<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/NCT03821519</url>
  </required_header>
  <id_info>
    <org_study_id>EudraCT 2018-000716-24</org_study_id>
    <nct_id>NCT03821519</nct_id>
  </id_info>
  <brief_title>Infusion of Donor Derived Cytokine Induced Killer (CIK) Cells in Hematological Patients Relapsed After Haploidentical Stem Cell Transplant</brief_title>
  <acronym>Haplo-CIK</acronym>
  <official_title>Phase I/II Trial of Donor Derived Cytokine Induced Killer (CIK) Cells Infusion for Relapsed Hematologic Malignancy After Haploidentical Stem Cell Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>A.O. Ospedale Papa Giovanni XXIII</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>A.O. Ospedale Papa Giovanni XXIII</source>
  <oversight_info>
    <has_dmc>Yes</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>
      The haematological neoplasia relapse is the cause of higher mortality after allogeneic stem&#xD;
      cell transplantation (HSCT). When transplantation fails the most common therapeutic strategy&#xD;
      is to increase the antitumor activity of the donor's immune system through the infusion of&#xD;
      donor Lymphocytes (DLI). The use of DLI may limit the relapse, but may induce transplantation&#xD;
      disease against the host (GvHD), in 40-60% of patients. With advances in transplantation&#xD;
      procedures, the use of non-compatible (HLA-mismatched) haploidentical (aplo) donor cells has&#xD;
      become feasible and is increasing. However, strategies for immune control of relapse after&#xD;
      HSCT from haploidentical donor are hampered by the absence of prospective data that can guide&#xD;
      treatment and limit the induction of GvHD in the setting of the HLA difference between the&#xD;
      donor and the recipient. Cytokine-induced Killer Cells (CIK) are T lymphocytes from&#xD;
      haploidentical donor expressing CD56 (e.g., double positive cells at CD3 / CD56). CIK are a&#xD;
      product of advanced cell therapy (Advanced Therapeutic Medicinal Product, ATMP) for somatic&#xD;
      cell therapy and have a reduced histocompatibility (MHC) complex: are cytotoxic, anti-tumor&#xD;
      cells, possess the characteristics of both T cells and Natural Killer (NK) and show in vivo a&#xD;
      very strong cytolytic activity against leukemia, but a low reactivity against the host.&#xD;
      Therefore, this study has as its primary objective to investigate the safety of CIK cells&#xD;
      deriving from the donor, especially in terms of the onset of GvHD, used as a treatment for&#xD;
      relapse after transplantation with haploidentical stem cells. The study will allow to&#xD;
      evaluate the possibility of using CIK cells, at the indicated dose combination (5x10 * 6&#xD;
      cells / kg, 5x10 * 6 and 10x10 * 6 cells / kg) as an effective and safe therapy in the&#xD;
      context of haploidentical transplantation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Disease relapse is a major cause of mortality following allogeneic hematopoietic stem cell&#xD;
      transplantation (HSCT) for hematologic malignancies. When allogeneic transplant fails the&#xD;
      most common therapeutic strategy is to increase the anti-tumor activity of donor immune&#xD;
      system through infusion of donor lymphocytes (DLI). Use of DLI can effectively treat limited&#xD;
      relapses, but can induce graft-versus-host disease (GvHD) in the range of 40-60% of the&#xD;
      patients. With the advances in HSCT procedure, the use of HLA-mismatched (haplo) family&#xD;
      donors became feasible and extended the opportunity for HSCT to almost all patients lacking&#xD;
      an HLA-matched donor. Due to the promising results of the procedure and the easier access to&#xD;
      the donor, the number of haplo-HSCT transplant is steeply increasing. However, strategies&#xD;
      aiming at eliciting the immune control of the relapse after haplo-HSCT are hampered by&#xD;
      absence of prospective data that guide treatment and the fear of inducing GvHD in this&#xD;
      setting of profound HLA disparity between donor and recipient.&#xD;
&#xD;
        -  Despite the use of DLI in haplo-HSCT is not a standard practice, DLI are occasionally&#xD;
           empirically used, mainly due to the lack of alternative treatment.&#xD;
&#xD;
        -  Cytokine Induced Killer (CIK) cells are T lymphocytes expressing the CD56 marker, i.e.&#xD;
           CIK are CD3/CD56 double positive cells. CIK cells are produced in vitro by incubating&#xD;
           blood leukocytes according to a specific expansion protocol which includes initial&#xD;
           stimulation with Interferon-gamma and anti-CD3 antibody, followed by expansion with&#xD;
