previously diagnosed with another malignancy and have any evidence of residual&#xD;
             disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are&#xD;
             not excluded if they have undergone resection&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents, within 30 days of the&#xD;
             start of this trial and throughout the duration of this trial&#xD;
&#xD;
          -  Patients with known central nervous system involvement should be excluded from this&#xD;
             clinical trial because of their poor prognosis and because they often develop&#xD;
             progressive neurologic dysfunction that would confound the evaluation of neurologic&#xD;
             and other AEs&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to MLN4924 (pevonedistat) or MLN9708 (ixazomib) (including boron or&#xD;
             boron-containing products)&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illness&#xD;
&#xD;
          -  Pregnant women are excluded from this study because MLN4924 (pevonedistat) is an NAE&#xD;
             inhibitory agent with the potential for teratogenic or abortifacient effects. Because&#xD;
             there is an unknown but potential risk for AEs in nursing infants secondary to&#xD;
             treatment of the mother with MLN4924 (pevonedistat), breastfeeding should be&#xD;
             discontinued if the mother is treated with MLN4924 (pevonedistat). These potential&#xD;
             risks may also apply to the use of MLN9708 (ixazomib) in this study&#xD;
&#xD;
          -  Major surgery within 14 days before the first dose of any study drug or a scheduled&#xD;
             surgery during study period&#xD;
&#xD;
          -  Patients with uncontrolled coagulopathy or bleeding disorder&#xD;
&#xD;
          -  Known hepatic impairment as defined by known hepatic cirrhosis, hepatitis B surface&#xD;
             antigen seropositive or known or suspected active hepatitis C infection&#xD;
&#xD;
               -  Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the&#xD;
                  setting of negative hepatitis B surface antigen and negative hepatitis B surface&#xD;
                  antibody) must have an undetectable hepatitis B viral load. Patients who have&#xD;
                  positive hepatitis C antibody may be included if they have an undetectable&#xD;
                  hepatitis C viral load&#xD;
&#xD;
          -  Known cardiopulmonary disease defined as:&#xD;
&#xD;
               -  Unstable angina;&#xD;
&#xD;
               -  Congestive heart failure (New York Heart Association [NYHA] class III or IV);&#xD;
&#xD;
               -  Myocardial infarction within 6 months prior to first dose (patients who had&#xD;
                  ischemic heart disease such as acute coronary syndrome [ACS], myocardial&#xD;
                  infarction, and/or revascularization greater than 6 months before screening and&#xD;
                  who are without cardiac symptoms may enroll);&#xD;
&#xD;
               -  Symptomatic cardiomyopathy&#xD;
&#xD;
               -  Clinically significant arrhythmia:&#xD;
&#xD;
                    -  History of polymorphic ventricular fibrillation or torsade de pointes,&#xD;
&#xD;
                    -  Permanent atrial fibrillation, defined as continuous atrial fibrillation for&#xD;
                       &gt;= 6 months,&#xD;
&#xD;
                    -  Persistent atrial fibrillation, defined as sustained atrial fibrillation&#xD;
                       lasting &gt; 7 days and/or requiring cardioversion in the 4 weeks before&#xD;
                       screening,&#xD;
&#xD;
                    -  Grade 3 atrial fibrillation defined as symptomatic and incompletely&#xD;
                       controlled medically, or controlled with device (e.g., pacemaker), or&#xD;
                       ablation in the past 6 months and&#xD;
&#xD;
                    -  Patients with paroxysmal atrial fibrillation or grade &lt; 3 atrial&#xD;
                       fibrillation for period of at least 6 months are permitted to enroll&#xD;
                       provided that their rate is controlled on a stable regimen&#xD;
&#xD;
               -  Clinically significant pulmonary hypertension requiring pharmacologic therapy&#xD;
&#xD;
          -  Uncontrolled high blood pressure (i.e., systolic blood pressure &gt; 180 mmHg, diastolic&#xD;
             blood pressure &gt; 95 mmHg)&#xD;
&#xD;
          -  Prolonged rate corrected QT (QTc) interval &gt;= 500 msec, calculated according to&#xD;
             institutional guidelines&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) &lt; 50% as assessed by echocardiogram&#xD;
&#xD;
          -  Known moderate to severe chronic obstructive pulmonary disease, interstitial lung&#xD;
             disease, and pulmonary fibrosis&#xD;
&#xD;
          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral&#xD;
             absorption or tolerance of MLN9708 (ixazomib), including difficulty swallowing&#xD;
&#xD;
          -  Peripheral neuropathy that is grade &gt;= 3, or grade 2 with pain on clinical examination&#xD;
             during the screening period&#xD;
&#xD;
          -  Patients that have previously been treated with MLN9708 (ixazomib)&#xD;
&#xD;
          -  Systemic treatment, within 14 days before the first dose of MLN9708 (ixazomib), with&#xD;
             strong CYP3A inducers (rifampin, rifapentine, rifabutin, ritonavir, carbamazepine,&#xD;
             phenytoin, phenobarbital), or use of St. John's wort. Clinically significant metabolic&#xD;
             enzyme inducers are not permitted during this study&#xD;
&#xD;
          -  Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days&#xD;
