<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/NCT04435691</url>
  </required_header>
  <id_info>
    <org_study_id>2020-0027</org_study_id>
    <secondary_id>NCI-2020-04163</secondary_id>
    <secondary_id>2020-0027</secondary_id>
    <nct_id>NCT04435691</nct_id>
  </id_info>
  <brief_title>Magrolimab, Azacitidine, and Venetoclax for the Treatment of Acute Myeloid Leukemia</brief_title>
  <official_title>An Open-Label Phase IB/II Study of Magrolimab in Combination With Azacitidine and Venetoclax for the Treatment of Patients With Acute Myeloid Leukemia (AML)</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 Ib/II trial studies the side effects and best dose of magrolimab and venetoclax&#xD;
      when given together with azacitidine and to see how well they work in treating patients with&#xD;
      acute myeloid leukemia. Magrolimab is a monoclonal antibody that may interfere with the&#xD;
      ability of cancer cells to grow and spread. Chemotherapy drugs, such as azacitidine, work in&#xD;
      different ways to stop the growth of cancer cells, either by killing the cells, by stopping&#xD;
      them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of&#xD;
      cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving magrolimab,&#xD;
      azacitidine, and venetoclax may help to control the disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the safety and maximum tolerable dose (MTD) of this combination in patients&#xD;
      with acute myeloid leukemia (AML).&#xD;
&#xD;
      II. To determine the response rate (RR) including CR (complete remission) + CRi (complete&#xD;
      remission with incomplete count recovery) within 3 months of treatment initiation of this&#xD;
      combination in patients with AML.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the CR + complete remission with partial hematological recovery (CRh) rate and&#xD;
      morphologic leukemia free (MLF) rate within 3 months of treatment initiation of this&#xD;
      combination in patients with AML.&#xD;
&#xD;
      II. To determine the duration of response (DOR), event-free survival (EFS), overall survival&#xD;
      (OS), MRD status at response and best MRD response attained by flow-cytometry, 4- and 8-week&#xD;
      mortality, and number of patients bridged to hematopoetic stem cell transplant (HSCT) and&#xD;
      median duration to HSCT from the initiation of the combination.&#xD;
&#xD;
      III. To investigate correlations of response to this combination with a pre- therapy,&#xD;
      on-therapy, and progression 81-gene panel of gene mutations in AML.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To investigate possible relationships between response and non-response to the combination&#xD;
      with pretherapy, on-therapy, and progression gene expression signatures.&#xD;
&#xD;
      II. To investigate the characterization of genetic heterogeneity in tumor cell populations,&#xD;
      by performing targeted single-cell sequencing on longitudinally collected AML tumor&#xD;
      populations from patients using a novel microfluidic approach that barcodes amplified genomic&#xD;
      deoxyribonucleic acid (DNA) from thousands of individual leukemia cells confined to droplets&#xD;
      (single cell sequencing).&#xD;
&#xD;
      III. To identify individual cell populations (AML blasts, T-cells - both bulk and T-cell&#xD;
      subsets and coreceptor/ligand expression, macrophages and their coreceptor/ligands) and how&#xD;
      their signaling state in disease relates to clinical outcomes.&#xD;
&#xD;
      IV. To store and/or analyze surplus blood or tissue including bone marrow, if available, for&#xD;
      potential future exploratory research into factors that may influence development of AML&#xD;
      and/or response to the combination (where response is defined broadly to include efficacy,&#xD;
      tolerability or safety).&#xD;
&#xD;
      OUTLINE: This is a phase Ib, dose-escalation study of venetoclax and magrolimab followed by a&#xD;
      phase II study.&#xD;
&#xD;
      Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30-60 minutes on&#xD;
      days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28 of cycle 1 (may be reduced to&#xD;
      days 1-21 for subsequent cycles after principal investigator approval), and magrolimab IV&#xD;
      over 2-3 hours on days 1, 4, 8, 11, 15, and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2,&#xD;