           (Interleukin-2) IL-2. CIK cells are non MHC restricted, cytotoxic, anti-tumoral cells&#xD;
           which share characteristics of both T and NK cells and show in vivo a very strong&#xD;
           cytolytic activity against leukemia, graft versus leukemia, while being essentially&#xD;
           devoid of graft versus host reactivity. They show a natural non-MHC restricted (T Cell&#xD;
           Receptor)TCR independent cytotoxicity against malignant targets cells, involving&#xD;
           perforin and granzyme release and NKG2D, as well as CD56 and other small target&#xD;
           molecules. In the past 15 years the investigators have extensively studied the use of&#xD;
           cytokine-induced killer (CIK) cells as alternative cellular therapy to treat disease&#xD;
           relapse after HSCT. The key feature of CIK cell therapy in the context of haplo- HSCT is&#xD;
           the lower risk of inducing GvHD compared to DLI, that could permit to avoid the&#xD;
           devastating effect of acute and chronic GvHD in terms of decreased survival, quality of&#xD;
           life, disability and need of additional care. Indeed, beyond the dramatic impact in the&#xD;
           quality and quantity of life of patients, costs for the health system of the management&#xD;
           of acute and chronic GvHD are exceedingly high. At this regard, CIK cells have been&#xD;
           regarded as the cellular therapy that is associated with a more favourable therapeutic&#xD;
           index compared to DLI.&#xD;
&#xD;
        -  In an early Phase I study the investigators observed remissions in 3 of 11 patients who&#xD;
           were treated with infusion of CIK cells at a time when malignant cells were detectable.&#xD;
           In each of these 3 cases, the patient had been previously treated unsuccessfully with&#xD;
           conventional DLI. Successful remission induction by infusion of CIK cells after&#xD;
           unsuccessful DLI suggests that the (Graft Versus Leukemia) GVL activity of CIK cells was&#xD;
           attributable to NK-T cells. In a subsequent phase I clinical trial was assessed the&#xD;
           feasibility of using CIK cells from HLA-matched sibling donors. Using a dose escalation&#xD;
           design, the investigators showed that CIK cells could be given at doses as high as&#xD;
           1x10^8 per kg recipient body weight without causing acute infusion-related toxicity. The&#xD;
           investigators recently reported the final results of a phase II multicenter pilot study,&#xD;
           showing that CIK cell treatment for the relapse after HSCT is effective with a low&#xD;
           toxicity in terms of GvHD compared to DLI. Importantly for the present proposal, in this&#xD;
           study, 5 patients were treated in the context of haplo- HSCT. These did not show any&#xD;
           different response or safety concern compared to other patients, suggesting the&#xD;
           feasibility of this approach in a haploidentical context. Similarly, another study of&#xD;
           CIK cellular therapy in HSCT including also patients with haploidentical donors&#xD;
           confirmed the feasibility and safety of this approach. Considering that infused T cells&#xD;
           are associated with risk of GvHD induction, especially in the haploidentical&#xD;
           transplantation setting, novel cellular therapies manipulated to minimize GvHD while&#xD;
           enhancing the graft-versus leukemia efficacy need to be tested in early phase clinical&#xD;
           trials. Thus, the aim of the present proposal is to use CIK cells as a platform for a&#xD;
           safe and effective cellular therapy in the context of haploidentical transplantation. As&#xD;
           no dose limiting toxicity has been reached in phase I/II studies and no clear&#xD;
           relationship among dose and both toxicity and response emerged so far, in the present&#xD;
           study the investigators planned to use the final standard dose of our previous phase II&#xD;
           study of 5x106 cells/kg, 5x10^6 and 10x10^6 cells/kg with no schedule modification .&#xD;
           Three infusion of CIK cells will be administered every 3 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 13, 2019</start_date>
  <completion_date type="Anticipated">May 2023</completion_date>
  <primary_completion_date type="Anticipated">May 2022</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>
    <intervention_model_description>Patients relapse after haplo-HSCT for hematologic malignancies</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of deaths related to study treatment death</measure>
