<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/NCT03259516</url>
  </required_header>
  <id_info>
    <org_study_id>18/17-n</org_study_id>
    <nct_id>NCT03259516</nct_id>
  </id_info>
  <brief_title>Nivolumab With Chemotherapy in Refractory MDS</brief_title>
  <official_title>Pilot Open-label Trial of Nivolumab Combined With Chemotherapy in Refractory Myelodysplastic Syndromes.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Petersburg State Pavlov Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>St. Petersburg State Pavlov Medical University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      There is evidence of involvement of checkpoint pathways, including PD-1, in the pathogenesis&#xD;
      and resistance of myelodysplastic syndrome (MDS). However monotherapy with checkpoint&#xD;
      inhibitors was ineffective in a number of studies, indicating the presence of several&#xD;
      mechanisms of resistance. This pilot study evaluates the safety and preliminary efficacy of&#xD;
      nivolumab combination with currently existing treatments in MDS patients who failed at least&#xD;
      one line of therapy. The study evaluates if there is a combination which induces objective&#xD;
      responses.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Slow recruitment rate&#xD;
  </why_stopped>
  <start_date type="Actual">May 25, 2017</start_date>
  <completion_date type="Actual">December 25, 2018</completion_date>
  <primary_completion_date type="Actual">December 25, 2018</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>Non-Randomized</allocation>
    <intervention_model>Parallel 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>6 months</time_frame>
    <description>Overall response rate (ORR) defined as complete response plus partial response (CR + PR) and hematological improvement (HI). MDS International Working Group criteria will be used to assess response.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment-related adverse events as assessed by CTCAE v4.03</measure>
    <time_frame>6 months</time_frame>
    <description>Toxicity parameters based on NCI CTCAE 4.03 grades: hematological toxicity (CBC), hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), fatigue (attending physician assessment), rash (attending physician assessment), colitis (attending physician assessment), pneumonitis (attending physician assessment), autoimmune disorders (level of hormones, presence of autoimmune antibodies, attending physician assessment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infectious complications</measure>
    <time_frame>6 months</time_frame>
    <description>Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Myelodysplastic Syndromes</condition>
  <arm_group>
    <arm_group_label>Nivo + FC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab 1 mg/kg days 1,15 iv q28days Fludarabine 25 mg/m2 days 1-3 iv q28days Cyclophosphamide 300 mg/m2 days 1-3 iv q28days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nivo + LDAC + ATRA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab 1 mg/kg days 1,15 iv q28days Cytarabine 10 mg/m2 bid days 1-10 sc q28days All-trans retinoic acid (ATRA) 45 mg/m2 po qd</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nivo + LDAC + Sildenafil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab 1 mg/kg days 1,15 iv q28days Cytarabine 10 mg/m2 bid days 1-10 sc q28days Sildenafil 20 mg tid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nivo + Melphalan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab 1 mg/kg days 1,15 iv q28days Melphalan 2 mg qd days 1-10 q28days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nivo + 5-aza</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab 1 mg/kg days 1,15 iv q28days 5-azacitidine 75 mg/m2 days 1-7 q28days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>1 mg/kg by vein on Days 1 and 15 of a 28 day cycle</description>
    <arm_group_label>Nivo + 5-aza</arm_group_label>
    <arm_group_label>Nivo + FC</arm_group_label>
    <arm_group_label>Nivo + LDAC + ATRA</arm_group_label>
    <arm_group_label>Nivo + LDAC + Sildenafil</arm_group_label>
    <arm_group_label>Nivo + Melphalan</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azacitidine</intervention_name>
    <description>75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle</description>
    <arm_group_label>Nivo + 5-aza</arm_group_label>
    <other_name>5-azacitidine</other_name>
    <other_name>Vidaza</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>25 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle. Dose reduction to 15 mg/m2 is permitted in cases of grade 4 hematological toxicity after first cycle.</description>
    <arm_group_label>Nivo + FC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle.</description>
    <arm_group_label>Nivo + FC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <description>10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle</description>
    <arm_group_label>Nivo + LDAC + ATRA</arm_group_label>
    <arm_group_label>Nivo + LDAC + Sildenafil</arm_group_label>
    <other_name>Ara-C, LDAC</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>all trans retinoic acid</intervention_name>
