<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/NCT03823365</url>
  </required_header>
  <id_info>
    <org_study_id>EudraCT Nr 2018-000086-36</org_study_id>
    <nct_id>NCT03823365</nct_id>
  </id_info>
  <brief_title>Blinatumomab Expanded T-cells (BET) in Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia</brief_title>
  <acronym>BET2017</acronym>
  <official_title>Immune Reconstitution With Blinatumomab Expanded T-cells (BET) After First-line Treatment With Fludarabine-Cyclophosphamide-Rituximab or Bendamustine-Rituximab in CD20+ Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia: a Phase I Study</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>
      Non-Hodgkin CD20 + Indolent Lymphoma (iNHL) and Chronic Lymphatic Leukemia (CLL) are the most&#xD;
      frequent neoplasms of B lymphocytes. They include various histologies (follicular NHL,&#xD;
      marginal zone NHL and Lymphocytic NHL/ CLL) characterized by a chronic course and prolonged&#xD;
      survival, but while patients with a limited disease could be cured, those with advanced&#xD;
      disease or relapsed after localized radiation therapy are generally considered untreatable&#xD;
      through standard treatments. The options for first-line therapy include the use of the FCR&#xD;
      scheme, based on Fludarabine, Cyclophosphamide and Rituximab or the BR, with Bendamustine and&#xD;
      Rituximab. Despite good results, treatment with these two regimens (FCR or BR) is associated&#xD;
      with severe immunosuppression which worsens the immunological dysfunction already present at&#xD;
      diagnosis in several patients. It has been shown previously that the adoptive transfer of ex&#xD;
      vivo anti-CD3/CD28 co-stimulated autologous T cells can successfully accelerate a robust&#xD;
      early recovery of T cells after autologous transplantation in multiple myeloma. These&#xD;
      CD3/CD28 expanded T cells cannot however be used in NHLi and CLL due to the presence of&#xD;
      contaminating tumor cells in the preparation. Polyclonal T cells can also be expanded in&#xD;
      vitro in presence of Blinatumomab and recombinant human IL2 (rhIL2) and have been called BET&#xD;
      (Blinatumomab-expanded T cells). They are a product of Advanced Therapeutic Medicinal Product&#xD;
      (ATMP) composed of polyclonal CD8 and CD4 T cells that are still functional and devoid of&#xD;
      contaminating CD19+ neoplastic cells. Based on these data, it was hypothesized that infusion&#xD;
      of BET in patients with iNHL/CLL, after the first treatment line (with FCR or BR), could&#xD;
      induce adequate immunological recovery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      -  Indolent non-Hodgkin lymphomas (iNHL) and chronic lymphocytic leukemia (CLL) are among&#xD;
           the most frequent B-cell neoplasms. They include different histologies (i.e. follicular&#xD;
           NHL, marginal zone NHL and lymphocytic NHL/CLL) characterized by chronic course and&#xD;
           prolonged survival. While some patients with limited stage disease may be cured, those&#xD;
           presenting with advance stage or relapsing after local radiotherapy are generally&#xD;
           considered not curable with standard treatments.&#xD;
&#xD;
        -  First-line treatment of CLL/LL is currently based on the biologic profile of the&#xD;
           disease. Excluding high risk patients harboring the del(17p) and/or TP53 mutations,&#xD;
           first line chemoimmunotherapy options includes the use of either fludarabine,&#xD;
           cyclophosphamide and rituximab (FCR) or BR. Despite the good results, treatment with FCR&#xD;
           or BR regimens is associated with severe immunosuppression that worsens the immune&#xD;
           dysfunctions already present at diagnosis in several patients. In the CLL phase III&#xD;
           trial, high frequency of grade 3/4 infections was reported in FCR and BR, being observed&#xD;
           in 39% and 25% of the patients, respectively. In iNHL, infections have been observed in&#xD;
           37-55% of the patients treated with BR, with grade 3/4 events in 7-12% of the cases.&#xD;
&#xD;
        -  Blinatumomab-expanded T cells (BET) are an Advanced Therapeutic Medicinal Product (ATMP)&#xD;
           composed of autologous polyclonal activated T cells expanded in vitro using blinatumomab&#xD;