             will be considered a sufficient interval between treatment and administration of the&#xD;
             MLN9708 (ixazomib)&#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)&#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)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nisha Joseph</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emory University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Smilow Cancer Center/Yale-New Haven Hospital</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center-International Plaza</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33607</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center - McKinley Campus</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University Hospital/Winship Cancer Institute</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kentucky/Markey Cancer Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>December 7, 2018</study_first_submitted>
  <study_first_submitted_qc>December 7, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <results_first_submitted>August 16, 2023</results_first_submitted>
  <results_first_submitted_qc>August 16, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">September 6, 2023</results_first_posted>
  <last_update_submitted>August 16, 2023</last_update_submitted>
  <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 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>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ixazomib</mesh_term>
    <mesh_term>Enzyme Inhibitors</mesh_term>
    <mesh_term>Pevonedistat</mesh_term>
    <mesh_term>Glycine</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>June 1, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT03770260/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Dose Level 1</title>
          <description>Pevonedistat 20 mg/meter squared given by infusion and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
        <group group_id="P2">
          <title>Dose Level 2</title>
          <description>Pevonedistat 40 mg/meter squared given by infusion and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
        <group group_id="P3">
          <title>Dose Level 3</title>
          <description>Pevonedistat 60 mg/meter squared given by infusion and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
        <group group_id="P4">
          <title>Dose Expansion</title>
          <description>Pevonedistat at the maximum tolerated dose determined in the dose levels given by infusion and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Disease progression</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Dose Level 1</title>
          <description>Pevonedistat 20 mg/m^2 given by a vein in the arm and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
        <group group_id="B2">
          <title>Dose Level 2</title>
          <description>Pevonedistat 40 mg/m^2 given by a vein in the arm and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
        <group group_id="B3">
          <title>Dose Level 3</title>
          <description>Pevonedistat 60 mg/m^2 given by a vein in the arm and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
        <group group_id="B4">
          <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="3"/>
            <count group_id="B2" value="4"/>
            <count group_id="B3" value="1"/>
            <count group_id="B4" value="8"/>
          </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" 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 group_id="B4" 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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants Experiencing a Dose Limiting Toxicity (Dose Escalation)</title>
        <description>Number of participants experiencing a dose limiting toxicity to determine the maximum tolerated dose (MTD)</description>
        <time_frame>At Day 28</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1</title>
            <description>Patients receive pevonedistat 20 mg/meter squared by infusion and ixazomib citrate 4 mg by mouth on days 1, 8, and 15 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level 2</title>
            <description>Patients receive pevonedistat 40 mg/meter squared by infusion and ixazomib citrate 4 mg by mouth on days 1, 8, and 15 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Dose Level 3</title>
            <description>Patients receive pevonedistat 20 mg/meter squared by infusion and ixazomib citrate 4 mg by mouth on days 1, 8, and 15 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Experiencing a Dose Limiting Toxicity (Dose Escalation)</title>
          <description>Number of participants experiencing a dose limiting toxicity to determine the maximum tolerated dose (MTD)</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="4"/>
                <count group_id="O3" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Experienced a Dose Limiting Toxicity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Did Not Experience a Dose Limiting Toxicity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Withdrew from Treatment</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants Experiencing a Grade 3-5 Adverse Event (Dose Expansion)</title>
        <description>Number of participants who experienced a grade 3-5 adverse event in the dose expansion group</description>
        <time_frame>Up to 2 years after Treatment</time_frame>
        <population>Did not complete dose escalation phase to enroll to the dose expansion phase.</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Expansion</title>
