<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/NCT02226861</url>
  </required_header>
  <id_info>
    <org_study_id>140180</org_study_id>
    <secondary_id>14-H-0180</secondary_id>
    <nct_id>NCT02226861</nct_id>
  </id_info>
  <brief_title>Ultra-Low Dose IL-2 Therapy as GVHD Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation</brief_title>
  <official_title>Ultra Low Dose IL-2 Therapy as GVHD Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Stem cell transplantation from a partially matched donor can lead to graft-versus-host&#xD;
      disease (GVHD). Researchers want to learn how to improve these transplantations.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To see if very low doses of Interleukin-2 after a partially matched transplantation prevent&#xD;
      GVHD.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Recipients: age 18 65, with certain bone marrow or lymphatic system diseases and an&#xD;
           available family member with partial tissue match.&#xD;
&#xD;
        -  Donors: age 18 80.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Recipients will be screened with medical history, physical exam, and many tests&#xD;
           including blood and tissue tying.&#xD;
&#xD;
        -  Donors will be screened with medical history, physical exam, blood tests and tissue&#xD;
           typing.&#xD;
&#xD;
        -  Recipients will stay in the hospital 3 6 weeks.&#xD;
&#xD;
        -  All participants will have apheresis. Blood is drawn from one arm, run through a machine&#xD;
           that collects white blood cells, then returned into the other arm.&#xD;
&#xD;
        -  Recipients will have:&#xD;
&#xD;
        -  Intravenous (IV) line placed under the skin and into a neck vein, to stay throughout&#xD;
           transplant and recovery. They may also have a catheter inserted for collecting immune&#xD;
           cells.&#xD;
&#xD;
        -  Bone marrow sample taken by needle. They will have 3 more after transplant.&#xD;
&#xD;
        -  Donors will have:&#xD;
&#xD;
        -  Filgrastim injected once daily for 5 6 days.&#xD;
&#xD;
        -  Stem and immune cells collected by another apheresis.&#xD;
&#xD;
        -  Recipients will get:&#xD;
&#xD;
        -  Eight 30-minute doses of radiation, sitting at a machine.&#xD;
&#xD;
        -  Donor immune cells by IV, 6 days before the transplant day.&#xD;
&#xD;
        -  Chemotherapy drugs by IV.&#xD;
&#xD;
      &lt;TAB&gt;&lt;TAB&gt;- Donor stem cells by IV on transplant day.&#xD;
&#xD;
        -  After transplant, recipients will give self-injections of very low doses of&#xD;
           Interleukin-2 once daily for about 12 weeks.&#xD;
&#xD;
        -  Before and after transplant, recipients will get medicine to suppress the immune system&#xD;
           and antibiotics to prevent infections&#xD;
&#xD;
        -  Recipients must stay near NIH for 3 6 months after transplant.&#xD;
&#xD;
        -  All recipients and donors will have 3 years of follow-up.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Although allogeneic stem cell transplantation (allo-SCT) is a curative option for many&#xD;
      hematologic malignancies, not all have a suitable donor. Haploidentical peripheral blood stem&#xD;
      cell transplantation (haplo-SCT) has the advantage of immediate availability, higher stem&#xD;
      cell dose, and feasibility of repeated cell collections for generating lymphocyte infusions&#xD;
      to treat or prevent relapse or infection. However, haplo-SCT incurs a risk of bidirectional&#xD;
      rejection with either severe graft versus host disease (GVHD) or graft rejection by the&#xD;
      recipient. Therefore it is important to develop novel strategies to optimize the outcome of&#xD;
      haplo-SCT. Designing a haplo-SCT that incorporates the concepts of modulating the immune&#xD;
      system and allowing the opportunity for graft manipulation and/or adoptive immunotherapy may&#xD;
      improve the treatment outcome. To achieve this, we are first interested in studying the&#xD;
      immune modulatory effect of ultra-low dose Interleukin 2 (ULD IL-2) as GVHD prophylaxis.&#xD;
&#xD;
      This is an investigator initiated pilot study to determine the safety and feasibility of ULD&#xD;
      IL-2 as GVHD prophylaxis in haploidentical allogeneic stem cell transplantation for patients&#xD;
      with hematologic malignancies. Because GVHD has previously been associated with low numbers&#xD;
      of circulating CD4+ CD25+FOXP3+ regulatory T cells (T(regs)), research efforts in increasing&#xD;
      T(regs) either ex-vivo with adoptive transfer of T(regs) or in vivo using immunomodulatory&#xD;
      agents such as IL-2, have shown promise in reducing incidences of GVHD.&#xD;
&#xD;
