<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/NCT03238248</url>
  </required_header>
  <id_info>
    <org_study_id>VICC HEM 16146</org_study_id>
    <secondary_id>NCI-2017-01377</secondary_id>
    <nct_id>NCT03238248</nct_id>
  </id_info>
  <brief_title>Pevonedistat and Azacitidine in MDS or MDS/MPN Patients Who Fail Primary Therapy With DNA Methyl Transferase Inhibitors</brief_title>
  <official_title>A Phase II Trial of Pevonedistat and Azacitidine in MDS or MDS/MPN Patients Who Fail Primary Therapy With DNA Methyl Transferase Inhibitors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt-Ingram Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt-Ingram Cancer Center</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 study will evaluate the treatment combination of pevonedistat and azacitidine in the&#xD;
      setting of DNA methyltransferase inhibitor(s) failure in patients with relapsed/refractory&#xD;
      myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative neoplasm.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objective:&#xD;
&#xD;
      To compare survival of patients treated with a combination of pevonedistat and azacitidine&#xD;
      after failure of DNA methyltransferase inhibitors (DNMTi) to historical survival for patients&#xD;
      with relapsed/refractory myelodysplastic syndrome (MDS) or myelodysplastic/&#xD;
      myeloproliferative overlap syndromes (MDS/MPN) who are ineligible for hematopoietic stem cell&#xD;
      transplant (HSCT)&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
        -  To determine the rate of hematologic improvement (HI) in patients with&#xD;
           relapsed/refractory MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi&#xD;
           failure&#xD;
&#xD;
        -  To determine the complete remission (CR) and marrow CR rates in patients with&#xD;
           relapsed/refractory MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi&#xD;
           failure&#xD;
&#xD;
        -  To determine the reduction of bone marrow blasts in patients with relapsed/refractory&#xD;
           MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi failure&#xD;
&#xD;
      Exploratory Objectives:&#xD;
&#xD;
        -  To correlate the mutation burden in patients with relapsed/refractory MDS or MDS/MPN&#xD;
           with response to treatment with pevonedistat and azacitidine&#xD;
&#xD;
        -  To correlate genomic aberrations with rate of response and survival in&#xD;
           relapsed/refractory MDS or MDS/MPN patients treated with pevonedistat and azacitidine&#xD;
&#xD;
        -  To measure the effect of pevonedistat treatment in combination with azacitidine on&#xD;
           quality of life in patients with relapsed/refractory MDS or MDS/MPN&#xD;
&#xD;
        -  To define epigenetic biomarkers for pevonedistat use in relapsed/refractory MDS or&#xD;
           MDS/MPN&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 7, 2017</start_date>
  <completion_date type="Anticipated">September 2023</completion_date>
  <primary_completion_date type="Actual">September 30, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival</measure>
    <time_frame>1 year</time_frame>
    <description>Overall survival will be summarized using the method of Kaplan and Meier and compared among important subgroups using the logrank test.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to progression</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>Progression-free survival will be summarized using the method of Kaplan and Meier and compared among important subgroups using the logrank test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of complete response</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>Differences in the frequency of objective response by treatment will be compared using the chi-square test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of hematologic response per IWG</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>Will assess complete and differential blood counts (peripheral blood), and transfusion requirements. Differences in the frequency of objective response by treatment will be compared using the chi-square test.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Rate of marrow complete response (mCR)</measure>
    <time_frame>Up to 24 months.</time_frame>