            <description>Patients receive pevonedistat the maximum tolerated dose (MTD) as determined in the dose escalation phase by infusion ande ixazomib citrate 4 mg by mouth on days 1, 8, and 15 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Experiencing a Grade 3-5 Adverse Event (Dose Expansion)</title>
          <description>Number of participants who experienced a grade 3-5 adverse event in the dose expansion group</description>
          <population>Did not complete dose escalation phase to enroll to the dose expansion phase.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Overall Response Rate (Dose Expansion)</title>
        <description>To determine the overall responses in patients receiving pevonedistat and ixazomib</description>
        <time_frame>Up to 2 Years after Treatment</time_frame>
        <population>The dose escalation phase was not completed in order to enroll to the dose expansion phase</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Expansion</title>
            <description>Patients receive pevonedistat the maximum tolerated dose (MTD) as determined in the dose escalation phase by infusion ande ixazomib citrate 4 mg by mouth on days 1, 8, and 15 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (Dose Expansion)</title>
          <description>To determine the overall responses in patients receiving pevonedistat and ixazomib</description>
          <population>The dose escalation phase was not completed in order to enroll to the dose expansion phase</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Characterize the Pharmacokinetics (PK) of Pevonedistat and Ixazomib (Dose Escalation)</title>
        <description>To understand the concentration-effect relationship of both agents when taken together</description>
        <time_frame>Up to 3 months</time_frame>
        <population>This data was not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1</title>
            <description>Patients receive pevonedistat 20 mg/meter squared by infusion and ixazomib citrate 4 mg by mouth on days 1, 8, and 15 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level 2</title>
            <description>Patients receive pevonedistat 40 mg/meter squared by infusion and ixazomib citrate 4 mg by mouth on days 1, 8, and 15 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Dose Level 3</title>
            <description>Patients receive pevonedistat 20 mg/meter squared by infusion and ixazomib citrate 4 mg by mouth on days 1, 8, and 15 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Characterize the Pharmacokinetics (PK) of Pevonedistat and Ixazomib (Dose Escalation)</title>
          <description>To understand the concentration-effect relationship of both agents when taken together</description>
          <population>This data was not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 2 years and 2 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Dose Level 1</title>
          <description>Pevonedistat 20 mg/m^2 given by a vein in the arm and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
        <group group_id="E2">
          <title>Dose Level 2</title>
          <description>Pevonedistat 40 mg/m^2 given by a vein in the arm and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
        <group group_id="E3">
          <title>Dose Level 3</title>
          <description>Pevonedistat 60 mg/m^2 given by a vein in the arm and ixazomib 4 mg taken by mouth on days 1, 8 and 15 of every 28-day cycle.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (v4.0)</default_vocab>
        <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="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Non-cardiac Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (v4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </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="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BUN elevated</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </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="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Blood lactate dehydrogenase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>carpel tunnel repair</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Lower Leg Cramping</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Alteration in Breathing Pattern</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Blisters</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </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>
    <limitations_and_caveats>Enrollment was stopped by the drug company during the third dose level of the Dose Escalation Phase. They discontinued clinical trials using pevonedistat. No participants were enrolled to the Dose Expansion Phase.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Grants Administrative Manager</name_or_title>
      <organization>Johns Hopkins University/SKCCC</organization>
      <phone>4439273568</phone>
      <email>jmurra33@jhmi.edu</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/NCT03770260
org study id: NCI-2018-03121
secondary id: NCI-2018-03121
secondary id: 10249
secondary id: 10249
secondary id: UM1CA186691
nct id: NCT03770260
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase Ib trial studies side effects and best dose of pevonedistat when given together
      with ixazomib in treating patients with multiple myeloma that has come back or does not
      respond to treatment. Pevonedistat and ixazomib may stop the growth of tumor cells by
      blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of MLN4924
      (pevonedistat) in combination with MLN9708 (ixazomib citrate [ixazomib]) in relapsed and/or
      refractory multiple myeloma (RRMM) patients after more than one previous line of treatment.