    <time_frame>Within 3 weeks after the last CIK cells infusion.</time_frame>
    <description>Death, with related attributed cause of the event (e.g. treatment, toxicities, disease, other) will be assessed</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of grade &gt;=III acute GvHD</measure>
    <time_frame>Within 3 weeks after the last CIK cells infusion.</time_frame>
    <description>Will be collected: date of onset, organ involvement and maximum grade of acute GVHD Staging and Grading of Acute GvHD will be evaluated according to Glucksberg.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of grade &gt;= III acute GvHD</measure>
    <time_frame>at +100 days after the last infusion of CIK cells</time_frame>
    <description>Will be collected: date of onset, organ involvement and maximum grade of acute GVHD. Staging and Grading of Acute GvHD will be evaluated according to Glucksberg.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of any grade acute GvHD</measure>
    <time_frame>at day +100 after last CIK infusion</time_frame>
    <description>Will be collected: date of onset, organ involvement and maximum grade of acute GVHD. Staging and Grading of Acute GvHD will be evaluated according to Glucksberg criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of any grade chronic GvHD</measure>
    <time_frame>at days +100, +365 after last CIK infusion</time_frame>
    <description>Chronic GVHD will be evaluated according to the National Institutes of Health&#xD;
Consensus Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:&#xD;
Diagnosis and Staging Working Group Report. The following data will be collected: date of onset, organ involvement, maximum organ score and maximum global scoring of chronic GVHD.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse events (AEs) and laboratory abnormalities.</measure>
    <time_frame>Up to 365 days from last CIK infusion</time_frame>
    <description>Number, causality and intensity of all adverse events occurring during the study will be evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.03 and MedDRA code (current version).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of Response of Disease</measure>
    <time_frame>at day +21, +100 and +365 after the last CIK cell infusion, or before if clinically indicated according to Investigator's judgment. For patients with acute leukemia disease response will be evaluated also after 60 days from the last CIK infusion.</time_frame>
    <description>Response of Disease will be assessed based on detection of any evidence of molecular, cytogenetic, chimerism or hematologic disease progression, including loss of complete donor chimerism.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>Since enrollment up to 1 year after last cells infusion (day +365).</time_frame>
    <description>Progression free survival will be estimated as the probability of patients of being alive free of progression (stable disease) or free of disease since enrollment up to&#xD;
1 year after last cells infusion (day +365). Thus, death for disease, disease relapse and disease progression are treated as events. (Death for other cause than disease will treated as competing events). Patients alive, patients in stable disease and those free of disease at their last follow-up will be censored.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Since enrollment up to 365 days after last CIK infusion</time_frame>
    <description>Overall survival will be estimated as the probability of survival irrespective of disease state since enrollment up to 1 year after last cells infusion (day +365).&#xD;
Patients alive at their last follow-up are censored.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Relapsed Hematologic Malignancy</condition>
  <arm_group>
    <arm_group_label>Relapsed after Haplo transplant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>donor-derived CIK cells</intervention_name>
    <description>Treatment plan will be based on three infusions of donor derived CIK cells given by 3 weeks intervals at increasing dose levels. No dose changes are allowed and the following planned dose levels will be administered to each patient enrolled: 5x106, 5x106 and 10x106 cells/Kg according to the dose escalating program</description>
    <arm_group_label>Relapsed after Haplo transplant</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female patients 18 years or older&#xD;
&#xD;
          2. Patients treated with haploidentical allogeneic transplantation for hematologic&#xD;
             malignancies, excluding Chronic Myeloid Leukemia (CML), such as acute myeloid leukemia&#xD;
             (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), myelofibrosis (MF)&#xD;
