<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/NCT02988258</url>
  </required_header>
  <id_info>
    <org_study_id>UCL 08/0214</org_study_id>
    <secondary_id>2008-006649-18</secondary_id>
    <secondary_id>G0701703</secondary_id>
    <secondary_id>08/0214</secondary_id>
    <nct_id>NCT02988258</nct_id>
  </id_info>
  <brief_title>Study of Adoptive Immunotherapy With Donor-derived CMV-specific T Cells for Recipients of Allo-HSCT</brief_title>
  <acronym>CMV_TCR-001</acronym>
  <official_title>CMV TCR Gene Therapy: A Phase I Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy With CMV TCR-transduced Donor-derived T Cells for Recipients of Allogeneic Haematopoietic Stem Cell Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University College, London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University College, London</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study will test the hypothesis that CMV TCR-transduced T cells, at a specific T-cell&#xD;
      dose/kg, can generate a functional CMV immune response post-transplant, where CMV-specific&#xD;
      donor T cells cannot be isolated by conventional means. This will be tested in the context of&#xD;
      adult HLA-matched sibling allogeneic HSCT.&#xD;
&#xD;
      In the proposed trial, an HLA-A*0201-restricted CMV pp65-specific T cell receptor (TCR) will&#xD;
      be introduced into donor T cells via ex vivo GMP retroviral transduction. Donor T cells will&#xD;
      be isolated from peripheral blood following a simple venesection procedure. The CMV&#xD;
      TCR-transduced T cells will be tested for TCR expression, CMV-specific cytokine secretion and&#xD;
      microbiological contamination before being frozen and stored at -80C. CMV seropositive&#xD;
      transplant recipients will be tested weekly for CMV reactivation by quantitative PCR on&#xD;
      peripheral blood. On first detection of CMV DNA &gt; 200 copies/ml, 104 (cohort 1) or 105&#xD;
      (cohort 2) bulk CMV TCR-transduced T cells/kg recipient weight will be infused into the&#xD;
      patient.&#xD;
&#xD;
      Blood will be taken regularly to determine persistence and expansion of the CMV&#xD;
      TCR-transduced T cells. Weekly CMV PCR will be continued. Patients will be examined at&#xD;
      appropriate intervals (daily if inpatients, twice weekly in BMT clinic if outpatients) for&#xD;
      the development of graft versus host disease (GVHD) or other potential side effects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Reactivation of the latent human herpes virus, Cytomegalovirus (CMV), post allogeneic&#xD;
      haematopoietic stem cell transplantation (Allo-HSCT) can result in significant morbidity and&#xD;
      mortality unless treated promptly. Anti-viral therapy is usually effective, but has serious&#xD;
      side effects typically requiring prolonged inpatient admission, such as myelosuppression&#xD;
      (Ganciclovir) or nephrotoxicity (Foscarnet). Cellular immunotherapy for CMV has been tested&#xD;
      in Phase I/II trials in the UK and Europe. In these trials CMV-specific T cells were isolated&#xD;
      from the peripheral blood of CMV seropositive donors and re-infused into recipients following&#xD;
      CMV reactivation resulting in sustained anti-viral responses. It is clear that&#xD;
      post-transplant recovery of CD8+ CMV-specific cytotoxic T-cells (CTL) abrogates the&#xD;
      development of CMV-related disease. An advantage of cellular therapy for CMV reactivation is&#xD;
      the transfer of immunological memory, which can reduce the number of subsequent&#xD;
      reactivations. This is important, as rapidly increasing numbers of highly immunosuppressive&#xD;
      (or T cell depleted) reduced intensity conditioning Allo-HSCTs are being performed in the UK.&#xD;
      These approaches reduce the toxicity of transplantation in older patients with more&#xD;
      co-morbidities. Reduced intensity allogeneic transplants are currently part of the UK MRC&#xD;
      AML15 trial and are to be recommended in the proposed MRC/ECOG UKALL14 study and again in UK&#xD;
      MRC AML17. In addition, a number of NCRN approved UK multicentre extended Phase II studies&#xD;
      have recently started using reduced intensity Allo-HSCT in various lymphoma subtypes.&#xD;
&#xD;
      Transplant recipients with CMV seronegative donors cannot benefit from currently available&#xD;
      cellular immunotherapy approaches due to the lack of CMV-specific memory T cells in these&#xD;
      donors. At present, there is no reliable strategy to isolate virus specific T cells from&#xD;
      uninfected naïve individuals, as the precursor frequency is low or absent and the in vitro&#xD;
      priming of T-cell responses is inefficient. T-cell receptor (TCR) gene transfer offers a&#xD;
      strategy to produce antigen-specific T cells independent of precursor frequency and without&#xD;
      the need for T-cell priming. As approximately 50% of adult individuals have been previously&#xD;
      infected with CMV, there are significant numbers of CMV 'mismatched' Allo-HSCT performed,&#xD;
      where the donor is CMV seronegative and the recipient CMV seropositive. The proposed study&#xD;
      will test the feasibility of generating donor-derived CMV-specific T cells via the ex vivo&#xD;
      introduction of a CMV-specific T cell receptor using a GMP grade retroviral vector.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Suspended</overall_status>
  <why_stopped>
    Protocol being re-written to allow inclusion of more patients&#xD;
  </why_stopped>
  <start_date>July 2013</start_date>
  <completion_date type="Anticipated">August 2019</completion_date>