      (Dose-escalation phase) II. Describe the safety profile and tolerability of the combination
      of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in the proteasome inhibitor (PI)-sensitive
      and PI-refractory populations. (Dose-expansion phase) III. Determine the anti-tumor activity
      and overall response rates (ORR) in patients with RRMM with the use of MLN9708 (ixazomib) and
      MLN4924 (pevonedistat) in combination. (Dose-expansion phase)

      SECONDARY OBJECTIVE:

      I. Attain pharmacokinetic (PK) characterization of MLN4924 (pevonedistat) in combination with
      MLN9708 (ixazomib) for the purpose of understanding concentration-effect relationships of
      both agents. (Dose-escalation phase)

      EXPLORATORY OBJECTIVE:

      I. To correlate and predict disease response using the following tests: NAD(P)H dehydrogenase
      (quinone) 1 (NQO1) and cystine/glutamate transporter (SLC7A11) (nuclear factor
      [erythroid-derived 2]-like 2 [NRF2] target genes): evaluated on whole blood as markers of
      MLN4924 (pevonedistat) activity.

      OUTLINE: This is a dose-escalation study of pevonedistat.

      Patients receive ixazomib citrate orally (PO) once daily (QD) on days 1, 8, and 15 of each
      cycle and pevonedistat intravenously (IV) over 60 minutes on days 1, 8, and 15 of each cycle.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, then every 2-3
      months for up to 2 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants Experiencing a Dose Limiting Toxicity (Dose Escalation)
time frame: At Day 28
description: Number of participants experiencing a dose limiting toxicity to determine the maximum tolerated dose (MTD)
measure: Number of Participants Experiencing a Grade 3-5 Adverse Event (Dose Expansion)
time frame: Up to 2 years after Treatment
description: Number of participants who experienced a grade 3-5 adverse event in the dose expansion group
measure: Overall Response Rate (Dose Expansion)
time frame: Up to 2 Years after Treatment
description: To determine the overall responses in patients receiving pevonedistat and ixazomib
measure: Characterize the Pharmacokinetics (PK) of Pevonedistat and Ixazomib (Dose Escalation)
time frame: Up to 3 months
description: To understand the concentration-effect relationship of both agents when taken together
arm group label: Treatment (ixazomib citrate, pevonedistat)
arm group type: Experimental
description: Patients receive ixazomib citrate PO QD on days 1, 8, and 15 of each cycle and pevonedistat IV over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Ixazomib Citrate
description: Given PO
arm group label: Treatment (ixazomib citrate, pevonedistat)
other name: MLN-9708
other name: MLN9708
other name: Ninlaro
intervention type: Drug
intervention name: Pevonedistat
description: Given IV
arm group label: Treatment (ixazomib citrate, pevonedistat)
other name: MLN4924
other name: Nedd8-Activating Enzyme Inhibitor MLN4924
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nisha Joseph
role: Principal Investigator
affiliation: Emory University
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Ixazomib
mesh term: Enzyme Inhibitors
mesh term: Pevonedistat
mesh term: Glycine
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: 
limitations and caveats: Enrollment was stopped by the drug company during the third dose level of the Dose Escalation Phase. They discontinued clinical trials using pevonedistat. No participants were enrolled to the Dose Expansion Phase.
point of contact: 