    <description>45 mg/m2 per os daily during the whole course of treatment</description>
    <arm_group_label>Nivo + LDAC + ATRA</arm_group_label>
    <other_name>ATRA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sildenafil</intervention_name>
    <description>20 mg per os three times a day during the whole course of treatment</description>
    <arm_group_label>Nivo + LDAC + Sildenafil</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Melphalan</intervention_name>
    <description>2 mg per os daily during the whole course of treatment</description>
    <arm_group_label>Nivo + Melphalan</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with myelodysplastic syndrome (MDS) (up to 20% blasts) of any risk. Patients&#xD;
             with lower risk MDS (low and int-1 by IPSS) should have failed prior&#xD;
             non-hypomethylating agent therapy (ie growth factors or lenalidomide). Patients with&#xD;
             higher risk MDS (int-2 or high by IPSS) should have failed prior at least one therapy&#xD;
             with a hypomethylating agent or Ara-C.&#xD;
&#xD;
          -  Age 18 years or older.&#xD;
&#xD;
          -  No severe organ dysfunction: creatinine &lt;=2.5 x ULN; serum bilirubin &lt;=2.5 x ULN; AST&#xD;
             and ALT &lt;=5 x ULN.&#xD;
&#xD;
          -  Karnofsky index &gt;=70%&#xD;
&#xD;
          -  Females of childbearing potential must have a negative serum or urine beta human&#xD;
             chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours prior to the&#xD;
             first dose of treatment and must agree to use an effective contraception to avoid&#xD;
             pregnancy for 24 weeks&#xD;
&#xD;
          -  Males who have partners of childbearing potential must agree to use an effective&#xD;
             contraceptive method during the study and for 24 weeks after the last dose of&#xD;
             nivolumab.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Another malignancy requiring treatment at the time of inclusion&#xD;
&#xD;
          -  History of interstitial lung disease or pneumonitis&#xD;
&#xD;
          -  Patients with any other known concurrent severe and/or uncontrolled medical condition&#xD;
             (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure&#xD;
             NYHA Class III or IV, myocardial infarction within 6 months, and poorly controlled&#xD;
             hypertension; chronic renal failure; or active uncontrolled infection) which, in the&#xD;
             opinion of the investigator could compromise participation in the study&#xD;
&#xD;
          -  Active, known or suspected autoimmune disease requiring treatment at the time of&#xD;
             inclusion&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Patients unwilling or unable to comply with the protocol&#xD;
&#xD;
          -  Somatic or psychiatric disorder making the patient unable to sign informed consent&#xD;
&#xD;
          -  Prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA4 therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>First Pavlov State Medical University of St. Petersburg</name>
      <address>
        <city>Saint-Petersburg</city>
        <zip>197089</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>August 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 23, 2017</study_first_posted>
  <last_update_submitted>April 3, 2019</last_update_submitted>
  <last_update_submitted_qc>April 3, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 5, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>St. Petersburg State Pavlov Medical University</investigator_affiliation>
    <investigator_full_name>Ivan S Moiseev</investigator_full_name>
    <investigator_title>Vice-director for science, R.M. Gorbacheva memorial institute</investigator_title>
  </responsible_party>
  <keyword>myelodysplastic syndrome</keyword>
  <keyword>nivolumab</keyword>
  <keyword>5-azacitidine</keyword>
  <keyword>cytarabine</keyword>
  <keyword>melphalan</keyword>
  <keyword>all-trans retinoic acid</keyword>
  <keyword>lymphodepletion</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Melphalan</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Azacitidine</mesh_term>
    <mesh_term>Tretinoin</mesh_term>
    <mesh_term>Sildenafil Citrate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03259516
org study id: 18/17-n
nct id: NCT03259516
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
There is evidence of involvement of checkpoint pathways, including PD-1, in the pathogenesis
      and resistance of myelodysplastic syndrome (MDS). However monotherapy with checkpoint
      inhibitors was ineffective in a number of studies, indicating the presence of several
      mechanisms of resistance. This pilot study evaluates the safety and preliminary efficacy of
      nivolumab combination with currently existing treatments in MDS patients who failed at least
      one line of therapy. The study evaluates if there is a combination which induces objective
      responses.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate
time frame: 6 months
description: Overall response rate (ORR) defined as complete response plus partial response (CR + PR) and hematological improvement (HI). MDS International Working Group criteria will be used to assess response.