      The primary objective of this study is to evaluate safety and feasibility. Secondary&#xD;
      objectives are to determine the incidences of acute and chronic GVHD, engraftment, overall&#xD;
      survival, transplant related mortality, and relapse.&#xD;
&#xD;
      We will adopt the 2 step haplo-SCT method developed by Grosso et. al1 to study our method of&#xD;
      GVHD prophylaxis. This 2 step approach, in which the lymphoid and myeloid portions of the&#xD;
      graft are given in two separate steps in order to control and optimize T-cell, has already&#xD;
      been published as a feasible and safe platform for haplo SCT for patients with hematologic&#xD;
      malignancies and has been adopted by the Jefferson University Hospital (PA, USA), where they&#xD;
      continue to treat patients under this protocol. As an additional GVHD prophylaxis, we will&#xD;
      use sirolimus, an previously established GVHD prophylaxis which may work with ULD IL-2&#xD;
      synergistically to increase T(regs) .&#xD;
&#xD;
      The haploidentical donor will be mobilized by G-CSF and undergo one apheresis to collect&#xD;
      lymphocytes and CD34+ stem cell product after Miltenyi CD34+ selection. The products will be&#xD;
      cryopreserved until the time of transplantation. Recipients will receive a myeloablative&#xD;
      conditioning regimen of fludarabine and total body irradiation (TBI) on days -10 to -6. After&#xD;
      the last fraction of TBI, a donor lymphocyte infusion (DLI) product (2 times 10(8) CD3+/kg)&#xD;
      will be given. Cyclophosphamide will be given on days -3 and -2, followed by CD 34+ selected&#xD;
      donor stem cell product infused on day 0. Sirolimus will be initiated on day -1 until day+60.&#xD;
      ULD-IL2 (100,000 IU/m2) will give subcutaneously daily for 12 weeks starting day +1.&#xD;
&#xD;
      This study will evaluate 14 recipients (ages greater than or equal to 18 - less than or equal&#xD;
      to 75; planned accrual up to 20 recipient in event of replacement) with hematologic&#xD;
      malignancies meeting indication for transplant but who do not have matched related or&#xD;
      unrelated donor available. Safety will be monitored continuously with a stopping rule for&#xD;
      toxicity based on the treatment-related serious adverse event rate (TRSAE). Safety monitoring&#xD;
      will continue until at least 114 days after transplantation, and recipients experiencing&#xD;
      adverse events will be monitored until toxicity resolution or stabilization. Stopping rule is&#xD;
      defined as nonrelapse mortality and steroid refractory GVHD during the period of safety&#xD;
      monitoring for ULD IL-2. Recipients will be followed for up to 1 year to evaluate the&#xD;
      incidences of acute and chronic GVHD, engraftment, overall survival, transplant related&#xD;
      mortality, and relapse.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 26, 2014</start_date>
  <completion_date type="Actual">June 27, 2018</completion_date>
  <primary_completion_date type="Actual">May 23, 2018</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of ULD IL-2 as GVHD proph</measure>
    <time_frame>4 months</time_frame>
    <description>The primary endpoint to this study is to evaluate the safety of ULD IL-2 as GVHD prophylaxis in haploidentical transplantation.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Acute Lymphoblastic Leukemia (ALL)</condition>
  <condition>Acute Myelogenous Leukemia (AML)</condition>
  <condition>Chronic Lymphocytic Leukemia (CLL)</condition>
  <condition>Chronic Myelogenous Leukemia (CML)</condition>
  <condition>MDS</condition>
  <arm_group>
    <arm_group_label>1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive CD34-selected stem cells followed by fixed dose ULG IL-2 (100,000 IU/m2) given subcutaneously for 12 weeks+Sirolimus until Day +60</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>CliniMACS CD34 selection system</intervention_name>
    <description>Stem cells will be selected with the CliniMACS system before transplant.</description>
    <arm_group_label>1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ULD IL-2</intervention_name>
    <description>sterile, white to off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution</description>
    <arm_group_label>1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA RECIPIENT:&#xD;
&#xD;
          -  Ages 18-70 years inclusive&#xD;
&#xD;
          -  Haploidentical donor available&#xD;
&#xD;
          -  Any one of the following hematologic conditions meeting a standard indication for&#xD;
             allogeneic stem cell transplant:&#xD;
&#xD;
               -  Chronic myelogenous leukemia (CML): Subjects under the age of 21 in chronic phase&#xD;
