<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/NCT04493138</url>
  </required_header>
  <id_info>
    <org_study_id>2019-1178</org_study_id>
    <secondary_id>NCI-2020-05261</secondary_id>
    <secondary_id>2019-1178</secondary_id>
    <nct_id>NCT04493138</nct_id>
  </id_info>
  <brief_title>Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations</brief_title>
  <official_title>Phase I/II Study of Azacitidine in Combination With Quizartinib for Patients With Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms With FLT3 or CBL Mutations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>M.D. Anderson 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>M.D. Anderson Cancer Center</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 I/II trial studies the side effects and best dose of quizartinib when given with&#xD;
      azacitidine and to see how well they work in treating patients with myelodysplastic syndrome&#xD;
      or myelodysplastic/myeloproliferative neoplasm with FLT3 or CBL mutations. Chemotherapy&#xD;
      drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either&#xD;
      by killing the cells, by stopping them from dividing, or by stopping them from spreading.&#xD;
      Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for&#xD;
      cell growth. Giving azacitidine and quizartinib may help to control myelodysplastic syndrome&#xD;
      or myelodysplastic/myeloproliferative neoplasm.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the safety, tolerability and maximum tolerable dose (MTD) of quizartinib in&#xD;
      combination with azacytidine.&#xD;
&#xD;
      II. To assess overall response (ORR) rate to quizartinib in combination with azacitidine.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess overall survival (OS), duration of response, leukemia-free survival (LFS),&#xD;
      relapse-free survival (RFS) and safety profile.&#xD;
&#xD;
      II. Correlative studies.&#xD;
&#xD;
      OUTLINE: This is a phase I, dose-escalation study of quizartinib followed by a phase II&#xD;
      study.&#xD;
&#xD;
      Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over about 30 minutes&#xD;
      on days 1-5 and quizartinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28&#xD;
      days in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 21, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <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 response rate</measure>
    <time_frame>At least 4 cycles of therapy in the absence of progression (1 cycle = 28 days)</time_frame>
    <description>Will be defined as complete remission, partial remission, complete remission with incomplete count recovery, marrow compete remission or hematological improvement. Will be estimated for all patients along with the 95% credible interval.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Time from treatment start till death or last follow-up, assessed up to 2 years</time_frame>
    <description>Will be listed and summarized by the Kaplan-Meier estimator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Duration of response</measure>
    <time_frame>Duration from the first documented onset of partial response or complete response to the date of progressive disease/relapse, assessed up to 2 years</time_frame>
    <description>Will be listed and summarized by the Kaplan-Meier estimator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Relapse-free survival</measure>
    <time_frame>Time from start of response to the date of event defined as the first documented progressive disease/relapse or death, whichever comes first, assessed up to 2 years</time_frame>
    <description>Will be listed and summarized by the Kaplan-Meier estimator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Leukemia free survival</measure>
    <time_frame>Time from treatment start to the time of progression to leukemia or death, assessed up to 2 years</time_frame>
    <description>Will be listed and summarized by the Kaplan-Meier estimator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of adverse events (AEs)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The severity of the toxicities will be graded according to the latest version of National Cancer Institute Common Terminology Criteria for Adverse Events. The number and percent of subjects with treatment-emergent adverse events will be summarized according to intensity and drug relationship, and categorized by System Organ Class and preferred term by dose level/Part. All reported AEs that occur after signing informed consent will be included in the analysis of all reported AEs. Exposure to study drug and reasons for discontinuation of study drug will be tabulated.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">58</enrollment>
  <condition>Chronic Myelomonocytic Leukemia</condition>