    <description>Will assess morphologic features (e.g. presence of dysplastic features), presence of cytogenetic and/or molecular aberrancies, and myeloblast count.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in number of mutations as assessed by next generation sequencing (NGS)</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>Number of specific molecular mutations in a NGS panel of 37 genes frequently mutated in myeloid malignancies will be determined by next generation sequencing before and after protocol-directed therapy. Results will be correlated with response. Clonal evolution and the relationship between response rates and mutations will be explored.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in allele frequency assessed by next generation sequencing (NGS)</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>Allele frequency of specific molecular mutations in a NGS panel of 37 genes frequently mutated in myeloid malignancies will be determined by next generation sequencing before and after protocol-directed therapy. Results will be correlated with response. Clonal evolution and the relationship between response rates and mutations will be explored.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">71</enrollment>
  <condition>Myelodysplastic Syndromes</condition>
  <condition>Myeloproliferative Neoplasm</condition>
  <arm_group>
    <arm_group_label>Pevonedistat and Azacitidine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive Azacitidine (via an injection under the skin, or via an intravenous infusion (IV bag) on days 1, 2, 3, 4 and 5 of each 28-day cycle.&#xD;
Participants will receive Pevonedistat (through a vein in the arm) on Days 1, 3 and 5 of each 28-day cycle.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azacitidine Subcutaneous Injection or Intravenous Infusion</intervention_name>
    <description>75 mg/m2</description>
    <arm_group_label>Pevonedistat and Azacitidine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pevonedistat Infusion</intervention_name>
    <description>20 mg/m2</description>
    <arm_group_label>Pevonedistat and Azacitidine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Bone Marrow Biopsy &amp; Aspirate</intervention_name>
    <description>Removal of a small piece of bone and bone marrow by inserting a needle into hip bone.</description>
    <arm_group_label>Pevonedistat and Azacitidine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion:&#xD;
&#xD;
          -  Signed and dated voluntary written informed consent before performance of any study&#xD;
             related procedure not part of standard medical care, with the understanding that&#xD;
             consent may be withdrawn by the patient at any time without prejudice to future&#xD;
             medical care.&#xD;
&#xD;
          -  Male or female ≥ 18 years of age.&#xD;
&#xD;
          -  Morphologically confirmed diagnosis of MDS or MDS/MPN in accordance with WHO&#xD;
             diagnostic criteria.&#xD;
&#xD;
          -  ECOG performance status of 0, 1 or 2.&#xD;
&#xD;
          -  Expected survival ≥ 3 months after consenting.&#xD;
&#xD;
          -  Refractory/relapsed disease following DNMTi failure. Refractory disease defined as&#xD;
             either:&#xD;
&#xD;
               -  failure to achieve an objective response after at least 4 cycles of DNMTi&#xD;
                  therapy, or&#xD;
&#xD;
               -  failure to achieve an objective response with clear progressive disease on bone&#xD;
                  marrow biopsy after at least 2 cycles of DNMTi therapy. Relapsed disease is&#xD;
                  defined as having progressive disease after achieving an objective response after&#xD;
                  at least 2 cycles of DNMTi therapy.&#xD;
&#xD;
        Previous DNMTi therapy may include 5'azacitidine, decitabine, or DNMTi therapy currently in&#xD;
        clinical trials (e.g. SGI-110 (guadecitabine), ASTX727 or CC-486).To be considered DNMTi&#xD;
        treatment failure, during each prior treatment cycle, patients must have received&#xD;
        equivalent to minimum dosing of:&#xD;
&#xD;
        decitabine 15mg/m2 daily x 5 days, or&#xD;
&#xD;
        5'azacitidine 50mg/m2 IV/SC daily x 5 days,&#xD;
&#xD;
        SGI-110 (guadecitabine) 60mg/m2 SC daily x 5 days, or&#xD;
&#xD;
        oral DNMTi therapy with ASTX727 20/100mg daily x 5 days, or&#xD;
&#xD;
        oral DNMTi therapy with CC-486 200mg daily x 14 days&#xD;
&#xD;
          -  Recovery to ≤ Grade 1 or baseline of any toxicity due to prior systemic treatments,&#xD;
             excluding alopecia.&#xD;
&#xD;
          -  Patient consent to collection of fresh bone marrow biopsy and aspirate for exploratory&#xD;
             research obtained from a procedure performed no more than 28 days prior to initiating&#xD;
             treatment on Cycle 1, Day 1. Requirement for bone marrow biopsy may be waived with&#xD;
             approval of the study chair in the event that a bone marrow biopsy cannot be obtained.&#xD;
