<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/NCT04487106</url>
  </required_header>
  <id_info>
    <org_study_id>2020-0506</org_study_id>
    <secondary_id>NCI-2020-05350</secondary_id>
    <secondary_id>2020-0506</secondary_id>
    <nct_id>NCT04487106</nct_id>
  </id_info>
  <brief_title>Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome</brief_title>
  <official_title>A Phase II Study of Azacitidine, Venetoclax and Trametinib for Patients With Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome</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 II trial investigates how well azacitidine, venetoclax, and trametinib work in&#xD;
      treating patients with acute myeloid leukemia or higher-risk myelodysplastic syndrome that&#xD;
      has come back (relapsed) or has not responded to treatment (refractory). Chemotherapy drugs,&#xD;
      such as azacitidine, work in different ways to stop the growth of cancer cells, either by&#xD;
      killing the cells, by stopping them from dividing, or by stopping them from spreading.&#xD;
      Venetoclax and trametinib may stop the growth of cancer cells by blocking some of the enzymes&#xD;
      needed for cell growth. The goal of this study is learn if the combination of azacitidine,&#xD;
      venetoclax, and trametinib can help to control acute myeloid leukemia or myelodysplastic&#xD;
      syndrome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine overall survival rate at 1 year of the regimen in patients with newly&#xD;
      diagnosed acute myeloid leukemia (AML). (Cohort A) II. To determine the complete remission&#xD;
      (CR)/complete remission without recovery of counts (CRi) rate of the regimen in patients with&#xD;
      relapsed/refractory AML or high-risk myelodysplastic syndrome (MDS). (Cohort B)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow&#xD;
      cytometry, relapse-free survival, event-free survival, and overall survival).&#xD;
&#xD;
      II. To assess proportion of patients proceeding to hematopoietic stem cell transplantation&#xD;
      (HSCT).&#xD;
&#xD;
      III. To determine the safety of the combination regimen.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the impact of baseline genomic alterations on response and survival of the&#xD;
      combination regimen.&#xD;
&#xD;
      II. To evaluate clonal evolution from diagnosis to relapse.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      INDUCTION (CYCLE 1): Patients receive azacitidine intravenously (IV) over 30-60 minutes or&#xD;
      subcutaneously (SC) on days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28, and&#xD;
      trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days&#xD;
      1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats&#xD;
      every 28 days for up to 23 cycles in the absence of disease progression or unacceptable&#xD;
      toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days, and then every 6&#xD;
      months thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 21, 2020</start_date>
  <completion_date type="Actual">February 9, 2023</completion_date>
  <primary_completion_date type="Actual">February 9, 2023</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 (Cohort A)</measure>
    <time_frame>From the first day of treatment to time of death from any cause, assessed at 1 year</time_frame>
    <description>Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Complete remission(CR)/complete remission without recovery of counts (CRi) (Cohort B)</measure>
    <time_frame>Up to 6 cycles of treatment (each cycle = 28 days)</time_frame>
    <description>Will estimate the CR/CRi for the combination treatment (defined as the proportion of patients achieving CR or CRi within 6 cycles of treatment), along with the 95% credible interval.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Complete response rate</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be estimated along with 95% credible intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimal residual disease negativity</measure>
    <time_frame>Up to time of relapse, assessed up to 3 years</time_frame>
    <description>Will be assessed by flow cytometry and estimated along with 95% credible intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse-free survival</measure>
    <time_frame>From documented CR/CRi until relapse or death, assessed up to 3 years</time_frame>
    <description>Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-free survival</measure>
    <time_frame>From the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death), assessed up to 3 years</time_frame>
    <description>Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From the first day of treatment to time of death from any cause, assessed up to 3 years</time_frame>
    <description>Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients proceeding to hematopoietic stem cell transplantation</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be estimated along with 95% credible intervals.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Recurrent Acute Myeloid Leukemia</condition>
  <condition>Recurrent Chronic Myelomonocytic Leukemia</condition>
  <condition>Recurrent Myelodysplastic Syndrome</condition>
  <condition>Refractory Acute Myeloid Leukemia</condition>
  <condition>Refractory Chronic Myelomonocytic Leukemia</condition>
  <condition>Refractory Myelodysplastic Syndrome</condition>
  <arm_group>
    <arm_group_label>Treatment (azacitidine, venetoclax, trametinib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.&#xD;
CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles 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 IV or SC</description>
    <arm_group_label>Treatment (azacitidine, venetoclax, trametinib)</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>Trametinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (azacitidine, venetoclax, trametinib)</arm_group_label>