      and days 1 and 15 of cycle 3 and subsequent cycles. Treatment repeats every 28 days for up to&#xD;
      12 cycles in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 and 100 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 28, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</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>Maximum tolerated dose of the combination drugs (phase Ib)</measure>
    <time_frame>28 days</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Response rate (complete remission + complete remission with incomplete count recovery) (phase II)</measure>
    <time_frame>Within 3 months of treatment initiation</time_frame>
    <description>Will be monitored simultaneously. Will be estimated along with 95% credible intervals. Chi-square tests or Fisher's exact test will be used to evaluate the association between patient's prognostic factor and response.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of adverse events (phase II)</measure>
    <time_frame>Within 3 months of treatment initiation</time_frame>
    <description>Toxicities are defined as drug-related non-hematological grade &gt;= 3 adverse events.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Event-free survival (phase II)</measure>
    <time_frame>Time duration from the start of treatment to disease progression/death or censored at last follow-up while on the drug, assessed up to 100 days</time_frame>
    <description>Kaplan-Meier method will be used.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Duration of response (phase II)</measure>
    <time_frame>Up to 100 days</time_frame>
    <description>Kaplan-Meier method will be used.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall survival (phase II)</measure>
    <time_frame>Up to 100 days</time_frame>
    <description>Kaplan-Meier method will be used.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in gene expression (phase II)</measure>
    <time_frame>Baseline up to 100 days</time_frame>
    <description>Paired t-tests will be used.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in clinical variables (phase II)</measure>
    <time_frame>Baseline up to 100 days</time_frame>
    <description>Paired t-tests will be used.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">98</enrollment>
  <condition>Acute Myeloid Leukemia</condition>
  <condition>Recurrent Acute Myeloid Leukemia</condition>
  <condition>Refractory Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>Treatment (azacitidine, venetoclax, magrolimab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive azacitidine SC or IV over 30-60 minutes on days 1-7, venetoclax PO QD on days 1-28 of cycle 1 (may be reduced to days 1-21 for subsequent cycles after principal investigator approval), and magrolimab IV over 2-3 hours on days 1, 4, 8, 11, 15, and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2, and days 1 and 15 of cycle 3 and subsequent cycles. Treatment repeats every 28 days for up to 12 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 SC or IV</description>
    <arm_group_label>Treatment (azacitidine, venetoclax, magrolimab)</arm_group_label>
    <other_name>5 AZC</other_name>
    <other_name>5-AC</other_name>
    <other_name>5-Azacytidine</other_name>
    <other_name>5-AZC</other_name>
    <other_name>Azacytidine</other_name>
    <other_name>Azacytidine, 5-</other_name>
    <other_name>Ladakamycin</other_name>
    <other_name>Mylosar</other_name>
    <other_name>Onureg</other_name>
    <other_name>U-18496</other_name>
    <other_name>Vidaza</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Magrolimab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (azacitidine, venetoclax, magrolimab)</arm_group_label>
    <other_name>Hu5F9-G4</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Venetoclax</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (azacitidine, venetoclax, magrolimab)</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 of 1) Pathology diagnosis of AML (excluding acute promyelocytic leukemia&#xD;
             [APL])&#xD;
&#xD;
          -  Phase Ib dose finding cohort: Patients aged &gt;= 18 years old with relapsed/refractory&#xD;
             AML are eligible if they are not eligible for potentially curative therapy such as&#xD;
             effective salvage therapy or hematopoietic stem cell transplantation or who refuse&#xD;
             these options at the time of enrollment. Patients must have received at least one&#xD;