           and rhIL-2, to be used for somatic cell therapy in an autologous setting. Indeed the&#xD;
           investigators have developed a method using blinatumomab and rhIL2 to expand and&#xD;
           activate ex vivo the T lymphocytes present in the peripheral blood from CLL and iNHL&#xD;
           patients, while at the same time eliminating contaminating CD19+ neoplastic cells. The&#xD;
           resulting polyclonal T cells can be used for immuno-reconstitution purposes. The Cell&#xD;
           Factory &quot;Centro di Terapia Cellulare G. Lanzani&quot; showed the functionality of BET in a&#xD;
           mouse B-cell NHL xenograft model. Upon in vivo inoculation, BET retain functional&#xD;
           activity: upon engagement with blinatumomab in vivo, BET were able to efficiently kill&#xD;
           the B-cell NHL cells. Importantly, BET did not showed any toxicity in animals, even at&#xD;
           high doses and in presence of blinatumomab.&#xD;
&#xD;
        -  About clinical experience, it has been previously shown that adoptive transfer of ex&#xD;
           vivo (anti-CD3/anti-CD28) co-stimulated autologous T cells can successfully accelerate a&#xD;
           robust T-cell recovery early after autologous transplant for multiple myeloma. However,&#xD;
           the invariable presence of clonal disease in cell product of iNHL/CLL patients hampered&#xD;
           this possibility up to now. In contrast BET cell expansion leads to lysis of&#xD;
           contaminating neoplastic cells. BET can therefore be expanded from CLL patients&#xD;
           peripheral blood in GMP (Good Manufacturing Practice) conditions for adoptive therapy.&#xD;
           Starting from only 10 mL of peripheral blood, a mean 5.15x108 CD3+ cells can be expanded&#xD;
           in 3 weeks with a rapid clearance of CLL contamination. The resulting&#xD;
           blinatumomab-expanded T cells (BET) were polyclonal CD4+ and CD8+ T cells and mostly&#xD;
           effector and central memory cells. They showed a normalized expression of the synapse&#xD;
           inhibitors CD272 and CD279 compared with starting T cells and were functionally active,&#xD;
           showing cytotoxicity against CD19+ targets in presence of Blinatumomab in vitro and in&#xD;
           vivo.&#xD;
&#xD;
        -  On the basis of these data the investigators hypothesize that BET infusion after&#xD;
           first-line treatment of iNHL/CLL with either FCR or BR could lead to an adequate immune&#xD;
           recovery.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 17, 2018</start_date>
  <completion_date type="Anticipated">November 2022</completion_date>
  <primary_completion_date type="Actual">November 11, 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>
    <intervention_model_description>CD20+ Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia Patients After First-line Treatment with Fludarabine-Cyclophosphamide-Rituximab or Bendamustine-Rituximab.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>This study is a phase I open-label, single center study. The patient population will consist of adults diagnosed with indolent non-Hodgkin lymphomas (iNHL) or chronic lymphocytic leukemia (CLL) in need of first line treatment consisting of either FCR or BR as per investigator assessment. Chemotherapy treatment will consist of a minimum of 4 to a maximum of 6 cycles of standard FCR or BR.Patients will be enrolled in the study after the last planned cycle of chemo-immunotherapy and, if eligibility criteria are met, BET dose level will be assigned.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of grade 3 or 4 adverse events (AE) possibly related to therapy</measure>
    <time_frame>The period of observation is during 14 days after BET infusion</time_frame>
    <description>Description and grading of all adverse events will be based on the NCI -CTCAE v4.03 and MedDra code (current version).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Adverse event (AE) and laboratory abnormalities.</measure>
    <time_frame>From date of study start up to 180 days after BET infusion</time_frame>
    <description>Number, causality and intensity of all adverse events 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 Optimal Biological Dose (ODB) of BET cells</measure>
    <time_frame>+90 days after infusion</time_frame>