             and myelodysplastic syndrome (MDS)&#xD;
&#xD;
          3. To be enrolled to the safety run-in cohort, patients must have:&#xD;
&#xD;
             - Evidence of relapsed disease after allogeneic transplantation, including molecular,&#xD;
             cytogenetic or overt hematologic relapse&#xD;
&#xD;
             To be enrolled to the phase II cohort, patients must have:&#xD;
&#xD;
               -  Evidence of relapsed disease after allogeneic transplantation, including,&#xD;
                  molecular, cytogenetic or overt hematologic relapse, or&#xD;
&#xD;
               -  Mixed chimerism after the day +90, defined as &lt;75% donor in unfractionated bone&#xD;
                  marrow and/or &lt;75% donor in unfractionated Peripheral blood (PB) and/or &lt;75%&#xD;
                  donor in fractionated CD3+ peripheral blood.&#xD;
&#xD;
          4. Availability of a donor willing to donate peripheral blood mononuclear cells&#xD;
&#xD;
          5. Withdrawn of immune suppression at least 3 weeks before the beginning of the cell&#xD;
             therapy program&#xD;
&#xD;
          6. Written informed consent prior to any study procedures being performed&#xD;
&#xD;
          7. For female patients:&#xD;
&#xD;
               1. being postmenopausal for at least 1 year before the screening visit,OR&#xD;
&#xD;
               2. being surgically sterile, OR&#xD;
&#xD;
               3. if they are of childbearing potential, must agree to practice highly effective&#xD;
                  method of contraception and one additional effective (barrier) method from the&#xD;
                  time of signing the informed consent until the end of study. Highly effective&#xD;
                  method of contraception includes: (i) combined (estrogen and progestogen&#xD;
                  containing) hormonal contraception associated with inhibition of ovulation: oral,&#xD;
                  intravaginal, transdermal; (ii) progestogen-only hormonal contraception&#xD;
                  associated with inhibition of ovulation: oral, injectable, implantable&#xD;
                  (intrauterine device (IUD), intrauterine hormone-releasing system (IUS),&#xD;
                  bilateral tubal occlusion, vasectomized partner, sexual abstinence) OR&#xD;
&#xD;
               4. must agree to practice true abstinence, when this is in line with the preferred&#xD;
                  and usual lifestyle of the subject from the time of signing the informed consent&#xD;
                  until the end of study. [Periodic abstinence (eg, calendar, ovulation,&#xD;
                  symptothermal, postovulation methods), withdrawal, spermicides only, and&#xD;
                  lactational amenorrhea are not acceptable methods of contraception. Female and&#xD;
                  male condoms should not be used together.]&#xD;
&#xD;
          8. For male patients, even if surgically sterilized (i.e., status postvasectomy): a) with&#xD;
             female partners of childbearing potential: must agree to practice barrier&#xD;
             contraception (condom with or without spermicide) from the time of signing the&#xD;
             informed consent until the end of study and his female partner must agree to practice&#xD;
             method of contraception including one of the following: estrogen and progestogen&#xD;
             containing hormonal contraception; inhibition of ovulation: oral, intravaginal,&#xD;
             transdermal; progestogen-only hormonal contraception associated with inhibition of&#xD;
             ovulation: oral, injectable, implantable (intrauterine device (IUD), intrauterine&#xD;
             hormone-releasing system (IUS), bilateral tubal occlusion) from the time of signing&#xD;
             the informed consent until the end of study.b) must agree to practice true abstinence,&#xD;
             when this is in line with the preferred and usual lifestyle of the subject from the&#xD;
             time of signing the informed consent until the end of study. [Periodic abstinence (eg,&#xD;
             calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides&#xD;
             only, and lactational amenorrhea are not acceptable methods of contraception. Female&#xD;
             and male condoms should not be used together.] c) must agree to refrain from donating&#xD;
             sperm&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        The presence of any of the following will exclude a subject from study enrolment 1. Donors&#xD;
        positive for HIV, (Hepatitis B virus) HBV, (Hepatitis C virus) HCV, Treponema or unfit to&#xD;
        donate peripheral blood mononuclear cells 2. Patients with active grade 2 or more acute or&#xD;