&#xD;
          -  Clinical laboratory values as specified below:&#xD;
&#xD;
               -  Serum albumin &gt; 2.7 g/dL&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x ULN&#xD;
&#xD;
               -  ALT and AST ≤ 2 x ULN&#xD;
&#xD;
               -  Calculated creatinine clearance ≥ 50 mL/min (per the Cockcroft-Gault formula)&#xD;
&#xD;
               -  WBC ≤ 50,000/µL (use of hyroxyurea is permitted)&#xD;
&#xD;
          -  Hgb &lt;8g/dL should be transfused to provide adequate tissue perfusion as per the&#xD;
             discretion of the investigators and local practice. Rechecking Hgb level prior to&#xD;
             start on Cycle 1 Day 1 is not necessary as long as patients do not have inadequate&#xD;
             oxygenation, underlying cardiopulmonary compromise, and/or any other reason deemed&#xD;
             clinically significant to delay therapy per the investigator.&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test; and&#xD;
             additionally agree to simultaneously use at least 2 methods of effective contraception&#xD;
             or abstain from heterosexual intercourse from the time of signing consent, and until 4&#xD;
             months after patient's last dose of protocol-indicated treatment. Periodic abstinence&#xD;
             (e.g. calendar,ovulation, symptothermal, postovulation methods for the female partner)&#xD;
             and withdrawal are not acceptable methods of contraception.&#xD;
&#xD;
        Women of child bearing potential are defined as those not surgically sterile or not&#xD;
        post-menopausal. If a female patient has not had a bilateral tubal ligation, a bilateral&#xD;
        oophorectomy, or a complete hysterectomy; or has not been amenorrheic for at least 1 year&#xD;
        in the absence of an alternative medical cause, then patient will be considered a female of&#xD;
        childbearing potential. Postmenopausal status in females under 55 years of age should be&#xD;
        confirmed with a serum FSH level within laboratory reference range for postmenopausal&#xD;
        women.&#xD;
&#xD;
        - Men, even if surgically sterilized (i.e. status post-vasectomy), who are sexually active&#xD;
        with women of childbearing potential must agree to follow instructions for effective&#xD;
        barrier contraception from the time of signing consent and until 4 months after last dose&#xD;
        of protocol-indicated treatment. Periodic abstinence (e.g. calendar, ovulation,&#xD;
        symptothermal, postovulation methods for the female partner) and withdrawal are not&#xD;
        acceptable methods of contraception.&#xD;
&#xD;
        Exclusion:&#xD;
&#xD;
          -  Diagnosis of acute myeloid leukemia (i.e. ≥ 20% peripheral or marrow blasts).&#xD;
&#xD;
          -  Any HSCT within 6 months prior to signing informed consent.&#xD;
&#xD;
          -  Any patient who is eligible for HSCT at the time of study screening.&#xD;
&#xD;
          -  Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation&#xD;
             of treatment or treatment escalation within 21 days, and/or &gt; Grade 1 persistent or&#xD;
             clinically significant non-hematologic toxicity related to HSCT&#xD;
&#xD;
          -  Any previous treatment with pevonedistat or other NEDD8 inhibitor.&#xD;
&#xD;
          -  Treatment with any investigational products within 14 days before the first dose of&#xD;
             protocol-indicated treatment.&#xD;
&#xD;
          -  Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose&#xD;
             of any study drug.&#xD;
&#xD;
          -  Major surgery requiring general anesthesia within 14 days before the first dose of any&#xD;
             study drug or a scheduled surgery during study period. (Placement of a central line or&#xD;
             port-a-catheter is acceptable within this time frame and does not exclude the&#xD;
             patient.)&#xD;
&#xD;
          -  Treatment with clinically significant metabolic CYP3A inducers within 14 days before&#xD;
             the first dose of study drug. Clinically significant CYP3A inducers are not permitted&#xD;
             during the study.&#xD;
&#xD;
          -  Prolonged QTc interval &gt; 500 msec, calculated according to Fredericia's formula&#xD;
&#xD;
          -  Known cardiopulmonary disease defined as having one or more of the following:&#xD;
&#xD;
               -  Uncontrolled high blood pressure (i.e. systolic &gt; 180 mmHg or diastolic &gt; 95&#xD;
                  mmHg);&#xD;
&#xD;
               -  Symptomatic cardiomyopathy;&#xD;
&#xD;
               -  Ischemic heart disease; Patients with acute coronary syndrome, myocardial&#xD;