    <description>OBD of BET will be defined as the absolute number of BET cell that will allow a CD3+ count of &gt; 600 x106/L at +90 days after infusion in at least 70% of the patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of general Immune Reconstitution after BET infusion</measure>
    <time_frame>at +0 (4 hours), +30, +90 and +180 days after infusion</time_frame>
    <description>Absolute numbers of B, T, and NK cells reconstitution and its correlation with BET cell infused and its composition (in terms of T-cell subsets and NK cells)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of ex vivo transfer of anti-viral immunity</measure>
    <time_frame>at +0 (4 hours), +30, +90 and +180 days after infusion</time_frame>
    <description>Ex vivo transfer of anti-viral immunity in terms of tetramer-based quantification of CMV-specific CD8+ T lymphocytes (this will be done only for CMV positive patients for whom CMV specific tetramers stain positive in starting peripheral blood or BET).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia</condition>
  <arm_group>
    <arm_group_label>Indolent NHL or CLL patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Adults diagnosed with indolent non-Hodgkin lymphomas (iNHL) or chronic lymphocytic leukemia (CLL) in need of first line treatment consisting of either FCR or BR as per investigator assessment</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Blinatumomab Expanded T-cells (BET)</intervention_name>
    <description>Two to five days after the last chemotherapy infusion, BET will be administered. An accelerated titration dose escalation design will be used. During dose escalation, up to four dose levels (see table) will be evaluated or until (Maximum Tolerated Dose) MTD is reached.&#xD;
Dose level BET dose(Counted on CD3+ cells)&#xD;
(starting dose) 3.0 x 109&#xD;
6.0 x 109&#xD;
9.0 x 109&#xD;
12.0 x 109</description>
    <arm_group_label>Indolent NHL or CLL patients</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1. Male or female patients 18 years or older 2. Confirmed diagnosis of the following&#xD;
             CD20+ iNHL or CLL according to (World Health Organization ) WHO criteria:&#xD;
&#xD;
               -  Follicular NHL&#xD;
&#xD;
               -  Marginal zone NHL (splenic, extranodal or nodal)&#xD;
&#xD;
               -  Lymphocytic lymphoma/CLL without del(17p) or TP53 mutations 3. No previous&#xD;
                  chemotherapy. Previous radiotherapy for localized disease is admitted 4.&#xD;
                  Requirement for treatment:&#xD;
&#xD;
               -  For CLL, active disease is defined as meeting at least one of the International&#xD;
                  Workshop on CLL guidelines (Hallek et al., 2008)&#xD;
&#xD;
               -  For iNHL, active disease is defined as meeting at least one of the Groupe&#xD;
                  d'Etudes des Lymphomes Folliculaires (GELF) criteria (Brice et al., 1997) 5.&#xD;
                  Indication to treatment with either fludarabine, cyclophosphamide and rituximab&#xD;
                  or bendamustine and rituximab 6. Presence of peripheral blood clone ≥10% of total&#xD;
                  lymphocytes (with absolute lymphocyte count &gt;800 x106/L) at study entrance 7.&#xD;
                  Written informed consent prior to any study procedures being performed&#xD;
&#xD;
        Additional inclusion criteria to be met at study entry (i.e. before BET infusion):&#xD;
&#xD;
        8. Achieving at least a partial response after three chemo-immunotherapy cycles 9. Absence&#xD;
        of any serious therapy-related complications that might affect interpretation of the&#xD;
        results of the study or render the subject at high risk from treatment complications 10.&#xD;
        Production of adequate BET numbers (counted on CD3+ cells: ≥0.5 x 109) 11. For female&#xD;
        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 method&#xD;
             of contraception and one additional effective (barrier) method from the time of&#xD;
             signing the informed consent until the end of study. Highly effective method of&#xD;
             contraception includes: (i) combined (estrogen and progestogen containing) hormonal&#xD;
             contraception associated with inhibition of ovulation: oral, intravaginal,&#xD;
             transdermal; (ii) progestogen-only hormonal contraception associated with inhibition&#xD;
             of ovulation: oral, injectable, implantable (intrauterine device (IUD), intrauterine&#xD;
             hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner,&#xD;
             sexual abstinence) OR&#xD;
&#xD;
          4. must agree to practice true abstinence, when this is in line with the preferred and&#xD;
             usual lifestyle of the subject from the time of signing the informed consent until the&#xD;
             end of study. [Periodic abstinence (eg, calendar, ovulation, symptothermal,&#xD;
             postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are&#xD;
             not acceptable methods of contraception. Female and male condoms should not be used&#xD;
             together.]&#xD;
&#xD;
        For male patients, even if surgically sterilized (i.e., status postvasectomy):&#xD;
&#xD;
          1. with 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.&#xD;
&#xD;
          2. must agree to practice true abstinence, when this is in line with the preferred and&#xD;
             usual lifestyle of the subject from the time of signing the informed consent until the&#xD;
             end of study. [Periodic abstinence (eg, calendar, ovulation, symptothermal,&#xD;
             postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are&#xD;
             not acceptable methods of contraception. Female and male condoms should not be used&#xD;
             together.]&#xD;
&#xD;
          3. must agree to refrain from donating sperm&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. ECOG (Eastern Cooperative Oncology Group) Performance Status &gt;2&#xD;
&#xD;
          2. Active central nervous system (CNS) disease&#xD;
&#xD;
          3. Calculated creatinine clearance (by Cockroft-Gault) of &lt; 50 ml/min or serum creatinine&#xD;
             &gt; 1.5x ULN (Upper Limit of Normal )&#xD;
&#xD;
          4. Concomitant or previous diagnosis of autoimmune hemolytic anemia or thrombocytopenia&#xD;
&#xD;
          5. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,&#xD;
             type I diabetes mellitus, residual hypothyroidism due to autoimmune condition&#xD;
             requiring the sole hormone replacement are allowed to participate. Psoriasis requiring&#xD;
             systemic treatment, or conditions expected to recur at the presence of an external&#xD;
             trigger are excluded.&#xD;
&#xD;
          6. Known infection with human immunodeficiency virus (HIV) or treponema&#xD;
&#xD;
          7. Active hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections&#xD;
&#xD;
          8. Any suspected or known active infection&#xD;
&#xD;
          9. History of other diseases, metabolic dysfunctions, physical examination findings, or&#xD;
             clinical laboratory findings giving reasonable suspicion of a disease or condition&#xD;
             that contraindicates use of an investigational drug or that might affect&#xD;
             interpretation of the results of the study or render the subject at high risk from&#xD;
             treatment complications&#xD;
&#xD;
         10. Residual CD19+ B cells in BET final cell product ≥0.5%&#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>ASST - Papa Giovanni XXIII</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ASST - Papa Giovanni XXIII</name>
      <address>
        <city>Bergamo</city>
        <zip>24127</zip>
        <country>Italy</country>
      </address>
    </facility>
  </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 29, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 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</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Blinatumomab</mesh_term>
  </intervention_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/NCT03823365
org study id: EudraCT Nr 2018-000086-36
nct id: NCT03823365
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Non-Hodgkin CD20 + Indolent Lymphoma (iNHL) and Chronic Lymphatic Leukemia (CLL) are the most
      frequent neoplasms of B lymphocytes. They include various histologies (follicular NHL,
      marginal zone NHL and Lymphocytic NHL/ CLL) characterized by a chronic course and prolonged
      survival, but while patients with a limited disease could be cured, those with advanced
      disease or relapsed after localized radiation therapy are generally considered untreatable
      through standard treatments. The options for first-line therapy include the use of the FCR
      scheme, based on Fludarabine, Cyclophosphamide and Rituximab or the BR, with Bendamustine and