  <condition>Myelodysplastic Syndrome</condition>
  <condition>Myeloproliferative Neoplasm</condition>
  <condition>Recurrent Chronic Myelomonocytic Leukemia</condition>
  <condition>Recurrent Myelodysplastic Syndrome</condition>
  <condition>Recurrent Myeloproliferative Neoplasm</condition>
  <arm_group>
    <arm_group_label>Treatment (azacitidine, quizartinib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive azacitidine SC or IV over about 30 minutes on days 1-5 and quizartinib PO QD on days 1-28. 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>Azacitidine</intervention_name>
    <description>Given SC or IV</description>
    <arm_group_label>Treatment (azacitidine, quizartinib)</arm_group_label>
    <other_name>5 AZC</other_name>
    <other_name>5-AC</other_name>
    <other_name>5-Azacytidine</other_name>
    <other_name>5-AZC</other_name>
    <other_name>Azacytidine</other_name>
    <other_name>Azacytidine, 5-</other_name>
    <other_name>Ladakamycin</other_name>
    <other_name>Mylosar</other_name>
    <other_name>U-18496</other_name>
    <other_name>Vidaza</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Quizartinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (azacitidine, quizartinib)</arm_group_label>
    <other_name>AC-220</other_name>
    <other_name>AC010220</other_name>
    <other_name>AC220</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN)&#xD;
             including chronic myelomonocytic leukemia (CMML) according to World Health&#xD;
             Organization (WHO)&#xD;
&#xD;
          -  For hypomethylating agent naive patients: int-2 or higher by International Prognostic&#xD;
             Scoring System (IPSS) or &gt; 5% bone marrow blasts if MDS or dysplastic CMML (white&#xD;
             blood cell [WBC] &lt; 13 x 10^9/L). Patients with proliferative (WBC &gt;= 13 x 10^9/L) CMML&#xD;
             or MDS/MPN, or those with dysplastic CMML with high-risk molecular features (mutations&#xD;
             in ASXL1, TP53 or more than 3 mutations) are also eligible independently of IPSS risk&#xD;
             score or bone marrow blast percentage&#xD;
&#xD;
          -  For patients with prior hypomethylating agent therapy: no response after 6 cycles of&#xD;
             azacitidine, decitabine, guadecitabine or ASTX727 or relapse or progression after any&#xD;
             number of cycles&#xD;
&#xD;
          -  Detectable FLT3-ITD mutation in bone marrow and/or peripheral blood, or presence of&#xD;
             CBL exon 8 or 9 deletions or point mutations&#xD;
&#xD;
          -  Serum creatinine =&lt; 2 x upper limit of normal (ULN)&#xD;
&#xD;
          -  Total bilirubin &lt; 2 x ULN (will allow less than 5 x ULN if Gilbert's at investigator's&#xD;
             discretion)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =&lt; 3 x ULN&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2&#xD;
&#xD;
          -  Patient (or patient's legally authorized representative) must have signed an informed&#xD;
             consent document indicating that the patient understands the purpose of and procedures&#xD;
             required for the study and is willing to participate in the study&#xD;
&#xD;
          -  Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors&#xD;
             (eg, granulocyte colony stimulating factor [G-CSF], granulocyte-macrophage&#xD;
             colony-stimulating factor [GM-CSF], procrit, aranesp, thrombopoietins) is allowed at&#xD;
             any time prior to or during study if considered to be in the best interest of the&#xD;
             patient&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled infection not adequately responding to appropriate antibiotics&#xD;
&#xD;
          -  Screening electrocardiogram (ECG) with a corrected QT interval by Fridericia's formula&#xD;
             (QTcF) &gt; 450 msec. The QTcF interval will be calculated by Fridericia's correction&#xD;
             factor (QTcF). The QTcF will be derived from the average QTcF in triplicate. Patients&#xD;
             are excluded if they have QTcF &gt; 450. Subjects with prolonged QTcF interval in the&#xD;
             setting of RBBB (right bundle branch block) may participate upon review and approval&#xD;
             by the principal investigator and following evaluation by cardiology consult&#xD;
&#xD;
          -  Patients with congenital long QT syndrome&#xD;
&#xD;
          -  History or presence of sustained ventricular tachycardia requiring medical&#xD;
             intervention&#xD;
&#xD;
          -  Any history of clinically significant ventricular fibrillation or torsades de pointes&#xD;
&#xD;
          -  Known history of second- or third-degree heart block (may be eligible if the patient&#xD;
             currently has a pacemaker)&#xD;
&#xD;
          -  Sustained heart rate of &lt; 50/minute on screening ECG&#xD;