        moderate chronic GVHD at study entry or before CIK infusion 3. Patients with rapidly&#xD;
        progressive disease or not controlled by palliative supportive treatments, including&#xD;
        chemotherapy, and with life expectancy less than 8 weeks 4. Any serious medical or&#xD;
        psychiatric illness, including drug or alcohol abuse, that could, in the investigator's&#xD;
        opinion, potentially interfere with the completion of treatment according to this protocol&#xD;
&#xD;
        -&#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>Alessandro Rambaldi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>A.O. Ospedale Papa Giovanni XXIII</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Alessandro Rambaldi, MD</last_name>
    <phone>+39 035 2673683</phone>
    <email>arambaldi@asst-pg23.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Federico Lussana, MD.</last_name>
    <phone>+39 035 2673678</phone>
    <email>flussana@asst-pg23.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>A O Papa Giovanni XXIII</name>
      <address>
        <city>Bergamo</city>
        <zip>24127</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alessandro Rambaldi, MD</last_name>
      <phone>035 2673683</phone>
      <phone_ext>0039</phone_ext>
      <email>arambaldi@asst-pg23.it</email>
    </contact>
    <contact_backup>
      <last_name>Federico Lussana, MD</last_name>
      <phone>035 2673678</phone>
      <phone_ext>0039</phone_ext>
      <email>flussana@asst-pg23.it</email>
    </contact_backup>
    <investigator>
      <last_name>Federico Lussana, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Giuseppe Gritti, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Martino Introna, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Josee Golay, Biol.SC</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
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  <verification_date>December 2021</verification_date>
  <study_first_submitted>January 22, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 29, 2019</study_first_posted>
  <last_update_submitted>December 22, 2021</last_update_submitted>
  <last_update_submitted_qc>December 22, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 23, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>A.O. Ospedale Papa Giovanni XXIII</investigator_affiliation>
    <investigator_full_name>Rambaldi Alessandro</investigator_full_name>
    <investigator_title>Head Hematology and Bone Marrow Transplant Unit</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Hematologic Neoplasms</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/NCT03821519
org study id: EudraCT 2018-000716-24
nct id: NCT03821519
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The haematological neoplasia relapse is the cause of higher mortality after allogeneic stem
      cell transplantation (HSCT). When transplantation fails the most common therapeutic strategy
      is to increase the antitumor activity of the donor's immune system through the infusion of
      donor Lymphocytes (DLI). The use of DLI may limit the relapse, but may induce transplantation
      disease against the host (GvHD), in 40-60% of patients. With advances in transplantation
      procedures, the use of non-compatible (HLA-mismatched) haploidentical (aplo) donor cells has
      become feasible and is increasing. However, strategies for immune control of relapse after
      HSCT from haploidentical donor are hampered by the absence of prospective data that can guide
      treatment and limit the induction of GvHD in the setting of the HLA difference between the
      donor and the recipient. Cytokine-induced Killer Cells (CIK) are T lymphocytes from
      haploidentical donor expressing CD56 (e.g., double positive cells at CD3 / CD56). CIK are a
      product of advanced cell therapy (Advanced Therapeutic Medicinal Product, ATMP) for somatic
      cell therapy and have a reduced histocompatibility (MHC) complex: are cytotoxic, anti-tumor
      cells, possess the characteristics of both T cells and Natural Killer (NK) and show in vivo a
      very strong cytolytic activity against leukemia, but a low reactivity against the host.
      Therefore, this study has as its primary objective to investigate the safety of CIK cells
      deriving from the donor, especially in terms of the onset of GvHD, used as a treatment for
      relapse after transplantation with haploidentical stem cells. The study will allow to
      evaluate the possibility of using CIK cells, at the indicated dose combination (5x10 * 6
      cells / kg, 5x10 * 6 and 10x10 * 6 cells / kg) as an effective and safe therapy in the
      context of haploidentical transplantation.