                  OR subjects ages 18-65 in chronic phase who have failed treatment with imatinib&#xD;
                  or have intolerance to imatinib OR Subjects ages 18-65 in accelerated phase or&#xD;
                  blast transformation. OR&#xD;
&#xD;
               -  Acute lymphoblastic leukemia (ALL): any of these categories: Adult ALL including&#xD;
                  standard risk. All second or subsequent remissions, primary induction failure,&#xD;
                  partially responding or untreated relapse. OR&#xD;
&#xD;
               -  Acute myelogenous leukemia (AML): AML in first remission - except AML with good&#xD;
                  risk karyotypes: AML M3 (t15; 17), AML M4Eo (inv 16), c-kit unmutated AML t (8;&#xD;
                  21). All AML in second or subsequent remission, primary induction failure and&#xD;
                  resistant relapse. OR&#xD;
&#xD;
               -  Myelodysplasticsyndromes(MDS): any of these categories - refractory anemia with&#xD;
                  transfusion dependence, refractory anemia with ANC&lt;500/ (Micro)L, refractory&#xD;
                  anemia with excess of blasts, transformation to acute leukemia, chronic&#xD;
                  myelomonocytic leukemia, atypical MDS/myeloproliferative syndromes. OR&#xD;
&#xD;
               -  Myeloproliferative disorders including atypical (Ph-negative) chronic myeloid and&#xD;
                  neutrophilic leukemias, progressing myelofibrosis, and polycythemia vera,&#xD;
                  essential thrombocythemia either in transformation to acute leukemia or with&#xD;
                  progressive transfusion requirements or pancytopenia. OR&#xD;
&#xD;
               -  Non-Hodgkin s lymphoma including Mantle cell lymphoma relapsing or refractory to&#xD;
                  standard of care treatments. OR&#xD;
&#xD;
               -  Multiple myeloma, Waldenstroms macroglobulinemia, unresponsive or relapsed&#xD;
                  following standard of care treatments. OR&#xD;
&#xD;
               -  Hodgkin's Lymphoma relapsing following an autologous transplant. OR&#xD;
&#xD;
               -  Other rare hematologic malignancies for which hematopoietic stem cell&#xD;
                  transplantation has been performed and offers a durable remission or as the only&#xD;
                  option with a potential for cure.&#xD;
&#xD;
                    -  Chemotherapy-resistant multisystem Langerhans cell histiocytosis (MSLCH)&#xD;
                       especially involving organs like the bone marrow, liver, spleen, and lungs&#xD;
&#xD;
                    -  Aggressive systemic mastocytosis, and mast cell leukemia (MCL) in first CR&#xD;
                       (CR1)&#xD;
&#xD;
                    -  Hypereosinophilic syndrome who have failed imatinib therapy or&#xD;
                       FIP1L1-PDGFRa-negative patients who develop end-organ dysfunction&#xD;
&#xD;
                    -  Adult T-cell leukemia/lymphoma at first diagnosis&#xD;
&#xD;
                    -  Refractory or disseminated nasal-type extranodal NK/T-lymphoma or aggressive&#xD;
                       Natural killer cell leukemia/lymphoma&#xD;
&#xD;
                    -  Mycosis fungoides and S(SqrRoot)(Copyright)zary syndrome after failure of&#xD;
                       two or three initial therapies&#xD;
&#xD;
                    -  Primary or relapsed refractory Angioimmunoblastic T-cell lymphoma at first&#xD;
                       diagnosis&#xD;
&#xD;
                    -  Hepatosplenic T-cell lymphoma (gamma/delta T-cell lymphoma) at first&#xD;
                       diagnosis&#xD;
&#xD;
                    -  T-cell prolymphocytic leukemia at first diagnosis&#xD;
&#xD;
                    -  Subcutaneous panniculitic T-cell lymphoma at first diagnosis&#xD;
&#xD;
                    -  Hematodermic neoplasm (blastic natural killer cell lymphoma or Blastic&#xD;
                       plasmacytoid dendritic cell neoplasm) at first diagnosis&#xD;
&#xD;
               -  Ability to comprehend the investigational nature of the study and provide&#xD;
                  informed consent.&#xD;
&#xD;
        EXCLUSION CRITERIA RECIPIENT (ANY OF THE FOLLOWING):&#xD;
&#xD;
          -  HLA identical (6/6) related or (8/8 allele level matched) unrelated donor available&#xD;
             and readily accessible at time of transplantation evaluation&#xD;
&#xD;
          -  Major anticipated illness or organ failure incompatible with survival from transplant&#xD;
&#xD;
          -  Severe psychiatric illness or mental deficiency sufficiently severe as to make&#xD;
             compliance with the transplant treatment unlikely and making informed consent&#xD;
             impossible.&#xD;
&#xD;
          -  Positive pregnancy test for women of childbearing age&#xD;
&#xD;