&#xD;
          -  Right bundle branch block + left anterior hemiblock (bifascicular block)&#xD;
&#xD;
          -  Complete left bundle branch block&#xD;
&#xD;
          -  Atrial fibrillation documented within 2 weeks prior to first dose of study drug&#xD;
&#xD;
          -  New York Heart Association (NYHA) class III or IV congestive heart failure or left&#xD;
             ventricular ejection fraction (LVEF) &lt; 50 by echocardiogram or multigated acquisition&#xD;
             (MUGA) scan&#xD;
&#xD;
          -  History of myocardial infarction within the last 6 months or unstable/uncontrolled&#xD;
             angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias&#xD;
&#xD;
          -  Patients who are actively taking a strong CYP3A4 inducing medication&#xD;
&#xD;
          -  Patients who require treatment with concomitant drugs that prolong QT/corrected QT&#xD;
             (QTc) interval or strong CYP3A4 inhibitors with the exception of antibiotics,&#xD;
             antifungals, and antivirals that are used as standard of care to prevent or treat&#xD;
             infections, antiemetics (such as ondansetron) and other such drugs that are considered&#xD;
             absolutely essential for the care of the subject or if the Investigator believes that&#xD;
             beginning therapy with a potentially QTc-prolonging medication (such as anti-emetic)&#xD;
             is vital to an individual subject's care while on study&#xD;
&#xD;
          -  Female patients who are pregnant or lactating&#xD;
&#xD;
          -  Patients with reproductive potential who are unwilling to following contraception&#xD;
             requirements (including condom use for males with sexual partners, and for females:&#xD;
             prescription oral contraceptives [birth control pills], contraceptive injections,&#xD;
             intrauterine devices [IUD], double-barrier method [spermidical jelly or foam with&#xD;
             condoms or diaphragm], contraceptive patch, or surgical sterilization) throughout the&#xD;
             study&#xD;
&#xD;
          -  Female patients with reproductive potential who do not have a negative urine or blood&#xD;
             beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening&#xD;
&#xD;
          -  Patients receiving any other concurrent investigational agent or chemotherapy,&#xD;
             radiotherapy, or immunotherapy&#xD;
&#xD;
          -  Patients known to be positive for hepatitis B surface antigen expression or with&#xD;
             active hepatitis C infection (positive by polymerase chain reaction or on antiviral&#xD;
             therapy for hepatitis C within the last 6 months). Patients with history of human&#xD;
             immunodeficiency virus (HIV) disease are also excluded from the study&#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>Guillermo M Bravo</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Guillermo M. Bravo</last_name>
    <phone>713-794-3604</phone>
    <email>ggarciam@mdanderson.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Guillermo M. Bravo</last_name>
      <phone>713-794-3604</phone>
    </contact>
    <investigator>
      <last_name>Guillermo M. Bravo</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>http://www.mdanderson.org</description>
  </link>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>July 27, 2020</study_first_submitted>
  <study_first_submitted_qc>July 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <last_update_submitted>September 11, 2023</last_update_submitted>
  <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Acute</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Chronic</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Juvenile</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Myeloproliferative Disorders</mesh_term>
    <mesh_term>Myelodysplastic-Myeloproliferative Diseases</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azacitidine</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04493138
org study id: 2019-1178
secondary id: NCI-2020-05261
secondary id: 2019-1178
nct id: NCT04493138
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase I/II trial studies the side effects and best dose of quizartinib when given with
      azacitidine and to see how well they work in treating patients with myelodysplastic syndrome
      or myelodysplastic/myeloproliferative neoplasm with FLT3 or CBL mutations. Chemotherapy
      drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either
      by killing the cells, by stopping them from dividing, or by stopping them from spreading.
      Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for
      cell growth. Giving azacitidine and quizartinib may help to control myelodysplastic syndrome
      or myelodysplastic/myeloproliferative neoplasm.
PRIMARY OBJECTIVES:

      I. To determine the safety, tolerability and maximum tolerable dose (MTD) of quizartinib in
      combination with azacytidine.

      II. To assess overall response (ORR) rate to quizartinib in combination with azacitidine.

      SECONDARY OBJECTIVES:

      I. To assess overall survival (OS), duration of response, leukemia-free survival (LFS),
      relapse-free survival (RFS) and safety profile.

      II. Correlative studies.

      OUTLINE: This is a phase I, dose-escalation study of quizartinib followed by a phase II
      study.

      Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over about 30 minutes
      on days 1-5 and quizartinib orally (PO) once daily (QD) on days 1-28. 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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate
time frame: At least 4 cycles of therapy in the absence of progression (1 cycle = 28 days)
description: Will be defined as complete remission, partial remission, complete remission with incomplete count recovery, marrow compete remission or hematological improvement. Will be estimated for all patients along with the 95% credible interval.
measure: Overall survival
time frame: Time from treatment start till death or last follow-up, assessed up to 2 years
description: Will be listed and summarized by the Kaplan-Meier estimator.
measure: Duration of response
time frame: Duration from the first documented onset of partial response or complete response to the date of progressive disease/relapse, assessed up to 2 years
description: Will be listed and summarized by the Kaplan-Meier estimator.
measure: Relapse-free survival
time frame: Time from start of response to the date of event defined as the first documented progressive disease/relapse or death, whichever comes first, assessed up to 2 years
description: Will be listed and summarized by the Kaplan-Meier estimator.
measure: Leukemia free survival
time frame: Time from treatment start to the time of progression to leukemia or death, assessed up to 2 years
description: Will be listed and summarized by the Kaplan-Meier estimator.
measure: Incidence of adverse events (AEs)
time frame: Up to 2 years
description: The severity of the toxicities will be graded according to the latest version of National Cancer Institute Common Terminology Criteria for Adverse Events. The number and percent of subjects with treatment-emergent adverse events will be summarized according to intensity and drug relationship, and categorized by System Organ Class and preferred term by dose level/Part. All reported AEs that occur after signing informed consent will be included in the analysis of all reported AEs. Exposure to study drug and reasons for discontinuation of study drug will be tabulated.
arm group label: Treatment (azacitidine, quizartinib)
arm group type: Experimental
description: Patients receive azacitidine SC or IV over about 30 minutes on days 1-5 and quizartinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Azacitidine
description: Given SC or IV
arm group label: Treatment (azacitidine, quizartinib)
other name: 5 AZC
other name: 5-AC
other name: 5-Azacytidine
other name: 5-AZC
other name: Azacytidine
other name: Azacytidine, 5-
other name: Ladakamycin
other name: Mylosar
other name: U-18496
other name: Vidaza
intervention type: Drug
intervention name: Quizartinib
description: Given PO
arm group label: Treatment (azacitidine, quizartinib)
other name: AC-220
other name: AC010220
other name: AC220
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Guillermo M Bravo
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
last name: Guillermo M. Bravo
phone: 713-794-3604
email: ggarciam@mdanderson.org
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
url: http://www.mdanderson.org
description: http://www.mdanderson.org
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Neoplasms
mesh term: Preleukemia
mesh term: Leukemia, Myelomonocytic, Acute
mesh term: Leukemia, Myelomonocytic, Chronic
mesh term: Leukemia, Myelomonocytic, Juvenile
mesh term: Myelodysplastic Syndromes
mesh term: Myeloproliferative Disorders
mesh term: Myelodysplastic-Myeloproliferative Diseases
mesh term: Syndrome
mesh term: Recurrence
mesh term: Azacitidine