Disease relapse is a major cause of mortality following allogeneic hematopoietic stem cell
      transplantation (HSCT) for hematologic malignancies. When allogeneic transplant fails the
      most common therapeutic strategy is to increase the anti-tumor activity of donor immune
      system through infusion of donor lymphocytes (DLI). Use of DLI can effectively treat limited
      relapses, but can induce graft-versus-host disease (GvHD) in the range of 40-60% of the
      patients. With the advances in HSCT procedure, the use of HLA-mismatched (haplo) family
      donors became feasible and extended the opportunity for HSCT to almost all patients lacking
      an HLA-matched donor. Due to the promising results of the procedure and the easier access to
      the donor, the number of haplo-HSCT transplant is steeply increasing. However, strategies
      aiming at eliciting the immune control of the relapse after haplo-HSCT are hampered by
      absence of prospective data that guide treatment and the fear of inducing GvHD in this
      setting of profound HLA disparity between donor and recipient.

        -  Despite the use of DLI in haplo-HSCT is not a standard practice, DLI are occasionally
           empirically used, mainly due to the lack of alternative treatment.

        -  Cytokine Induced Killer (CIK) cells are T lymphocytes expressing the CD56 marker, i.e.
           CIK are CD3/CD56 double positive cells. CIK cells are produced in vitro by incubating
           blood leukocytes according to a specific expansion protocol which includes initial
           stimulation with Interferon-gamma and anti-CD3 antibody, followed by expansion with
           (Interleukin-2) IL-2. CIK cells are non MHC restricted, cytotoxic, anti-tumoral cells
           which share characteristics of both T and NK cells and show in vivo a very strong
           cytolytic activity against leukemia, graft versus leukemia, while being essentially
           devoid of graft versus host reactivity. They show a natural non-MHC restricted (T Cell
           Receptor)TCR independent cytotoxicity against malignant targets cells, involving
           perforin and granzyme release and NKG2D, as well as CD56 and other small target
           molecules. In the past 15 years the investigators have extensively studied the use of
           cytokine-induced killer (CIK) cells as alternative cellular therapy to treat disease
           relapse after HSCT. The key feature of CIK cell therapy in the context of haplo- HSCT is
           the lower risk of inducing GvHD compared to DLI, that could permit to avoid the
           devastating effect of acute and chronic GvHD in terms of decreased survival, quality of
           life, disability and need of additional care. Indeed, beyond the dramatic impact in the
           quality and quantity of life of patients, costs for the health system of the management
           of acute and chronic GvHD are exceedingly high. At this regard, CIK cells have been
           regarded as the cellular therapy that is associated with a more favourable therapeutic
           index compared to DLI.

        -  In an early Phase I study the investigators observed remissions in 3 of 11 patients who
           were treated with infusion of CIK cells at a time when malignant cells were detectable.
           In each of these 3 cases, the patient had been previously treated unsuccessfully with
           conventional DLI. Successful remission induction by infusion of CIK cells after
           unsuccessful DLI suggests that the (Graft Versus Leukemia) GVL activity of CIK cells was
           attributable to NK-T cells. In a subsequent phase I clinical trial was assessed the
           feasibility of using CIK cells from HLA-matched sibling donors. Using a dose escalation
           design, the investigators showed that CIK cells could be given at doses as high as
           1x10^8 per kg recipient body weight without causing acute infusion-related toxicity. The
           investigators recently reported the final results of a phase II multicenter pilot study,
           showing that CIK cell treatment for the relapse after HSCT is effective with a low
           toxicity in terms of GvHD compared to DLI. Importantly for the present proposal, in this
           study, 5 patients were treated in the context of haplo- HSCT. These did not show any
           different response or safety concern compared to other patients, suggesting the
           feasibility of this approach in a haploidentical context. Similarly, another study of
           CIK cellular therapy in HSCT including also patients with haploidentical donors
           confirmed the feasibility and safety of this approach. Considering that infused T cells
           are associated with risk of GvHD induction, especially in the haploidentical
           transplantation setting, novel cellular therapies manipulated to minimize GvHD while
           enhancing the graft-versus leukemia efficacy need to be tested in early phase clinical
           trials. Thus, the aim of the present proposal is to use CIK cells as a platform for a
           safe and effective cellular therapy in the context of haploidentical transplantation. As
           no dose limiting toxicity has been reached in phase I/II studies and no clear
           relationship among dose and both toxicity and response emerged so far, in the present
           study the investigators planned to use the final standard dose of our previous phase II
           study of 5x106 cells/kg, 5x10^6 and 10x10^6 cells/kg with no schedule modification .