             prior therapy for AML&#xD;
&#xD;
          -  Phase Ib dose finding cohort: Patients may have received up to 2 prior therapies for&#xD;
             AML (i.e. up to salvage 2 status allowed)&#xD;
&#xD;
          -  Phase Ib dose finding cohort: Eastern Cooperative Oncology Group (ECOG) performance&#xD;
             status =&lt; 2&#xD;
&#xD;
          -  Phase II (frontline cohort): Patients with newly diagnosed AML who are chemonaive who&#xD;
             are ineligible for intensive chemotherapy based on EITHER:&#xD;
&#xD;
               -  &gt;= 75 years of age OR&#xD;
&#xD;
               -  &lt; 75 years of age with at least 1 of the following relevant comorbidities:&#xD;
&#xD;
                    -  Poor performance status (ECOG) score of 2.&#xD;
&#xD;
                    -  Clinically significant heart or lung comorbidities, as reflected by at least&#xD;
                       1 of:&#xD;
&#xD;
                         -  Left ventricular ejection fraction (LVEF) =&lt; 50%.&#xD;
&#xD;
                         -  Lung diffusing capacity for carbon monoxide (DLCO) =&lt; 65% of expected.&#xD;
&#xD;
                         -  Forced expiratory volume in 1 second (FEV1) =&lt; 65% of expected.&#xD;
&#xD;
                         -  Chronic stable angina or congestive heart failure controlled with&#xD;
                            medication.&#xD;
&#xD;
                    -  Other contraindication(s) to anthracycline therapy (must be documented).&#xD;
&#xD;
                    -  Other comorbidity the investigator judges incompatible with intensive&#xD;
                       remission induction chemotherapy, which must be documented and approved by&#xD;
                       the principal investigator (PI)&#xD;
&#xD;
          -  Phase II (frontline cohort): For patients with prior MDS or chronic myelomonocytic&#xD;
             leukemia (CMML) or MPN who transformed to AML, therapy received for MDS, CMML, or MPN&#xD;
             is NOT considered as prior therapy for AML. Patients with MDS or CMML treated with&#xD;
             hypomethylating agent (HMA) therapies who progress to AML, and have no available&#xD;
             therapies or are not candidates for available therapies, will be eligible at the time&#xD;
             of progression to AML. Temporary prior measures such as apheresis, ATRA, steroids&#xD;
             while diagnostic work-up of AML is being performed are allowed and not counted as a&#xD;
             prior salvage&#xD;
&#xD;
          -  Phase II (relapsed/refractory prior venetoclax naive cohort): Patients aged &gt;= 18&#xD;
             years old with relapsed/refractory AML are eligible if they are not eligible for&#xD;
             potentially curative therapy such as effective salvage therapy or hematopoietic stem&#xD;
             cell transplantation or who refuse these options at the time of enrollment. Patients&#xD;
             must have received at least one prior therapy for AML. Patients may have received up&#xD;
             to 2 prior therapies for AML (i.e. up to salvage 2 status allowed). Eastern&#xD;
             Cooperative Oncology Group (ECOG) performance status =&lt; 2. Patients must not have&#xD;
             received prior venetoclax for MDS or AML&#xD;
&#xD;
          -  Phase II (relapsed/refractory prior venetoclax exposed cohort): Patients aged &gt;= 18&#xD;
             years old with relapsed/refractory AML are eligible if they are not eligible for&#xD;
             potentially curative therapy such as effective salvage therapy, targeted therapies, or&#xD;
             hematopoietic stem cell transplantation or who refuse these options at the time of&#xD;
             enrollment. Patients must have received at least one prior therapy for AML. Patients&#xD;
             may have received up to 2 prior therapies for AML (i.e. up to salvage 2 status&#xD;
             allowed). Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2. Patients&#xD;
             may have received prior venetoclax for MDS or AML&#xD;
&#xD;
          -  Patients with newly diagnosed AML with poor risk karyotype or complex karyotype per&#xD;
             ELN2017 and/or TP53 deletions/mutations of any age &gt;/= 18 years of age will be&#xD;
             eligible for the Phase II (frontline cohort) regardless of eligibility or fitness for&#xD;
             intensive chemotherapy&#xD;
&#xD;
          -  For Phase II (frontline cohort): Patients must be chemonaive, i.e., not have received&#xD;
