<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/NCT03825367</url>
  </required_header>
  <id_info>
    <org_study_id>T2016-002</org_study_id>
    <nct_id>NCT03825367</nct_id>
  </id_info>
  <brief_title>Nivolumab in Combination With 5-azacytidine in Childhood Relapsed/Refractory AML</brief_title>
  <official_title>A Phase I/II Study of Nivolumab in Combination With 5-azacytidine in Pediatric Patients With Relapsed/Refractory Acute Myeloid Leukemia (BMS Reference CA209-9JY)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Therapeutic Advances in Childhood Leukemia Consortium</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Therapeutic Advances in Childhood Leukemia Consortium</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 is a phase I/II Study of Nivolumab in Combination with 5-azacytidine in pediatric&#xD;
      patients with relapsed/refractory acute myeloid leukemia&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This proposed study will be the first to test nivolumab in combination with AZA in pediatric&#xD;
      patients with hematologic malignancies. Patients will receive the first dose of nivolumab on&#xD;
      day 1 along with AZA. After &quot;chemotherapy priming&quot;, a second dose of nivolumab will be given&#xD;
      at day 15 which will enhance the effect of nivolumab on the regenerating CD4+ and CD8+ memory&#xD;
      T cells.&#xD;
&#xD;
      To establish a recommended Phase II dose (RP2D)of nivolumab in combination with 5-azacytidine&#xD;
      in children with relapsed or refractory AML. To assess the clinical activity of Nivolumab in&#xD;
      combination with 5-azacytidine in AML patients with M2/M3 disease at study entry.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 29, 2019</start_date>
  <completion_date type="Anticipated">March 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2023</primary_completion_date>
  <phase>Phase 1/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>Dose Toxicity</measure>
    <time_frame>4 weeks</time_frame>
    <description>Occurrence of dose limiting toxicity (DLT) during Cycle 1 of therapy (Phase I)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Remission</measure>
    <time_frame>4 weeks</time_frame>
    <description>Achievement of complete remission (CR/CRp/CRi) at the end of cycle 1</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>AML, Childhood</condition>
  <arm_group>
    <arm_group_label>Open label design</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Nivolumab and 5-azacytidine,</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>The dose of Nivolumab will be 3 mg/kg which is the adult recommended dose and is the recommended dose in children in the phase 2 portion of COG ADVL1412.&#xD;
If 3 mg/kg is not tolerated in combination with 5-azacytidine, the dose will be stepped down to 1 mg/kg.</description>
    <arm_group_label>Open label design</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-azacytidine</intervention_name>
    <description>75mg/m2 subcutaneously will be given daily for 7 days on days 1 to 7.</description>
    <arm_group_label>Open label design</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Age Patients must be ≥ 1 and ≤30 years of age.&#xD;
&#xD;
        Diagnosis&#xD;
&#xD;
          1. Relapsed or refractory AML with ≥5% blasts (by morphology) in the bone marrow.&#xD;
&#xD;
               -  1st or greater relapse, OR&#xD;
&#xD;
               -  Failed to go into remission (i.e. refractory) after first or greater relapse, OR&#xD;
&#xD;
               -  Failed to go into remission from original diagnosis after two or more induction&#xD;
                  attempts.&#xD;
&#xD;
          2. Relapsed or refractory AML with ≤ 5% blasts (by morphology) and MRD positive disease&#xD;
             (M1/MRD+): Two serial marrows demonstrating stable or rising MRD ≥ 0.1 % (i.e. not&#xD;
             declining). MRD will be determined by multiparameter flow cytometry using&#xD;
             AML-associated phenotype markers, or real-time quantitative PCR for AML-associated&#xD;
             genetic lesions&#xD;
&#xD;
          3. Patients may have CNS 1 or 2 or other sites of extramedullary disease. No cranial&#xD;
             irradiation is allowed during the protocol therapy.&#xD;
&#xD;
          4. Patients with secondary AML are eligible.&#xD;
&#xD;
          5. Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are&#xD;
             excluded.&#xD;
&#xD;
          6. Patients with Down Syndrome will be eligible and will be included as an observation&#xD;
             cohort&#xD;
&#xD;
        Performance Level Karnofsky &gt; 50% for patients &gt; 16 years of age and Lansky &gt; 50% for&#xD;
        patients ≤ 16 years of age.&#xD;
&#xD;
        Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior&#xD;
        chemotherapy, immunotherapy, or radiotherapy prior to entering this study.&#xD;
&#xD;
        A. Myelosuppressive chemotherapy&#xD;
&#xD;
          1. Prior chemotherapy Patients must have fully recovered from the acute toxic effects of&#xD;
             all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.&#xD;
             At least 14 days must have elapsed since the completion of the cytotoxic therapy,&#xD;
             except Intrathecal chemotherapy.&#xD;
&#xD;
          2. Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up to 24&#xD;
