<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/NCT02185781</url>
  </required_header>
  <id_info>
    <org_study_id>LAL 2013</org_study_id>
    <nct_id>NCT02185781</nct_id>
  </id_info>
  <brief_title>Phase I Study of Adoptive Immunotherapy With Enriched and Expanded Autologous Natural Killer (NK) Cells for Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)</brief_title>
  <official_title>Phase I Protocol of Adoptive Immunotherapy With Enriched and Expanded Autologous Natural Killer (NK) Cells for Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) in Complete Hematologic Remission (CHR) But With Persistent/Recurrent Minimal Residual Disease (MRD) ≥60 Years or Not Eligible for Other Post-CHR Treatment Modalities</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gruppo Italiano Malattie EMatologiche dell'Adulto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Gruppo Italiano Malattie EMatologiche dell'Adulto</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The present study aims at studying how safe and tolerable a new therapy for patients with&#xD;
      Acute Lymphoblastic Leukemia (ALL) is.&#xD;
&#xD;
      This new therapy consists of an immunotherapy, that is an approach focusing on the immune&#xD;
      system, and it targets ALL patients in complete remission but who may still have the disease&#xD;
      at a cellular level (this is called 'minimal residual disease').&#xD;
&#xD;
      For any further information, please, discuss with your treating physician.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open label, multicenter, phase I study of adoptive immunotherapy with enriched and&#xD;
      expanded autologous natural killer (NK) cells for patients with Ph+ acute lymphoblastic&#xD;
      leukemia (ALL) in complete hematologic remission (CHR) but with persistent/recurrent minimal&#xD;
      residual disease (MRD) ≥60 years or not eligible for other post-CHR treatment modalities.&#xD;
&#xD;
      The study will investigate the safety and tolerability of a new type of NK-based&#xD;
      immunotherapy based on the infusion of escalating doses of ex-vivo expanded autologous NK&#xD;
      cells in Ph+ ALL patients. A maximum of 6 patients will be enrolled in two different steps.&#xD;
      No conditioning therapies will be administered before the infusion of the expanded NK cells.&#xD;
      Patients may receive tyrosine kinase inhibitor (TKI) maintenance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 28, 2015</start_date>
  <completion_date type="Actual">November 29, 2021</completion_date>
  <primary_completion_date type="Actual">November 2021</primary_completion_date>
  <phase>Phase 1</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>To determine the MTD and the recommended final dose (RD) to be used for further investigations.</measure>
    <time_frame>One year from start of treatment.</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of adverse events.</measure>
    <time_frame>Two years from start of treatment.</time_frame>
    <description>To assess the safety and tolerabilty of the treatment by evaluating frequency, type and intensity of adverse events (AEs) according to the CTC classification, as well as the patients' compliance and clinically relevant changes in the laboratory parameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients able to complete the study.</measure>
    <time_frame>One year from start of treatment.</time_frame>
    <description>To evaluate the feasibility of the procedure in terms of number of patients able to complete the study and time to complete enrolment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to complete enrolment.</measure>
    <time_frame>Three years from first patient enrollment.</time_frame>
    <description>Protocol feasibility.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number and characteristics of immunologic modifications.</measure>
    <time_frame>One year from start of treatment.</time_frame>
    <description>To assess the immunologic modifications induced by the procedure; in particular, to verify the functional and cytotoxic activity against tumor cell lines and primary fresh allogeneic and autologous blasts cryopreserved at diagnosis, and to monitor the frequency, phenotype and activation status of the infused NK cell populations by flow cytometry analyses, Chromium release cytotoxic assays and intracellular cytokine production.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who respond to treatment.</measure>
    <time_frame>One year from treatment start.</time_frame>
    <description>To evaluate the clinical response to the treatment in terms of control of MRD with quantitative (Q)- RT-PCR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients alive after treatment conclusion.</measure>
    <time_frame>Two years from treatment start.</time_frame>
    <description>To evaluate OS in terms of number of patients alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients alive without progression.</measure>