      Rituximab. Despite good results, treatment with these two regimens (FCR or BR) is associated
      with severe immunosuppression which worsens the immunological dysfunction already present at
      diagnosis in several patients. It has been shown previously that the adoptive transfer of ex
      vivo anti-CD3/CD28 co-stimulated autologous T cells can successfully accelerate a robust
      early recovery of T cells after autologous transplantation in multiple myeloma. These
      CD3/CD28 expanded T cells cannot however be used in NHLi and CLL due to the presence of
      contaminating tumor cells in the preparation. Polyclonal T cells can also be expanded in
      vitro in presence of Blinatumomab and recombinant human IL2 (rhIL2) and have been called BET
      (Blinatumomab-expanded T cells). They are a product of Advanced Therapeutic Medicinal Product
      (ATMP) composed of polyclonal CD8 and CD4 T cells that are still functional and devoid of
      contaminating CD19+ neoplastic cells. Based on these data, it was hypothesized that infusion
      of BET in patients with iNHL/CLL, after the first treatment line (with FCR or BR), could
      induce adequate immunological recovery.
-  Indolent non-Hodgkin lymphomas (iNHL) and chronic lymphocytic leukemia (CLL) are among
           the most frequent B-cell neoplasms. They include different histologies (i.e. follicular
           NHL, marginal zone NHL and lymphocytic NHL/CLL) characterized by chronic course and
           prolonged survival. While some patients with limited stage disease may be cured, those
           presenting with advance stage or relapsing after local radiotherapy are generally
           considered not curable with standard treatments.

        -  First-line treatment of CLL/LL is currently based on the biologic profile of the
           disease. Excluding high risk patients harboring the del(17p) and/or TP53 mutations,
           first line chemoimmunotherapy options includes the use of either fludarabine,
           cyclophosphamide and rituximab (FCR) or BR. Despite the good results, treatment with FCR
           or BR regimens is associated with severe immunosuppression that worsens the immune
           dysfunctions already present at diagnosis in several patients. In the CLL phase III
           trial, high frequency of grade 3/4 infections was reported in FCR and BR, being observed
           in 39% and 25% of the patients, respectively. In iNHL, infections have been observed in
           37-55% of the patients treated with BR, with grade 3/4 events in 7-12% of the cases.

        -  Blinatumomab-expanded T cells (BET) are an Advanced Therapeutic Medicinal Product (ATMP)
           composed of autologous polyclonal activated T cells expanded in vitro using blinatumomab
           and rhIL-2, to be used for somatic cell therapy in an autologous setting. Indeed the
           investigators have developed a method using blinatumomab and rhIL2 to expand and
           activate ex vivo the T lymphocytes present in the peripheral blood from CLL and iNHL
           patients, while at the same time eliminating contaminating CD19+ neoplastic cells. The
           resulting polyclonal T cells can be used for immuno-reconstitution purposes. The Cell
           Factory "Centro di Terapia Cellulare G. Lanzani" showed the functionality of BET in a
           mouse B-cell NHL xenograft model. Upon in vivo inoculation, BET retain functional
           activity: upon engagement with blinatumomab in vivo, BET were able to efficiently kill
           the B-cell NHL cells. Importantly, BET did not showed any toxicity in animals, even at
           high doses and in presence of blinatumomab.

        -  About clinical experience, it has been previously shown that adoptive transfer of ex
           vivo (anti-CD3/anti-CD28) co-stimulated autologous T cells can successfully accelerate a
           robust T-cell recovery early after autologous transplant for multiple myeloma. However,
           the invariable presence of clonal disease in cell product of iNHL/CLL patients hampered
           this possibility up to now. In contrast BET cell expansion leads to lysis of
           contaminating neoplastic cells. BET can therefore be expanded from CLL patients
           peripheral blood in GMP (Good Manufacturing Practice) conditions for adoptive therapy.