             any chemotherapy (except hydrea or up to 2 doses of ara-C for transient control of&#xD;
             hyperleukocytosis) for AML. They may have received transfusions, hematopoietic growth&#xD;
             factors or vitamins for an antecedent hematological disorder (AHD) or for AML.&#xD;
             Temporary prior measures such as apheresis, ATRA, steroids or hydrea while diagnostic&#xD;
             work-up is being performed are allowed and not counted as a prior salvage. Supportive&#xD;
             care therapy for MDS (growth factors, transfusions) will not be considered as prior&#xD;
             therapy for MDS/AML and these patients will be enrolled to the frontline cohort of the&#xD;
             study if they are otherwise eligible&#xD;
&#xD;
          -  In the absence of rapidly progressing disease, the interval from prior treatment to&#xD;
             time of initiation of protocol therapy will be at least 2 weeks or at least 5&#xD;
             half-lives (whichever is shorter). The half-life for the therapy in question will be&#xD;
             based on published pharmacokinetic literature (abstracts, manuscripts, investigator&#xD;
             brochure's, or drug-administration manuals) and will be documented in the protocol&#xD;
             eligibility document. The toxicity from prior therapy should have resolved to grade =&lt;&#xD;
             1, however alopecia and sensory neuropathy grade =&lt; 2 not constituting a safety risk&#xD;
             based on investigators judgement is acceptable. The use of chemotherapeutic or&#xD;
             anti-leukemic agents is not permitted during the study with the following exceptions:&#xD;
             (1) intrathecal (IT) therapy for patients with controlled central nervous system (CNS)&#xD;
             leukemia at the discretion of the PI. (2) Use of up to 2 doses of cytarabine (up to 2&#xD;
             g/m^2 each dose) for patients with rapidly proliferative disease is allowed before the&#xD;
             start of study therapy and for the first four weeks on therapy. Since the effect of&#xD;
             most immuno-oncology (IO)-agents, HMA-therapies, venetoclax may be delayed, use of&#xD;
             hydroxyurea for patients with rapidly proliferative disease is allowed on study and&#xD;
             before the start of study therapy and will not require a washout. These medications&#xD;
             will be recorded in the case-report form&#xD;
&#xD;
          -  Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS&#xD;
             disease is permitted. Patients with a known history of CNS disease or leukemic brain&#xD;
             metastasis must have been treated locally, have at least 2 consecutive LPs with no&#xD;
             evidence of CNS leukemia at the time of enrollment, and must be clinically stable for&#xD;
             at least 4 weeks prior to enrollment and have no ongoing neurological symptoms that in&#xD;
             the opinion of the treating physician are related to the CNS disease (sequelae that&#xD;
             are a consequence of the treatment of the CNS disease are acceptable)&#xD;
&#xD;
          -  Creatinine clearance (CrCl) &gt;= 30 mL/min calculated by the Cockcroft-Gault formula or&#xD;
             measured by 24 hours' urine collection.&#xD;
&#xD;
               -  For patients with body mass index (BMI) &gt; 23, adjusted body weight and not ideal&#xD;
                  body weight is the recommended parameter&#xD;
&#xD;
          -  Direct bilirubin &lt; 1.5 x ULN unless considered due to Gilbert's syndrome&#xD;
&#xD;
          -  Aspartate aminotransferase or alanine aminotransferase =&lt; 2.0 x ULN (aspartate&#xD;
             aminotransferase or alanine aminotransferase =&lt; 3.0 x ULN if deemed related to&#xD;
             leukemia by the treating physician)&#xD;
&#xD;
          -  White blood cell count &lt; 15 x 10^9/L. Patients must have a white blood cell (WBC)&#xD;
             count &lt; 15 x 10^9/L prior to each dose of magrolimab in cycle 1. Hydroxyurea may be&#xD;
             used to reduce the WBC count to =&lt; 15 x 10^9/L&#xD;
&#xD;
          -  Ability to understand and provide signed informed consent&#xD;
&#xD;
          -  Females must be surgically or biologically sterile or postmenopausal (amenorrheic for&#xD;
             at least 12 months) or if of childbearing potential, must have a negative serum or&#xD;