    <time_frame>One year from treatment start.</time_frame>
    <description>To evaluate the TTP in terms of number of patients alive without progression.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <condition>Complete Hematologic Remission (CHR)</condition>
  <condition>Persistent/Recurrent Minimal Residual Disease (MRD)</condition>
  <arm_group>
    <arm_group_label>Autologous NK Cells infusions</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Autologous NK cells infusions</intervention_name>
    <description>Each patient will receive repeated intravenous (IV) infusions of escalating doses of expanded autologous NK cells.&#xD;
The initial dose will be 1 x 106/kg of recipient body weight (BW), followed by half log increments of the dose level for each infusion, to a maximum of 1 x 108/kg of recipient BW or until they experience any toxicity, for a maximum of 5 infusions. The minimum interval between each infusion will be 28 days. No conditioning therapies will be administered before the infusion of the expanded NK cells. Patients may receive TKI maintenance.</description>
    <arm_group_label>Autologous NK Cells infusions</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult subjects with Ph+ ALL in CHR (1st or 2nd) with MRD positivity confirmed at&#xD;
             baseline, older or equal to 60 years or not eligible for other post-CHR treatment&#xD;
             modalities.&#xD;
&#xD;
          -  WHO score 0-1.&#xD;
&#xD;
          -  Hematopoietic, liver and renal normal functions defined as follows:&#xD;
&#xD;
        WBC bigger or equal to 2.000/mm3 lymphocytes bigger or equal to 500/mm3 neutrophils bigger&#xD;
        or equal to 1.000/mm3 platelets bigger or equal to 50.000/mm3 Hb bigger or equal to 9 g/dl&#xD;
        creatinine fewer or equal to 1.5 x ULN bilirubin fewer or equal to 1.5 x ULN AST and ALT&#xD;
        less than 3 times the upper limit of normal. LDH less than 2 times the upper limit of&#xD;
        normal.&#xD;
&#xD;
          -  For male and female subjects of childbearing potential, agreement to use effective&#xD;
             contraception.&#xD;
&#xD;
          -  Authorization by Istituto Superiore di Sanità (ISS) according to DM 2 March 2004.&#xD;
&#xD;
          -  Signed written informed consent according to ICH/EU/GCP and national local&#xD;
             regulations.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Concurrent chemotherapy or immunotherapy (TKI maintenance is permitted).&#xD;
&#xD;
          -  Any contraindications to perform a leukapheretic procedure for mononuclear cell&#xD;
             collection.&#xD;
&#xD;
          -  Active or chronic infection, including Treponema, HIV, HBV and/or HCV unless&#xD;
             antigen/PCR negative.&#xD;
&#xD;
          -  Presence of autoimmune symptoms.&#xD;
&#xD;
          -  Pregnant or lactating females.&#xD;
&#xD;
          -  Simultaneous participation in another clinical trial.&#xD;
&#xD;
          -  Any physical or psychological impediment in a patient that could lead the investigator&#xD;
             to suspect his/her poor compliance to the protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Roberto Foà</last_name>
    <role>Study Chair</role>
    <affiliation>Policlinico Umberto I di Roma</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Giovanni Torelli</last_name>
    <role>Study Director</role>
    <affiliation>Policlinico Umberto I di Roma</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ISS/AIFA</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale S. Eugenio</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Università Cattolica del Sacro Cuore - Policlinico A. Gemelli</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Università degli Studi &quot;Sapienza&quot; - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Università degli Studi - Policlinico di Tor Vergata</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Università Degli Studi Di Roma &quot;Sapienza&quot; - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 10, 2014</study_first_posted>
  <last_update_submitted>March 29, 2023</last_update_submitted>
  <last_update_submitted_qc>March 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Phase I</keyword>
  <keyword>Adoptive immunotherapy</keyword>
  <keyword>Enriched and expanded autologous natural killer (NK) cells</keyword>
  <keyword>Ph+ acute lymphoblastic leukemia</keyword>
  <keyword>≥60 years</keyword>
  <keyword>Not eligible for other post-CHR treatment modalities</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Neoplasm, Residual</mesh_term>
  </condition_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/NCT02185781
org study id: LAL 2013
nct id: NCT02185781
lead sponsor: 
has dmc: No
The present study aims at studying how safe and tolerable a new therapy for patients with
      Acute Lymphoblastic Leukemia (ALL) is.