             hours prior to the start of day 1 nivolumab and azacytidine. It is recommended to use&#xD;
             hydroxyurea in patients with significant leukocytosis (WBC &gt; 50,000/L) to control&#xD;
             blast count before initiation of systemic protocol therapy.&#xD;
&#xD;
        B. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a&#xD;
        HSCT are eligible provided they have no evidence of active GVHD, no past history of grade 3&#xD;
        or greater GVHD, and are at least 100 days post-transplant at the time of enrollment.&#xD;
        Patients should be off immune suppression for at least 2 weeks (excluding physiologic&#xD;
        replacement steroids).&#xD;
&#xD;
        C. Hematopoietic growth factors: It must have been at least 7 days since the completion of&#xD;
        therapy with GCSF or other growth factors at the time of enrollment. It must have been at&#xD;
        least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).&#xD;
&#xD;
        D. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic&#xD;
        agent. For agents that have known adverse events occurring beyond 7 days after&#xD;
        administration, this period must be extended beyond the time during which adverse events&#xD;
        are known to occur. The duration of this interval must be discussed with the study chair&#xD;
&#xD;
        E. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the&#xD;
        last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)&#xD;
&#xD;
        F. Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g.&#xD;
        tumor vaccines or CAR T-cells.&#xD;
&#xD;
        G. XRT: XRT is prohibited during protocol therapy. No washout period is necessary for&#xD;
        radiation given to non-CNS chloromas; ≥ 90 days must have elapsed if prior TBI or&#xD;
        craniospinal XRT.&#xD;
&#xD;
        Renal and hepatic function&#xD;
&#xD;
        Patients must have adequate renal and hepatic functions as indicated by the following&#xD;
        laboratory values:&#xD;
&#xD;
        A. Adequate renal function defined as: Patient must have a calculated creatinine clearance&#xD;
        or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in&#xD;
        the chart below:&#xD;
&#xD;
        B. Adequate Liver Function Defined as: Direct bilirubin &lt; 1.5 x upper limit of normal (ULN)&#xD;
        for age or normal, AND alanine transaminase (ALT) &lt; 5 x ULN for age. The hepatic&#xD;
        requirements are waived for patients with known or suspected liver involvement by leukemia.&#xD;
        This must be reviewed by and approved by the study chair or vice chair.&#xD;
&#xD;
        Adequate Cardiac Function Defined as: Shortening fraction of ≥ 27% OR ejection fraction of&#xD;
        ≥ 50%.&#xD;
&#xD;
        Reproductive Function A. Female patients of childbearing potential must have a negative&#xD;
        urine or serum pregnancy test confirmed within 24 hours prior to first dose.&#xD;
&#xD;
        B. Female patients with infants must agree not to breastfeed their infants while on this&#xD;
        study.&#xD;
&#xD;
        C. Male and female patients of child-bearing potential must agree to use an effective&#xD;
        method of contraception approved by the investigator during the study and for a minimum of&#xD;
        7 months after study treatment. Women of childbearing potential (WOCBP) receiving nivolumab&#xD;
        will be instructed to adhere to contraception for a period of 5 months after the last dose&#xD;
        of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will be&#xD;
        instructed to adhere to contraception for a period of 7 months after the last dose of&#xD;
        nivolumab.&#xD;
&#xD;
        Informed Consent Patients and/or their parents or legal guardians must be capable of&#xD;
        understanding the investigational nature, potential risks and benefits of the study. All&#xD;
        patients and/or their parents or legal guardians must sign a written informed consent. Age&#xD;
        appropriate assent will be obtained per institutional guidelines. To allow non-English&#xD;
        speaking patients to participate in this study, bilingual health services will be provided&#xD;
        in the appropriate language when feasible.&#xD;
&#xD;
        Protocol Approval All institutional, FDA, and OHRP requirements for human studies must be&#xD;
        met.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients will be excluded if they have a known allergy or hypersensitivity to nivolumab or&#xD;
        AZA used in the study.&#xD;
&#xD;
        Patients will be excluded if they have a systemic fungal, bacterial, viral or other&#xD;
        infection that is exhibiting ongoing signs/symptoms related to the infection without&#xD;
        improvement despite appropriate antibiotics or other treatment. The patient needs to be off&#xD;
        pressors and have negative blood cultures for 48 hours.&#xD;
&#xD;
        Patients will be excluded if there is a plan to administer non-protocol chemotherapy,&#xD;
        radiation therapy, or immunotherapy during the study period.&#xD;
&#xD;
        Patients will be excluded if they have significant concurrent disease, illness, psychiatric&#xD;
        disorder or social issue that would compromise patient safety or compliance with the&#xD;