             urine pregnancy test within 72 hours before the start of the treatment&#xD;
&#xD;
          -  Women of childbearing potential must agree to use an adequate method of contraception&#xD;
             during the study and until 4 months after the last treatment. Males must be surgically&#xD;
             or biologically sterile or agree to use an adequate method of contraception during the&#xD;
             study until 3 months after the last treatment. Adequate methods of contraception&#xD;
             include:&#xD;
&#xD;
               -  Total abstinence when this is in line with the preferred and usual lifestyle of&#xD;
                  the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,&#xD;
                  post-ovulation methods) and withdrawal are not acceptable methods of&#xD;
                  contraception.&#xD;
&#xD;
               -  Female sterilization (have had surgical bilateral oophorectomy with or without&#xD;
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.&#xD;
                  In case of oophorectomy alone, only when the reproductive status of the woman has&#xD;
                  been confirmed by follow up hormone level assessment&#xD;
&#xD;
               -  Male sterilization (at least 6 months prior to screening). For female patients on&#xD;
                  the study, the vasectomized male partner should be the sole partner for that&#xD;
                  patient&#xD;
&#xD;
               -  Combination of any of the two following (a+b or a+c or b+c)&#xD;
&#xD;
                    1. Use of oral, injected or implanted hormonal methods of contraception or&#xD;
                       other forms of hormonal contraception that have comparable efficacy (failure&#xD;
                       rate &lt; 1%), for example hormone vaginal ring or transdermal hormone&#xD;
                       contraception&#xD;
&#xD;
                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)&#xD;
&#xD;
                    3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or&#xD;
                       cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal&#xD;
                       suppository&#xD;
&#xD;
               -  In case of use of oral contraception, women should have been stable on the same&#xD;
                  pill before taking study treatment&#xD;
&#xD;
               -  Note: Oral contraceptives are allowed but should be used in conjunction with a&#xD;
                  barrier method of contraception due to unknown effect of drug-drug interaction.&#xD;
&#xD;
               -  Women are considered post-menopausal and not of child bearing potential if they&#xD;
                  have had 12 months of natural (spontaneous) amenorrhea with an appropriate&#xD;
                  clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have&#xD;
                  had surgical bilateral oophorectomy (with or without hysterectomy) or tubal&#xD;
                  ligation at least six weeks ago. In the case of oophorectomy alone, only when the&#xD;
                  reproductive status of the woman has been confirmed by follow up hormone level&#xD;
                  assessment is she considered not of child bearing potential.&#xD;
&#xD;
               -  Male patients who are sexually active with a WOCBP and who have not had&#xD;
                  vasectomies must be willing to use a barrier method of contraception during the&#xD;
                  study and for 3 months after the last dose of magrolimab, venetoclax or&#xD;
                  azacitidine, whichever ends later.&#xD;
&#xD;
               -  Women who are pregnant or breastfeeding will not be eligible&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with known allergy or hypersensitivity to magrolimab, venetoclax, azacitidine&#xD;
             or any of their components&#xD;
&#xD;
          -  Patients with any other known concurrent severe and/or uncontrolled medical condition&#xD;
             including but not limited to diabetes, cardiovascular disease including hypertension,&#xD;
             renal disease, or active uncontrolled infection, which could compromise participation&#xD;
             in the study. Patients on active antineoplastic or radiation therapy for a concurrent&#xD;
             malignancy at the time of screening. Maintenance therapy, hormonal therapy, or steroid&#xD;
             therapy for well-controlled malignancy is allowed&#xD;
&#xD;
          -  Prior organ transplantation including allogenic stem-cell transplantation within 3&#xD;