    <other_name>GSK1120212</other_name>
    <other_name>JTP-74057</other_name>
    <other_name>MEK Inhibitor GSK1120212</other_name>
    <other_name>Mekinist</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Venetoclax</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (azacitidine, venetoclax, trametinib)</arm_group_label>
    <other_name>ABT-0199</other_name>
    <other_name>ABT-199</other_name>
    <other_name>ABT199</other_name>
    <other_name>GDC-0199</other_name>
    <other_name>RG7601</other_name>
    <other_name>Venclexta</other_name>
    <other_name>Venclyxto</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis:&#xD;
&#xD;
               -  Cohort A (frontline): Newly diagnosed AML&#xD;
&#xD;
               -  Cohort B (relapsed/refractory): Relapsed/refractory AML or relapsed/refractory&#xD;
                  MDS or chronic myelomonocytic leukemia (CMML) that is intermediate-2 or high-risk&#xD;
                  by the International Prognostic Scoring System with &gt;= 10% blasts harboring a Ras&#xD;
                  pathway-activating mutation. Eligible mutations include: activating mutations of&#xD;
                  KIT, HRAS/NRAS/KRAS, BRAF, CBL or PTPN11 or loss of function mutation of NF1.&#xD;
                  Other mutations not listed here that are anticipated to activate Ras signaling&#xD;
                  may be considered for enrollment after discussion with the principal investigator&#xD;
                  (PI)&#xD;
&#xD;
          -  Performance status =&lt; 2 (Eastern Cooperative Oncology Group [ECOG] scale)&#xD;
&#xD;
          -  Total serum bilirubin =&lt; 2.5 x upper limit of normal (ULN), unless due to Gilbert's&#xD;
             syndrome, hemolysis or the underlying leukemia approved by the PI&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =&lt; 3 x ULN, unless&#xD;
             due to the underlying leukemia approved by the PI&#xD;
&#xD;
          -  Creatinine clearance &gt;= 30 mL/min&#xD;
&#xD;
          -  Ability to swallow&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients suitable for and willing to receive intensive induction chemotherapy (cohort&#xD;
             A only)&#xD;
&#xD;
          -  Active serious infection not controlled by oral or intravenous antibiotics (e.g.&#xD;
             persistent fever or lack of improvement despite antimicrobial treatment)&#xD;
&#xD;
          -  Patients with a prior or concurrent malignancy whose natural history or treatment is&#xD;
             not anticipated to interfere with the safety or efficacy assessment of the&#xD;
             investigational regimen may be included only after discussion with the PI&#xD;
&#xD;
          -  Consumed strong inducer of CYP3A or p-glycoprotein within 3 days of study enrollment.&#xD;
             Agents include but are not limited to: carbamazepine, phenytoin, rifampin, and St.&#xD;
             John's wart&#xD;
&#xD;
          -  Treatment with any investigational antileukemic agents or chemotherapy agents in the&#xD;
             last 7 days before study entry, unless full recovery from side effects has occurred or&#xD;
             patient has rapidly progressive disease judged to be life-threatening by the&#xD;
             investigator. Prior recent treatment with corticosteroids, hydroxyurea and/or&#xD;
             cytarabine (given for cytoreduction) permitted&#xD;
&#xD;
          -  Pregnant women will not be eligible; women of childbearing potential should have a&#xD;
             negative pregnancy test prior to entering on the study and be willing to practice&#xD;
             methods of contraception throughout the study period and for at least 6 months after&#xD;
             the last dose of study drugs. Women do not have childbearing potential if they have&#xD;
             had a hysterectomy or are postmenopausal without menses for 12 months. In addition,&#xD;
             men enrolled on this study should understand the risks to any sexual partner of&#xD;
             childbearing potential and should practice an effective method of birth control&#xD;
             throughout the study period and for at least 4 months after the last dose of study&#xD;
             drugs. Lactating women (or those planning to breastfeed) should not breastfeed during&#xD;
             treatment of trametinib and for at least 2 months after the last dose of trametinib&#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>Nicholas Short</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <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>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>M D Anderson Cancer Center</description>
  </link>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 21, 2020</study_first_submitted>
  <study_first_submitted_qc>July 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>March 3, 2023</last_update_submitted>
  <last_update_submitted_qc>March 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>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>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>
    <mesh_term>Venetoclax</mesh_term>
    <mesh_term>Trametinib</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/NCT04487106
org study id: 2020-0506
secondary id: NCI-2020-05350
secondary id: 2020-0506
nct id: NCT04487106
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial investigates how well azacitidine, venetoclax, and trametinib work in
      treating patients with acute myeloid leukemia or higher-risk myelodysplastic syndrome that
      has come back (relapsed) or has not responded to treatment (refractory). 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.
      Venetoclax and trametinib may stop the growth of cancer cells by blocking some of the enzymes
      needed for cell growth. The goal of this study is learn if the combination of azacitidine,
      venetoclax, and trametinib can help to control acute myeloid leukemia or myelodysplastic
      syndrome.
PRIMARY OBJECTIVES:

      I. To determine overall survival rate at 1 year of the regimen in patients with newly
      diagnosed acute myeloid leukemia (AML). (Cohort A) II. To determine the complete remission
      (CR)/complete remission without recovery of counts (CRi) rate of the regimen in patients with
      relapsed/refractory AML or high-risk myelodysplastic syndrome (MDS). (Cohort B)

      SECONDARY OBJECTIVES:

      I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow
      cytometry, relapse-free survival, event-free survival, and overall survival).

      II. To assess proportion of patients proceeding to hematopoietic stem cell transplantation
      (HSCT).

      III. To determine the safety of the combination regimen.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the impact of baseline genomic alterations on response and survival of the
      combination regimen.

      II. To evaluate clonal evolution from diagnosis to relapse.

      OUTLINE:

      INDUCTION (CYCLE 1): Patients receive azacitidine intravenously (IV) over 30-60 minutes or
      subcutaneously (SC) on days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28, and
      trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.

      CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days
      1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats
      every 28 days for up to 23 cycles in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up at 30 days, and then every 6
      months thereafter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall survival (Cohort A)
time frame: From the first day of treatment to time of death from any cause, assessed at 1 year
description: Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.
measure: Complete remission(CR)/complete remission without recovery of counts (CRi) (Cohort B)
time frame: Up to 6 cycles of treatment (each cycle = 28 days)
description: Will estimate the CR/CRi for the combination treatment (defined as the proportion of patients achieving CR or CRi within 6 cycles of treatment), along with the 95% credible interval.
measure: Complete response rate
time frame: Up to 3 years
description: Will be estimated along with 95% credible intervals.
measure: Minimal residual disease negativity
time frame: Up to time of relapse, assessed up to 3 years
description: Will be assessed by flow cytometry and estimated along with 95% credible intervals.
measure: Relapse-free survival
time frame: From documented CR/CRi until relapse or death, assessed up to 3 years
description: Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.
measure: Event-free survival
time frame: From the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death), assessed up to 3 years
description: Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.
measure: Overall survival
time frame: From the first day of treatment to time of death from any cause, assessed up to 3 years
description: Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.
measure: Proportion of patients proceeding to hematopoietic stem cell transplantation
time frame: Up to 3 years
description: Will be estimated along with 95% credible intervals.
arm group label: Treatment (azacitidine, venetoclax, trametinib)
arm group type: Experimental
description: INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Azacitidine
description: Given IV or SC
arm group label: Treatment (azacitidine, venetoclax, trametinib)
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: Trametinib
description: Given PO
arm group label: Treatment (azacitidine, venetoclax, trametinib)
other name: GSK1120212
other name: JTP-74057
other name: MEK Inhibitor GSK1120212
other name: Mekinist
intervention type: Drug
intervention name: Venetoclax
description: Given PO
arm group label: Treatment (azacitidine, venetoclax, trametinib)
other name: ABT-0199
other name: ABT-199
other name: ABT199
other name: GDC-0199
other name: RG7601
other name: Venclexta
other name: Venclyxto
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nicholas Short
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
country: United States
url: http://www.mdanderson.org
description: M D Anderson Cancer Center
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Preleukemia
mesh term: Leukemia, Myelomonocytic, Acute
mesh term: Leukemia, Myelomonocytic, Chronic
mesh term: Leukemia, Myelomonocytic, Juvenile
mesh term: Myelodysplastic Syndromes
mesh term: Syndrome
mesh term: Recurrence
mesh term: Azacitidine
mesh term: Venetoclax
mesh term: Trametinib