           Three infusion of CIK cells will be administered every 3 weeks.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Patients relapse after haplo-HSCT for hematologic malignancies
primary purpose: Treatment
masking: None (Open Label)
measure: Number of deaths related to study treatment death
time frame: Within 3 weeks after the last CIK cells infusion.
description: Death, with related attributed cause of the event (e.g. treatment, toxicities, disease, other) will be assessed
measure: Incidence of grade >=III acute GvHD
time frame: Within 3 weeks after the last CIK cells infusion.
description: Will be collected: date of onset, organ involvement and maximum grade of acute GVHD Staging and Grading of Acute GvHD will be evaluated according to Glucksberg.
measure: Incidence of grade >= III acute GvHD
time frame: at +100 days after the last infusion of CIK cells
description: Will be collected: date of onset, organ involvement and maximum grade of acute GVHD. Staging and Grading of Acute GvHD will be evaluated according to Glucksberg.
measure: Incidence of any grade acute GvHD
time frame: at day +100 after last CIK infusion
description: Will be collected: date of onset, organ involvement and maximum grade of acute GVHD. Staging and Grading of Acute GvHD will be evaluated according to Glucksberg criteria.
measure: Incidence of any grade chronic GvHD
time frame: at days +100, +365 after last CIK infusion
description: Chronic GVHD will be evaluated according to the National Institutes of Health
Consensus Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:
Diagnosis and Staging Working Group Report. The following data will be collected: date of onset, organ involvement, maximum organ score and maximum global scoring of chronic GVHD.
measure: Incidence of Adverse events (AEs) and laboratory abnormalities.
time frame: Up to 365 days from last CIK infusion
description: Number, causality and intensity of all adverse events occurring during the study will be evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.03 and MedDRA code (current version).
measure: Evaluation of Response of Disease
time frame: at day +21, +100 and +365 after the last CIK cell infusion, or before if clinically indicated according to Investigator's judgment. For patients with acute leukemia disease response will be evaluated also after 60 days from the last CIK infusion.
description: Response of Disease will be assessed based on detection of any evidence of molecular, cytogenetic, chimerism or hematologic disease progression, including loss of complete donor chimerism.
measure: Progression Free Survival
time frame: Since enrollment up to 1 year after last cells infusion (day +365).
description: Progression free survival will be estimated as the probability of patients of being alive free of progression (stable disease) or free of disease since enrollment up to
1 year after last cells infusion (day +365). Thus, death for disease, disease relapse and disease progression are treated as events. (Death for other cause than disease will treated as competing events). Patients alive, patients in stable disease and those free of disease at their last follow-up will be censored.
measure: Overall Survival
time frame: Since enrollment up to 365 days after last CIK infusion
description: Overall survival will be estimated as the probability of survival irrespective of disease state since enrollment up to 1 year after last cells infusion (day +365).
Patients alive at their last follow-up are censored.
arm group label: Relapsed after Haplo transplant
arm group type: Experimental
intervention type: Biological
intervention name: donor-derived CIK cells
description: Treatment plan will be based on three infusions of donor derived CIK cells given by 3 weeks intervals at increasing dose levels. No dose changes are allowed and the following planned dose levels will be administered to each patient enrolled: 5x106, 5x106 and 10x106 cells/Kg according to the dose escalating program
arm group label: Relapsed after Haplo transplant
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alessandro Rambaldi, MD
role: Principal Investigator
affiliation: A.O. Ospedale Papa Giovanni XXIII
last name: Alessandro Rambaldi, MD
phone: +39 035 2673683
email: arambaldi@asst-pg23.it
last name: Federico Lussana, MD.
phone: +39 035 2673678
email: flussana@asst-pg23.it
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Italy
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responsible party type: Principal Investigator
investigator affiliation: A.O. Ospedale Papa Giovanni XXIII
investigator full name: Rambaldi Alessandro
investigator title: Head Hematology and Bone Marrow Transplant Unit
mesh term: Neoplasms
mesh term: Hematologic Neoplasms