measure: Treatment-related adverse events as assessed by CTCAE v4.03
time frame: 6 months
description: Toxicity parameters based on NCI CTCAE 4.03 grades: hematological toxicity (CBC), hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), fatigue (attending physician assessment), rash (attending physician assessment), colitis (attending physician assessment), pneumonitis (attending physician assessment), autoimmune disorders (level of hormones, presence of autoimmune antibodies, attending physician assessment).
measure: Infectious complications
time frame: 6 months
description: Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment
arm group label: Nivo + FC
arm group type: Experimental
description: Nivolumab 1 mg/kg days 1,15 iv q28days Fludarabine 25 mg/m2 days 1-3 iv q28days Cyclophosphamide 300 mg/m2 days 1-3 iv q28days
arm group label: Nivo + LDAC + ATRA
arm group type: Experimental
description: Nivolumab 1 mg/kg days 1,15 iv q28days Cytarabine 10 mg/m2 bid days 1-10 sc q28days All-trans retinoic acid (ATRA) 45 mg/m2 po qd
arm group label: Nivo + LDAC + Sildenafil
arm group type: Experimental
description: Nivolumab 1 mg/kg days 1,15 iv q28days Cytarabine 10 mg/m2 bid days 1-10 sc q28days Sildenafil 20 mg tid
arm group label: Nivo + Melphalan
arm group type: Experimental
description: Nivolumab 1 mg/kg days 1,15 iv q28days Melphalan 2 mg qd days 1-10 q28days
arm group label: Nivo + 5-aza
arm group type: Experimental
description: Nivolumab 1 mg/kg days 1,15 iv q28days 5-azacitidine 75 mg/m2 days 1-7 q28days
intervention type: Drug
intervention name: Nivolumab
description: 1 mg/kg by vein on Days 1 and 15 of a 28 day cycle
arm group label: Nivo + 5-aza
arm group label: Nivo + FC
arm group label: Nivo + LDAC + ATRA
arm group label: Nivo + LDAC + Sildenafil
arm group label: Nivo + Melphalan
other name: Opdivo
intervention type: Drug
intervention name: Azacitidine
description: 75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle
arm group label: Nivo + 5-aza
other name: 5-azacitidine
other name: Vidaza
intervention type: Drug
intervention name: Fludarabine
description: 25 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle. Dose reduction to 15 mg/m2 is permitted in cases of grade 4 hematological toxicity after first cycle.
arm group label: Nivo + FC
intervention type: Drug
intervention name: Cyclophosphamide
description: 300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle.
arm group label: Nivo + FC
intervention type: Drug
intervention name: Cytarabine
description: 10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle
arm group label: Nivo + LDAC + ATRA
arm group label: Nivo + LDAC + Sildenafil
other name: Ara-C, LDAC
intervention type: Drug
intervention name: all trans retinoic acid
description: 45 mg/m2 per os daily during the whole course of treatment
arm group label: Nivo + LDAC + ATRA
other name: ATRA
intervention type: Drug
intervention name: Sildenafil
description: 20 mg per os three times a day during the whole course of treatment
arm group label: Nivo + LDAC + Sildenafil
intervention type: Drug
intervention name: Melphalan
description: 2 mg per os daily during the whole course of treatment
arm group label: Nivo + Melphalan
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
facility: 
country: Russian Federation
responsible party type: Principal Investigator
investigator affiliation: St. Petersburg State Pavlov Medical University
investigator full name: Ivan S Moiseev
investigator title: Vice-director for science, R.M. Gorbacheva memorial institute
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
mesh term: Syndrome
mesh term: Cytarabine
mesh term: Cyclophosphamide
mesh term: Melphalan
mesh term: Nivolumab
mesh term: Fludarabine
mesh term: Azacitidine
mesh term: Tretinoin
mesh term: Sildenafil Citrate
sharing ipd: Undecided