           Starting from only 10 mL of peripheral blood, a mean 5.15x108 CD3+ cells can be expanded
           in 3 weeks with a rapid clearance of CLL contamination. The resulting
           blinatumomab-expanded T cells (BET) were polyclonal CD4+ and CD8+ T cells and mostly
           effector and central memory cells. They showed a normalized expression of the synapse
           inhibitors CD272 and CD279 compared with starting T cells and were functionally active,
           showing cytotoxicity against CD19+ targets in presence of Blinatumomab in vitro and in
           vivo.

        -  On the basis of these data the investigators hypothesize that BET infusion after
           first-line treatment of iNHL/CLL with either FCR or BR could lead to an adequate immune
           recovery.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: CD20+ Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia Patients After First-line Treatment with Fludarabine-Cyclophosphamide-Rituximab or Bendamustine-Rituximab.
primary purpose: Treatment
masking: None (Open Label)
masking description: This study is a phase I open-label, single center study. The patient population will consist of adults diagnosed with indolent non-Hodgkin lymphomas (iNHL) or chronic lymphocytic leukemia (CLL) in need of first line treatment consisting of either FCR or BR as per investigator assessment. Chemotherapy treatment will consist of a minimum of 4 to a maximum of 6 cycles of standard FCR or BR.Patients will be enrolled in the study after the last planned cycle of chemo-immunotherapy and, if eligibility criteria are met, BET dose level will be assigned.
measure: Number of grade 3 or 4 adverse events (AE) possibly related to therapy
time frame: The period of observation is during 14 days after BET infusion
description: Description and grading of all adverse events will be based on the NCI -CTCAE v4.03 and MedDra code (current version).
measure: Number of Adverse event (AE) and laboratory abnormalities.
time frame: From date of study start up to 180 days after BET infusion
description: Number, causality and intensity of all adverse events 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 Optimal Biological Dose (ODB) of BET cells
time frame: +90 days after infusion
description: OBD of BET will be defined as the absolute number of BET cell that will allow a CD3+ count of > 600 x106/L at +90 days after infusion in at least 70% of the patients.
measure: Evaluation of general Immune Reconstitution after BET infusion
time frame: at +0 (4 hours), +30, +90 and +180 days after infusion
description: Absolute numbers of B, T, and NK cells reconstitution and its correlation with BET cell infused and its composition (in terms of T-cell subsets and NK cells)
measure: Evaluation of ex vivo transfer of anti-viral immunity
time frame: at +0 (4 hours), +30, +90 and +180 days after infusion
description: Ex vivo transfer of anti-viral immunity in terms of tetramer-based quantification of CMV-specific CD8+ T lymphocytes (this will be done only for CMV positive patients for whom CMV specific tetramers stain positive in starting peripheral blood or BET).
arm group label: Indolent NHL or CLL patients
arm group type: Experimental
description: Adults diagnosed with indolent non-Hodgkin lymphomas (iNHL) or chronic lymphocytic leukemia (CLL) in need of first line treatment consisting of either FCR or BR as per investigator assessment
intervention type: Biological
intervention name: Blinatumomab Expanded T-cells (BET)
description: Two to five days after the last chemotherapy infusion, BET will be administered. An accelerated titration dose escalation design will be used. During dose escalation, up to four dose levels (see table) will be evaluated or until (Maximum Tolerated Dose) MTD is reached.
Dose level BET dose(Counted on CD3+ cells)
(starting dose) 3.0 x 109
6.0 x 109
9.0 x 109
12.0 x 109
arm group label: Indolent NHL or CLL patients
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alessandro Rambaldi, MD
role: Principal Investigator
affiliation: ASST - Papa Giovanni XXIII
facility: 
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
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Lymphoma, Non-Hodgkin
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Blinatumomab