        protocol treatment or procedures, interfere with consent, study participation, follow up,&#xD;
        or interpretation of study results.&#xD;
&#xD;
        Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are&#xD;
        excluded.&#xD;
&#xD;
        Patients with a known history of severe interstitial lung disease or severe pneumonitis or&#xD;
        active pneumonitis that is uncontrolled in the opinion of the treating physician.&#xD;
&#xD;
        Patients who have previously been treated with nivolumab will be excluded.&#xD;
&#xD;
        Patients with a known history of any of the following autoimmune diseases are excluded: (a)&#xD;
        patients with a history of inflammatory bowel disease (including Crohn's disease and&#xD;
        ulcerative colitis) (b) patients with a history of rheumatoid arthritis, systemic&#xD;
        progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis&#xD;
        [e.g., Wegener's Granulomatosis]).&#xD;
&#xD;
        Patients with organ allografts (such as renal transplant) are excluded.&#xD;
&#xD;
        Patients with known Human Immunodeficiency Virus seropositivity will be excluded.&#xD;
&#xD;
        Known to be positive for hepatitis B by surface antigen expression. Known to have active&#xD;
        hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for&#xD;
        hepatitis C within the last 6 months).&#xD;
&#xD;
        Pregnant or breastfeeding.&#xD;
&#xD;
        Acute promyelocytic leukemia (APL).&#xD;
&#xD;
        CNS 3 disease.&#xD;
&#xD;
        Patients who have experienced their relapse after a HSCT and are less than 100 days&#xD;
        post-transplant at the time of enrollment, have active GVHD at time of enrollment, have&#xD;
        past history of grade 3 or greater GVHD, Patients on immune suppression (excluding&#xD;
        physiologic replacement steroids).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Children's Hospital of Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Healthcare of Atlanta</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins University</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Levine Cancer Institute</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Jude Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Health</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75235</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cook Children's Medical Center</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <zip>76104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Children's Hospital/Baylor College of Medicine</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Primary Children's Hospital</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Children's Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>January 28, 2019</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>October 10, 2022</last_update_submitted>
  <last_update_submitted_qc>October 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Relapse</keyword>
  <keyword>Refractory</keyword>
  <keyword>Leukemia</keyword>
  <keyword>Acute</keyword>
  <keyword>Pediatric</keyword>
  <keyword>nivolumab</keyword>
  <keyword>azacytidine</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Azacitidine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03825367
org study id: T2016-002
nct id: NCT03825367
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a phase I/II Study of Nivolumab in Combination with 5-azacytidine in pediatric
      patients with relapsed/refractory acute myeloid leukemia
This proposed study will be the first to test nivolumab in combination with AZA in pediatric
      patients with hematologic malignancies. Patients will receive the first dose of nivolumab on
      day 1 along with AZA. After "chemotherapy priming", a second dose of nivolumab will be given
      at day 15 which will enhance the effect of nivolumab on the regenerating CD4+ and CD8+ memory
      T cells.

      To establish a recommended Phase II dose (RP2D)of nivolumab in combination with 5-azacytidine
      in children with relapsed or refractory AML. To assess the clinical activity of Nivolumab in
      combination with 5-azacytidine in AML patients with M2/M3 disease at study entry.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose Toxicity
time frame: 4 weeks
description: Occurrence of dose limiting toxicity (DLT) during Cycle 1 of therapy (Phase I)
measure: Remission
time frame: 4 weeks
description: Achievement of complete remission (CR/CRp/CRi) at the end of cycle 1
arm group label: Open label design
arm group type: Other
description: Nivolumab and 5-azacytidine,
intervention type: Drug
intervention name: Nivolumab
description: The dose of Nivolumab will be 3 mg/kg which is the adult recommended dose and is the recommended dose in children in the phase 2 portion of COG ADVL1412.
If 3 mg/kg is not tolerated in combination with 5-azacytidine, the dose will be stepped down to 1 mg/kg.
arm group label: Open label design
intervention type: Drug
intervention name: 5-azacytidine
description: 75mg/m2 subcutaneously will be given daily for 7 days on days 1 to 7.
arm group label: Open label design
criteria: 
gender: All
minimum age: 1 Year
maximum age: 30 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Nivolumab
mesh term: Azacitidine
sharing ipd: No