  <primary_completion_date type="Anticipated">August 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Determination of the frequency of transduced donor-derived cells expressing the CMV-specific TCR by flow cytometry.</measure>
    <time_frame>5 years</time_frame>
    <description>CMV-TCR transduced cells express vbeta13 and murine constant beta chain (mCb), both of which can be easily detected by flow cytometry. The frequency of vbeta13+/mCb+ is used to calculate the efficiency of transduction of donor-derived cells.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluation of treatment toxicity according to the NCI Common Toxicity Criteria Scale (v4.03).</measure>
    <time_frame>5 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Documentation of anti-CMV responses post CMV-TCR transduced cell infusion using quantitative PCR to determine viral copy numbers in peripheral blood.</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of GvHD post CMV-TCR transduced cell infusion following allo-HSCT using standardised international criteria.</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of immune reconstitution post CMV-TCR transduced cell infusion following allo-HSCT.</measure>
    <time_frame>5 years</time_frame>
    <description>Flow cytometry and TCR repertoire analysis can be used to evaluate overall T-cell subset reconstitution.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the number of CMV-TCR transduced cells that are able to persist post-infusion using quantitative real-time PCR.</measure>
    <time_frame>5 years</time_frame>
    <description>Quantitative real-time PCR using primers specifically targeting nucleotide sequences that are only present in the introduced CMV-TCR can be used to determine the number of circulating CMV-TCR transduced cells post infusion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phenotypic characterisation of CMV-TCR transduced cells by flow cytometry in terms of relative expression of markers associated with cell differentiation, proliferation and intracellular cytokine production.</measure>
    <time_frame>5 years</time_frame>
    <description>Flow cytometry can be used to further characterise CMV-TCR transduced cells in terms of naive/memory subsets (based on the expression of CD45RO and CD62L differentiation markers), proliferation status (assessed by Ki-67) and ability to produce cytokines (such as IFN-gamma and TNF-alpha).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Haematological Malignancies</condition>
  <condition>CMV Infection</condition>
  <arm_group>
    <arm_group_label>Cohort 1 - 10^4 transduced cells/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The first 3 patients will receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10^4 T cells/kg recipient weight</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2 - 10^5 transduced cells/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>If no cases grade III-IV GVHD in Cohort 1 the remaining patients (N=7) each receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10^5 T cells/kg recipient weight</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 1a - 10^3 transduced cells/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>If 1 case grade III-IV GVHD in Cohort 1, next three patients to be treated with a single infusion of bulk CMV-TCR transduced donor-derived T cells of 1 x 10^3 T cells/kg recipient weight</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>CMV-TCR transduced donor-derived T cells</intervention_name>
    <description>Dose escalation</description>
    <arm_group_label>Cohort 1 - 10^4 transduced cells/kg</arm_group_label>
    <arm_group_label>Cohort 1a - 10^3 transduced cells/kg</arm_group_label>
    <arm_group_label>Cohort 2 - 10^5 transduced cells/kg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Patient Inclusion Criteria:&#xD;
&#xD;
          -  Undergoing matched sibling allogeneic HSCT for an underlying haematological malignancy&#xD;
             with a CMV seronegative donor&#xD;
&#xD;
          -  Age ≥ 18 years and ≤ 65 years&#xD;
&#xD;
          -  HLA-A*0201 positive&#xD;
&#xD;
          -  CMV seropositive (CMV IgG detected) pre-transplant&#xD;
&#xD;
          -  Informed consent in writing and ability to co-operate with treatment and follow up.&#xD;
&#xD;
               -  Prepared to undergo additional study procedures as per study schedule&#xD;
&#xD;
               -  Patient has undergone counselling about risk&#xD;
&#xD;
          -  Serologically negative for HIV 1&amp;2, Hep B, Hep C and syphilis&#xD;
&#xD;
          -  Female patients of child-bearing age must have a negative pregnancy test and agree to&#xD;
             use reliable contraceptive methods for the duration of the therapy and for 6 months&#xD;
             afterwards&#xD;
&#xD;
          -  Male patients must agree to use appropriate medically approved contraception during&#xD;
             the trial and for six months afterwards&#xD;
&#xD;
        And to be assessed prior to CMV-specific T cell infusion (for confirmation prior to product&#xD;
        release):&#xD;
&#xD;
          -  Donor engraftment (neutrophils &gt; 0.5x109/l).&#xD;
&#xD;
          -  Single positive CMV PCR result (&gt; 200 copies/ml)&#xD;
&#xD;
        Patient Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Co-existing medical problems that would place the patient at significant risk of death&#xD;
             due to GVHD or its sequelae&#xD;
&#xD;
          -  HIV infection&#xD;
&#xD;
        And to be assessed prior to CMV-specific T cell infusion (for confirmation prior to product&#xD;
        release):&#xD;
&#xD;
          -  Active acute GVHD &gt; Grade I&#xD;
&#xD;
          -  Concurrent use of systemic corticosteroids&#xD;
&#xD;
          -  Organ dysfunction as measured by&#xD;
&#xD;