      This new therapy consists of an immunotherapy, that is an approach focusing on the immune
      system, and it targets ALL patients in complete remission but who may still have the disease
      at a cellular level (this is called 'minimal residual disease').

      For any further information, please, discuss with your treating physician.
This is an open label, multicenter, phase I study of adoptive immunotherapy with enriched and
      expanded autologous natural killer (NK) cells for patients with Ph+ acute lymphoblastic
      leukemia (ALL) in complete hematologic remission (CHR) but with persistent/recurrent minimal
      residual disease (MRD) ≥60 years or not eligible for other post-CHR treatment modalities.

      The study will investigate the safety and tolerability of a new type of NK-based
      immunotherapy based on the infusion of escalating doses of ex-vivo expanded autologous NK
      cells in Ph+ ALL patients. A maximum of 6 patients will be enrolled in two different steps.
      No conditioning therapies will be administered before the infusion of the expanded NK cells.
      Patients may receive tyrosine kinase inhibitor (TKI) maintenance.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: To determine the MTD and the recommended final dose (RD) to be used for further investigations.
time frame: One year from start of treatment.
measure: Number of adverse events.
time frame: Two years from start of treatment.
description: To assess the safety and tolerabilty of the treatment by evaluating frequency, type and intensity of adverse events (AEs) according to the CTC classification, as well as the patients' compliance and clinically relevant changes in the laboratory parameters.
measure: Number of patients able to complete the study.
time frame: One year from start of treatment.
description: To evaluate the feasibility of the procedure in terms of number of patients able to complete the study and time to complete enrolment.
measure: Time to complete enrolment.
time frame: Three years from first patient enrollment.
description: Protocol feasibility.
measure: Number and characteristics of immunologic modifications.
time frame: One year from start of treatment.
description: To assess the immunologic modifications induced by the procedure; in particular, to verify the functional and cytotoxic activity against tumor cell lines and primary fresh allogeneic and autologous blasts cryopreserved at diagnosis, and to monitor the frequency, phenotype and activation status of the infused NK cell populations by flow cytometry analyses, Chromium release cytotoxic assays and intracellular cytokine production.
measure: Number of patients who respond to treatment.
time frame: One year from treatment start.
description: To evaluate the clinical response to the treatment in terms of control of MRD with quantitative (Q)- RT-PCR.
measure: Number of patients alive after treatment conclusion.
time frame: Two years from treatment start.
description: To evaluate OS in terms of number of patients alive.
measure: Number of patients alive without progression.
time frame: One year from treatment start.
description: To evaluate the TTP in terms of number of patients alive without progression.
arm group label: Autologous NK Cells infusions
arm group type: Experimental
intervention type: Other
intervention name: Autologous NK cells infusions
description: Each patient will receive repeated intravenous (IV) infusions of escalating doses of expanded autologous NK cells.
The initial dose will be 1 x 106/kg of recipient body weight (BW), followed by half log increments of the dose level for each infusion, to a maximum of 1 x 108/kg of recipient BW or until they experience any toxicity, for a maximum of 5 infusions. The minimum interval between each infusion will be 28 days. No conditioning therapies will be administered before the infusion of the expanded NK cells. Patients may receive TKI maintenance.
arm group label: Autologous NK Cells infusions
criteria: 
gender: All
minimum age: 60 Years
maximum age: N/A
healthy volunteers: No
last name: Roberto Foà
role: Study Chair
affiliation: Policlinico Umberto I di Roma
last name: Giovanni Torelli
role: Study Director
affiliation: Policlinico Umberto I di Roma
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Neoplasm, Residual