          -  Contraindication to receive IL-2 including:&#xD;
&#xD;
               -  Hypersensitivity to IL-2&#xD;
&#xD;
               -  Sustained ventricular tachycardia (&gt;5 beats)&#xD;
&#xD;
               -  Cardiac arrhythmias not controlled or unresponsive to management&#xD;
&#xD;
               -  Chest pain with ECG changes, consistent with angina or myocardial infarction&#xD;
&#xD;
               -  Cardiac tamponade&#xD;
&#xD;
               -  Intubation for &gt;72 hours&#xD;
&#xD;
               -  Renal failure requiring dialysis &gt;72 hours&#xD;
&#xD;
               -  Coma or toxic psychosis lasting &gt; 48 hours&#xD;
&#xD;
               -  Repetitive or difficult to control seizures&#xD;
&#xD;
               -  Active bowel ischemia or perforation&#xD;
&#xD;
               -  Active GI bleeding requiring surgery&#xD;
&#xD;
          -  DLCO adjusted for Hb and ventilation&lt; 50% predicted&#xD;
&#xD;
          -  Left ventricular ejection fraction &lt; 40% (evaluated by ECHO) or &lt; 30% (evaluated by&#xD;
             MUGA)&#xD;
&#xD;
          -  AST/SGOT &gt; 5 times ULN&#xD;
&#xD;
          -  Total bilirubin &gt; 3 times ULN&#xD;
&#xD;
          -  Estimated GFR &lt;60ml/min (calculated by CKD-EPI, a formula routinely used in Clinical&#xD;
             Research Center at National Institutes of Health. In case of borderline estimated GFR,&#xD;
             CKD-EPI creatinine-cystatin C formula will be used for more accurate estimation)&#xD;
&#xD;
          -  Prior allogeneic stem cell transplantation&#xD;
&#xD;
        INCLUSION CRITERIA DONOR:&#xD;
&#xD;
          -  Related donor who shares 1 haplotype with the recipient&#xD;
&#xD;
          -  Age greater than or equal to 18 or less than or equal to 80 years old&#xD;
&#xD;
          -  Ability to comprehend the investigational nature of the study and provide informed&#xD;
             consent.&#xD;
&#xD;
        EXCLUSION CRITERIA DONOR (ANY OF THE FOLLOWING):&#xD;
&#xD;
          -  Unfit to receive G-CSF and undergo apheresis such as abnormal blood counts, history of&#xD;
             stroke, uncontrolled hypertension&#xD;
&#xD;
          -  Sickling hemaglobinopathy including HbSS, HbAS, HbSC&#xD;
&#xD;
          -  Donors who are positive for HIV, active hepatitis B (HBV), hepatitis C (HCV) or human&#xD;
             T-cell lymphotropic virus (HTLV-I/II)&#xD;
&#xD;
          -  Severe psychiatric illness. Mental deficiency sufficiently severe as to make&#xD;
             compliance with the BMT treatment unlikely and making informed consent impossible.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sawa Ito, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Heart, Lung, and Blood Institute (NHLBI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Grosso D, Carabasi M, Filicko-O'Hara J, Kasner M, Wagner JL, Colombe B, Cornett Farley P, O'Hara W, Flomenberg P, Werner-Wasik M, Brunner J, Mookerjee B, Hyslop T, Weiss M, Flomenberg N. A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing. Blood. 2011 Oct 27;118(17):4732-9. doi: 10.1182/blood-2011-07-365338. Epub 2011 Aug 25.</citation>
    <PMID>21868572</PMID>
  </reference>
  <reference>
    <citation>Barrett J, Gluckman E, Handgretinger R, Madrigal A. Point-counterpoint: haploidentical family donors versus cord blood transplantation. Biol Blood Marrow Transplant. 2011 Jan;17(1 Suppl):S89-93. doi: 10.1016/j.bbmt.2010.10.024. No abstract available.</citation>
    <PMID>21195317</PMID>
  </reference>
  <reference>
    <citation>Fuchs EJ. Haploidentical transplantation for hematologic malignancies: where do we stand? Hematology Am Soc Hematol Educ Program. 2012;2012:230-6. doi: 10.1182/asheducation-2012.1.230.</citation>
    <PMID>23233586</PMID>
  </reference>
  <verification_date>June 27, 2018</verification_date>
  <study_first_submitted>August 26, 2014</study_first_submitted>
  <study_first_submitted_qc>August 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2014</study_first_posted>
  <last_update_submitted>July 3, 2018</last_update_submitted>
  <last_update_submitted_qc>July 3, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 5, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Acute Lymphoblastic Leukemia (ALL)</keyword>
  <keyword>MDS</keyword>
  <keyword>Chronic Myelogenous Leukemia (CML)</keyword>
  <keyword>Chronic Lymphocytic Leukemia (CLL)</keyword>
  <keyword>Acute Myelogenous Leukemia (AML)</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>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myelogenous, Chronic, BCR-ABL Positive</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</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/NCT02226861
org study id: 140180
secondary id: 14-H-0180
nct id: NCT02226861
lead sponsor: 
Background:

      - Stem cell transplantation from a partially matched donor can lead to graft-versus-host
      disease (GVHD). Researchers want to learn how to improve these transplantations.

      Objective:

      - To see if very low doses of Interleukin-2 after a partially matched transplantation prevent
      GVHD.

      Eligibility:

        -  Recipients: age 18 65, with certain bone marrow or lymphatic system diseases and an
           available family member with partial tissue match.

        -  Donors: age 18 80.

      Design:

        -  Recipients will be screened with medical history, physical exam, and many tests
           including blood and tissue tying.

        -  Donors will be screened with medical history, physical exam, blood tests and tissue
           typing.

        -  Recipients will stay in the hospital 3 6 weeks.

        -  All participants will have apheresis. Blood is drawn from one arm, run through a machine
           that collects white blood cells, then returned into the other arm.

        -  Recipients will have:

        -  Intravenous (IV) line placed under the skin and into a neck vein, to stay throughout
           transplant and recovery. They may also have a catheter inserted for collecting immune
           cells.

        -  Bone marrow sample taken by needle. They will have 3 more after transplant.

        -  Donors will have:

        -  Filgrastim injected once daily for 5 6 days.

        -  Stem and immune cells collected by another apheresis.

        -  Recipients will get:

        -  Eight 30-minute doses of radiation, sitting at a machine.

        -  Donor immune cells by IV, 6 days before the transplant day.

        -  Chemotherapy drugs by IV.

      <TAB><TAB>- Donor stem cells by IV on transplant day.

        -  After transplant, recipients will give self-injections of very low doses of
           Interleukin-2 once daily for about 12 weeks.

        -  Before and after transplant, recipients will get medicine to suppress the immune system
           and antibiotics to prevent infections

        -  Recipients must stay near NIH for 3 6 months after transplant.

        -  All recipients and donors will have 3 years of follow-up.
Although allogeneic stem cell transplantation (allo-SCT) is a curative option for many
      hematologic malignancies, not all have a suitable donor. Haploidentical peripheral blood stem
      cell transplantation (haplo-SCT) has the advantage of immediate availability, higher stem
      cell dose, and feasibility of repeated cell collections for generating lymphocyte infusions
      to treat or prevent relapse or infection. However, haplo-SCT incurs a risk of bidirectional
      rejection with either severe graft versus host disease (GVHD) or graft rejection by the
      recipient. Therefore it is important to develop novel strategies to optimize the outcome of
      haplo-SCT. Designing a haplo-SCT that incorporates the concepts of modulating the immune
      system and allowing the opportunity for graft manipulation and/or adoptive immunotherapy may
      improve the treatment outcome. To achieve this, we are first interested in studying the
      immune modulatory effect of ultra-low dose Interleukin 2 (ULD IL-2) as GVHD prophylaxis.

      This is an investigator initiated pilot study to determine the safety and feasibility of ULD
      IL-2 as GVHD prophylaxis in haploidentical allogeneic stem cell transplantation for patients
      with hematologic malignancies. Because GVHD has previously been associated with low numbers
      of circulating CD4+ CD25+FOXP3+ regulatory T cells (T(regs)), research efforts in increasing
      T(regs) either ex-vivo with adoptive transfer of T(regs) or in vivo using immunomodulatory
      agents such as IL-2, have shown promise in reducing incidences of GVHD.