                  infarction, and/or revascularization (e.g. coronary artery bypass graft, stent)&#xD;
                  within 6 months of first dose of study drug are excluded; Patients with a history&#xD;
                  of ischemic heart disease who have had revascularization greater than 6 months&#xD;
                  before screening and who are without cardiac symptoms may enroll;&#xD;
&#xD;
               -  Arrhythmia (e.g. history of polymorphic ventricular fibrillation or torsade de&#xD;
                  pointes). Patients with symptomatic atrial fibrillation (Afib) incompletely&#xD;
                  controlled medically, or controlled by device (e.g. pacemaker) or by ablation in&#xD;
                  the past 6 months are excluded. However, patients with stable, AFib for a period&#xD;
                  of at least 6 months, whose Afib is controlled with medication, or who have a&#xD;
                  history of paroxysmal AFib are permitted to enroll;&#xD;
&#xD;
               -  Implantable cardioverter defibrillator;&#xD;
&#xD;
               -  Congestive heart failure (New York Heart Association [NYHA] Class III or IV; or&#xD;
                  Class II with a recent decompensation requiring hospitalization or referral to a&#xD;
                  heart failure clinic within 4 weeks before screening),&#xD;
&#xD;
               -  Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing).&#xD;
                  Mild regurgitation is not excluded;&#xD;
&#xD;
               -  Pulmonary hypertension.&#xD;
&#xD;
          -  Female patients who are both lactating and breastfeeding, who have a positive serum&#xD;
             pregnancy test during screening, or who plan to become pregnant while in the trial or&#xD;
             within 90 days after receiving protocol-directed treatment.&#xD;
&#xD;
          -  Active uncontrolled infection. Patients with infection under active treatment and&#xD;
             controlled with antibiotics are not excluded.&#xD;
&#xD;
          -  Known Childs class B or C hepatic cirrhosis or severe pre-existing hepatic impairment.&#xD;
&#xD;
          -  Known hepatitis B surface antigen seropositivity or known or suspected active&#xD;
             hepatitis C infection. Note: Patients who have isolated positive hepatitis B core&#xD;
             antibody (i.e. in the setting of negative hepatitis B surface antigen and negative&#xD;
             hepatitis B surface antibody) must have an undetectable hepatitis B viral load.&#xD;
&#xD;
          -  Known human immunodeficiency virus (HIV) seropositivity.&#xD;
&#xD;
          -  Any serious concurrent condition that could, in the investigator's opinion,&#xD;
             significantly interfere with completion of study procedures or protocol compliance.&#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>Michael Savona, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt-Ingram Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Miami Miller School of Medicine</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center</name>
      <address>
        <city>Westwood</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan-Kettering</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Rochester Medical Center</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt-Ingram Cancer Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</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>July 25, 2017</study_first_submitted>
  <study_first_submitted_qc>August 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>November 15, 2022</last_update_submitted>
  <last_update_submitted_qc>November 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt-Ingram Cancer Center</investigator_affiliation>
    <investigator_full_name>Michael Savona</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Myeloproliferative Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azacitidine</mesh_term>
    <mesh_term>Pevonedistat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 16, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/48/NCT03238248/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <pending_results>
    <submitted>August 21, 2023</submitted>
    <returned>September 15, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03238248
org study id: VICC HEM 16146
secondary id: NCI-2017-01377
nct id: NCT03238248
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study will evaluate the treatment combination of pevonedistat and azacitidine in the
      setting of DNA methyltransferase inhibitor(s) failure in patients with relapsed/refractory
      myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative neoplasm.
Primary Objective:

      To compare survival of patients treated with a combination of pevonedistat and azacitidine
      after failure of DNA methyltransferase inhibitors (DNMTi) to historical survival for patients
      with relapsed/refractory myelodysplastic syndrome (MDS) or myelodysplastic/
      myeloproliferative overlap syndromes (MDS/MPN) who are ineligible for hematopoietic stem cell
      transplant (HSCT)

      Secondary Objectives:

        -  To determine the rate of hematologic improvement (HI) in patients with
           relapsed/refractory MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi
           failure

        -  To determine the complete remission (CR) and marrow CR rates in patients with
           relapsed/refractory MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi
           failure

        -  To determine the reduction of bone marrow blasts in patients with relapsed/refractory
           MDS or MDS/MPN treated with pevonedistat and azacitidine after DNMTi failure

      Exploratory Objectives:

        -  To correlate the mutation burden in patients with relapsed/refractory MDS or MDS/MPN
           with response to treatment with pevonedistat and azacitidine

        -  To correlate genomic aberrations with rate of response and survival in
           relapsed/refractory MDS or MDS/MPN patients treated with pevonedistat and azacitidine

        -  To measure the effect of pevonedistat treatment in combination with azacitidine on
           quality of life in patients with relapsed/refractory MDS or MDS/MPN

        -  To define epigenetic biomarkers for pevonedistat use in relapsed/refractory MDS or
           MDS/MPN
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall survival
time frame: 1 year
description: Overall survival will be summarized using the method of Kaplan and Meier and compared among important subgroups using the logrank test.
measure: Time to progression
time frame: Up to 24 months
description: Progression-free survival will be summarized using the method of Kaplan and Meier and compared among important subgroups using the logrank test.
measure: Rate of complete response
time frame: Up to 24 months
description: Differences in the frequency of objective response by treatment will be compared using the chi-square test.
measure: Rate of hematologic response per IWG
time frame: Up to 24 months
description: Will assess complete and differential blood counts (peripheral blood), and transfusion requirements. Differences in the frequency of objective response by treatment will be compared using the chi-square test.
measure: Rate of marrow complete response (mCR)
time frame: Up to 24 months.
description: Will assess morphologic features (e.g. presence of dysplastic features), presence of cytogenetic and/or molecular aberrancies, and myeloblast count.
measure: Change in number of mutations as assessed by next generation sequencing (NGS)
time frame: Up to 24 months
description: Number of specific molecular mutations in a NGS panel of 37 genes frequently mutated in myeloid malignancies will be determined by next generation sequencing before and after protocol-directed therapy. Results will be correlated with response. Clonal evolution and the relationship between response rates and mutations will be explored.
measure: Change in allele frequency assessed by next generation sequencing (NGS)
time frame: Up to 24 months
description: Allele frequency of specific molecular mutations in a NGS panel of 37 genes frequently mutated in myeloid malignancies will be determined by next generation sequencing before and after protocol-directed therapy. Results will be correlated with response. Clonal evolution and the relationship between response rates and mutations will be explored.
arm group label: Pevonedistat and Azacitidine
arm group type: Experimental
description: Participants will receive Azacitidine (via an injection under the skin, or via an intravenous infusion (IV bag) on days 1, 2, 3, 4 and 5 of each 28-day cycle.
Participants will receive Pevonedistat (through a vein in the arm) on Days 1, 3 and 5 of each 28-day cycle.
intervention type: Drug
intervention name: Azacitidine Subcutaneous Injection or Intravenous Infusion
description: 75 mg/m2
arm group label: Pevonedistat and Azacitidine
intervention type: Drug
intervention name: Pevonedistat Infusion
description: 20 mg/m2
arm group label: Pevonedistat and Azacitidine
intervention type: Procedure
intervention name: Bone Marrow Biopsy & Aspirate
description: Removal of a small piece of bone and bone marrow by inserting a needle into hip bone.
arm group label: Pevonedistat and Azacitidine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Savona, MD
role: Principal Investigator
affiliation: Vanderbilt-Ingram Cancer Center
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt-Ingram Cancer Center
investigator full name: Michael Savona
investigator title: Principal Investigator
mesh term: Myelodysplastic Syndromes
mesh term: Myeloproliferative Disorders
mesh term: Azacitidine
mesh term: Pevonedistat
sharing ipd: Undecided
provided document: 
submitted: August 21, 2023
returned: September 15, 2023