             months prior to planned enrollment, active graft versus host disease (GVHD) &gt; grade 1,&#xD;
             or requiring transplant-related immunosuppression, excluding prednisone 10 mg or&#xD;
             equivalent steroid&#xD;
&#xD;
          -  Known inherited or acquired bleeding disorders&#xD;
&#xD;
          -  Prior treatment with a CD47 or SIRPalpha targeting agent&#xD;
&#xD;
          -  Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia&#xD;
&#xD;
          -  Patients with a known human immunodeficiency virus (HIV) infection that is not well&#xD;
             controlled (i.e. any detectable circulating viral load) at the time of enrollment&#xD;
&#xD;
          -  Patients with known positive hepatitis B or C infection by serology, with the&#xD;
             exception of those with an undetectable viral load within 3 months (hepatitis B or C&#xD;
             testing is not required prior to study entry). Subjects with serologic evidence of&#xD;
             prior vaccination to hepatitis B virus (HBV) [i.e., hepatitis B surface antigen&#xD;
             (HBsAg)-, and anti-HBs+] may participate&#xD;
&#xD;
          -  Patients who have consumed grapefruit, grapefruit products, Seville oranges (including&#xD;
             marmalade containing Seville oranges) or starfruit within 3 days prior to the&#xD;
             initiation of study treatment&#xD;
&#xD;
          -  Patients who have had any major surgical procedure within 14 days of day 1&#xD;
&#xD;
          -  Other severe acute or chronic medical conditions that is active and not well&#xD;
             controlled including colitis, inflammatory bowel disease, or psychiatric conditions&#xD;
             including recent (within the past year) or active suicidal ideation or behavior; or&#xD;
             laboratory abnormalities that may increase the risk associated with study&#xD;
             participation or study treatment administration or may interfere with the&#xD;
             interpretation of study results and, in the judgment of the investigator, would make&#xD;
             the patient inappropriate for entry into this study&#xD;
&#xD;
          -  Active and uncontrolled disease (active infection requiring systemic therapy or fever&#xD;
             likely secondary to infection within prior 48 hours): prophylactic antibiotics or&#xD;
             prolonged course of IV antibiotics for controlled infection are allowed, uncontrolled&#xD;
             hypertension despite adequate medical therapy, active and uncontrolled congestive&#xD;
             heart failure New York Heart Association (NYHA) class III/IV, clinically significant&#xD;
             and uncontrolled arrhythmia) as judged by the treating physician&#xD;
&#xD;
          -  Patients unwilling or unable to comply with the protocol&#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>Naval G Daver</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>
    <status>Recruiting</status>
    <contact>
      <last_name>Naval G. Daver</last_name>
      <phone>713-794-4392</phone>
      <email>ndaver@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Naval G. Daver</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 15, 2020</study_first_submitted>
  <study_first_submitted_qc>June 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 17, 2020</study_first_posted>
  <last_update_submitted>August 29, 2023</last_update_submitted>
  <last_update_submitted_qc>August 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 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>
  </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>Magrolimab</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/NCT04435691
org study id: 2020-0027
secondary id: NCI-2020-04163
secondary id: 2020-0027
nct id: NCT04435691
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase Ib/II trial studies the side effects and best dose of magrolimab and venetoclax
      when given together with azacitidine and to see how well they work in treating patients with
      acute myeloid leukemia. Magrolimab is a monoclonal antibody that may interfere with the
      ability of cancer cells to grow and spread. 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 may stop the growth of
      cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving magrolimab,
      azacitidine, and venetoclax may help to control the disease.
PRIMARY OBJECTIVES:

      I. To determine the safety and maximum tolerable dose (MTD) of this combination in patients
      with acute myeloid leukemia (AML).

      II. To determine the response rate (RR) including CR (complete remission) + CRi (complete
      remission with incomplete count recovery) within 3 months of treatment initiation of this
      combination in patients with AML.

      SECONDARY OBJECTIVES:

      I. To assess the CR + complete remission with partial hematological recovery (CRh) rate and
      morphologic leukemia free (MLF) rate within 3 months of treatment initiation of this
      combination in patients with AML.

      II. To determine the duration of response (DOR), event-free survival (EFS), overall survival
      (OS), MRD status at response and best MRD response attained by flow-cytometry, 4- and 8-week
      mortality, and number of patients bridged to hematopoetic stem cell transplant (HSCT) and
      median duration to HSCT from the initiation of the combination.

      III. To investigate correlations of response to this combination with a pre- therapy,
      on-therapy, and progression 81-gene panel of gene mutations in AML.

      EXPLORATORY OBJECTIVES:

      I. To investigate possible relationships between response and non-response to the combination
      with pretherapy, on-therapy, and progression gene expression signatures.

      II. To investigate the characterization of genetic heterogeneity in tumor cell populations,
      by performing targeted single-cell sequencing on longitudinally collected AML tumor
      populations from patients using a novel microfluidic approach that barcodes amplified genomic
      deoxyribonucleic acid (DNA) from thousands of individual leukemia cells confined to droplets
      (single cell sequencing).

      III. To identify individual cell populations (AML blasts, T-cells - both bulk and T-cell
      subsets and coreceptor/ligand expression, macrophages and their coreceptor/ligands) and how
      their signaling state in disease relates to clinical outcomes.

      IV. To store and/or analyze surplus blood or tissue including bone marrow, if available, for
      potential future exploratory research into factors that may influence development of AML
      and/or response to the combination (where response is defined broadly to include efficacy,
      tolerability or safety).

      OUTLINE: This is a phase Ib, dose-escalation study of venetoclax and magrolimab followed by a
      phase II study.

      Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30-60 minutes on
      days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28 of cycle 1 (may be reduced to
      days 1-21 for subsequent cycles after principal investigator approval), and magrolimab IV
      over 2-3 hours on days 1, 4, 8, 11, 15, and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2,
      and days 1 and 15 of cycle 3 and subsequent cycles. Treatment repeats every 28 days for up to
      12 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 100 days.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of the combination drugs (phase Ib)
time frame: 28 days
measure: Response rate (complete remission + complete remission with incomplete count recovery) (phase II)
time frame: Within 3 months of treatment initiation
description: Will be monitored simultaneously. Will be estimated along with 95% credible intervals. Chi-square tests or Fisher's exact test will be used to evaluate the association between patient's prognostic factor and response.
measure: Incidence of adverse events (phase II)
time frame: Within 3 months of treatment initiation
description: Toxicities are defined as drug-related non-hematological grade >= 3 adverse events.
measure: Event-free survival (phase II)
time frame: Time duration from the start of treatment to disease progression/death or censored at last follow-up while on the drug, assessed up to 100 days
description: Kaplan-Meier method will be used.
measure: Duration of response (phase II)
time frame: Up to 100 days
description: Kaplan-Meier method will be used.
measure: Overall survival (phase II)
time frame: Up to 100 days
description: Kaplan-Meier method will be used.
measure: Change in gene expression (phase II)
time frame: Baseline up to 100 days
description: Paired t-tests will be used.
measure: Change in clinical variables (phase II)
time frame: Baseline up to 100 days
description: Paired t-tests will be used.
arm group label: Treatment (azacitidine, venetoclax, magrolimab)
arm group type: Experimental
description: Patients receive azacitidine SC or IV over 30-60 minutes on days 1-7, venetoclax PO QD on days 1-28 of cycle 1 (may be reduced to days 1-21 for subsequent cycles after principal investigator approval), and magrolimab IV over 2-3 hours on days 1, 4, 8, 11, 15, and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2, and days 1 and 15 of cycle 3 and subsequent cycles. Treatment repeats every 28 days for up to 12 cycles 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, venetoclax, magrolimab)
other name: 5 AZC
other name: 5-AC
other name: 5-Azacytidine
other name: 5-AZC
other name: Azacytidine
other name: Azacytidine, 5-
other name: Ladakamycin
other name: Mylosar
other name: Onureg
other name: U-18496
other name: Vidaza
intervention type: Biological
intervention name: Magrolimab
description: Given IV
arm group label: Treatment (azacitidine, venetoclax, magrolimab)
other name: Hu5F9-G4
intervention type: Drug
intervention name: Venetoclax
description: Given PO
arm group label: Treatment (azacitidine, venetoclax, magrolimab)
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: Naval G Daver
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Azacitidine
mesh term: Venetoclax
mesh term: Magrolimab