      The primary objective of this study is to evaluate safety and feasibility. Secondary
      objectives are to determine the incidences of acute and chronic GVHD, engraftment, overall
      survival, transplant related mortality, and relapse.

      We will adopt the 2 step haplo-SCT method developed by Grosso et. al1 to study our method of
      GVHD prophylaxis. This 2 step approach, in which the lymphoid and myeloid portions of the
      graft are given in two separate steps in order to control and optimize T-cell, has already
      been published as a feasible and safe platform for haplo SCT for patients with hematologic
      malignancies and has been adopted by the Jefferson University Hospital (PA, USA), where they
      continue to treat patients under this protocol. As an additional GVHD prophylaxis, we will
      use sirolimus, an previously established GVHD prophylaxis which may work with ULD IL-2
      synergistically to increase T(regs) .

      The haploidentical donor will be mobilized by G-CSF and undergo one apheresis to collect
      lymphocytes and CD34+ stem cell product after Miltenyi CD34+ selection. The products will be
      cryopreserved until the time of transplantation. Recipients will receive a myeloablative
      conditioning regimen of fludarabine and total body irradiation (TBI) on days -10 to -6. After
      the last fraction of TBI, a donor lymphocyte infusion (DLI) product (2 times 10(8) CD3+/kg)
      will be given. Cyclophosphamide will be given on days -3 and -2, followed by CD 34+ selected
      donor stem cell product infused on day 0. Sirolimus will be initiated on day -1 until day+60.
      ULD-IL2 (100,000 IU/m2) will give subcutaneously daily for 12 weeks starting day +1.

      This study will evaluate 14 recipients (ages greater than or equal to 18 - less than or equal
      to 75; planned accrual up to 20 recipient in event of replacement) with hematologic
      malignancies meeting indication for transplant but who do not have matched related or
      unrelated donor available. Safety will be monitored continuously with a stopping rule for
      toxicity based on the treatment-related serious adverse event rate (TRSAE). Safety monitoring
      will continue until at least 114 days after transplantation, and recipients experiencing
      adverse events will be monitored until toxicity resolution or stabilization. Stopping rule is
      defined as nonrelapse mortality and steroid refractory GVHD during the period of safety
      monitoring for ULD IL-2. Recipients will be followed for up to 1 year to evaluate the
      incidences of acute and chronic GVHD, engraftment, overall survival, transplant related
      mortality, and relapse.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Safety of ULD IL-2 as GVHD proph
time frame: 4 months
description: The primary endpoint to this study is to evaluate the safety of ULD IL-2 as GVHD prophylaxis in haploidentical transplantation.
arm group label: 1
arm group type: Experimental
description: Subjects will receive CD34-selected stem cells followed by fixed dose ULG IL-2 (100,000 IU/m2) given subcutaneously for 12 weeks+Sirolimus until Day +60
intervention type: Device
intervention name: CliniMACS CD34 selection system
description: Stem cells will be selected with the CliniMACS system before transplant.
arm group label: 1
intervention type: Biological
intervention name: ULD IL-2
description: sterile, white to off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution
arm group label: 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Sawa Ito, M.D.
role: Principal Investigator
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
facility: 
country: United States
citation: Grosso D, Carabasi M, Filicko-O'Hara J, Kasner M, Wagner JL, Colombe B, Cornett Farley P, O'Hara W, Flomenberg P, Werner-Wasik M, Brunner J, Mookerjee B, Hyslop T, Weiss M, Flomenberg N. A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing. Blood. 2011 Oct 27;118(17):4732-9. doi: 10.1182/blood-2011-07-365338. Epub 2011 Aug 25.
PMID: 21868572
citation: Barrett J, Gluckman E, Handgretinger R, Madrigal A. Point-counterpoint: haploidentical family donors versus cord blood transplantation. Biol Blood Marrow Transplant. 2011 Jan;17(1 Suppl):S89-93. doi: 10.1016/j.bbmt.2010.10.024. No abstract available.
PMID: 21195317
citation: Fuchs EJ. Haploidentical transplantation for hematologic malignancies: where do we stand? Hematology Am Soc Hematol Educ Program. 2012;2012:230-6. doi: 10.1182/asheducation-2012.1.230.
PMID: 23233586
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
mesh term: Leukemia, Myeloid, Acute