               -  creatinine &gt; 200 uM/l&#xD;
&#xD;
               -  bilirubin &gt; 50 uM/l&#xD;
&#xD;
               -  ALT &gt; 3x upper limit of normal&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Emma Morris, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>University College, London</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hans Stauss, Prof</last_name>
    <role>Study Chair</role>
    <affiliation>University College, London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospitals Birmingham NHS Foundation Trust</name>
      <address>
        <city>Birmingham</city>
        <zip>B15 2TH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals Bristol NHS Foundation Trust</name>
      <address>
        <city>Bristol</city>
        <zip>BS2 8ED</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University College London Hospital</name>
      <address>
        <city>London</city>
        <zip>NW1 2PG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nottingham University Hospital</name>
      <address>
        <city>Nottingham</city>
        <zip>NG5 1PB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>July 12, 2012</study_first_submitted>
  <study_first_submitted_qc>December 6, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 9, 2016</study_first_posted>
  <last_update_submitted>September 10, 2018</last_update_submitted>
  <last_update_submitted_qc>September 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 12, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Ex vivo gene therapy</keyword>
  <keyword>T cell receptor transduction</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>Allogeneic Haematopoietic Stem Cell Transplantation</keyword>
  <keyword>CMV</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytomegalovirus Infections</mesh_term>
    <mesh_term>Hematologic Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02988258
org study id: UCL 08/0214
secondary id: 2008-006649-18
secondary id: G0701703
secondary id: 08/0214
nct id: NCT02988258
lead sponsor: 
has dmc: Yes
The study will test the hypothesis that CMV TCR-transduced T cells, at a specific T-cell
      dose/kg, can generate a functional CMV immune response post-transplant, where CMV-specific
      donor T cells cannot be isolated by conventional means. This will be tested in the context of
      adult HLA-matched sibling allogeneic HSCT.

      In the proposed trial, an HLA-A*0201-restricted CMV pp65-specific T cell receptor (TCR) will
      be introduced into donor T cells via ex vivo GMP retroviral transduction. Donor T cells will
      be isolated from peripheral blood following a simple venesection procedure. The CMV
      TCR-transduced T cells will be tested for TCR expression, CMV-specific cytokine secretion and
      microbiological contamination before being frozen and stored at -80C. CMV seropositive
      transplant recipients will be tested weekly for CMV reactivation by quantitative PCR on
      peripheral blood. On first detection of CMV DNA > 200 copies/ml, 104 (cohort 1) or 105
      (cohort 2) bulk CMV TCR-transduced T cells/kg recipient weight will be infused into the
      patient.

      Blood will be taken regularly to determine persistence and expansion of the CMV
      TCR-transduced T cells. Weekly CMV PCR will be continued. Patients will be examined at
      appropriate intervals (daily if inpatients, twice weekly in BMT clinic if outpatients) for
      the development of graft versus host disease (GVHD) or other potential side effects.
Reactivation of the latent human herpes virus, Cytomegalovirus (CMV), post allogeneic
      haematopoietic stem cell transplantation (Allo-HSCT) can result in significant morbidity and
      mortality unless treated promptly. Anti-viral therapy is usually effective, but has serious
      side effects typically requiring prolonged inpatient admission, such as myelosuppression
      (Ganciclovir) or nephrotoxicity (Foscarnet). Cellular immunotherapy for CMV has been tested
      in Phase I/II trials in the UK and Europe. In these trials CMV-specific T cells were isolated
      from the peripheral blood of CMV seropositive donors and re-infused into recipients following
      CMV reactivation resulting in sustained anti-viral responses. It is clear that
      post-transplant recovery of CD8+ CMV-specific cytotoxic T-cells (CTL) abrogates the
      development of CMV-related disease. An advantage of cellular therapy for CMV reactivation is
      the transfer of immunological memory, which can reduce the number of subsequent
      reactivations. This is important, as rapidly increasing numbers of highly immunosuppressive
      (or T cell depleted) reduced intensity conditioning Allo-HSCTs are being performed in the UK.
      These approaches reduce the toxicity of transplantation in older patients with more
      co-morbidities. Reduced intensity allogeneic transplants are currently part of the UK MRC
      AML15 trial and are to be recommended in the proposed MRC/ECOG UKALL14 study and again in UK
      MRC AML17. In addition, a number of NCRN approved UK multicentre extended Phase II studies
      have recently started using reduced intensity Allo-HSCT in various lymphoma subtypes.

      Transplant recipients with CMV seronegative donors cannot benefit from currently available
      cellular immunotherapy approaches due to the lack of CMV-specific memory T cells in these
      donors. At present, there is no reliable strategy to isolate virus specific T cells from
      uninfected naïve individuals, as the precursor frequency is low or absent and the in vitro
      priming of T-cell responses is inefficient. T-cell receptor (TCR) gene transfer offers a
      strategy to produce antigen-specific T cells independent of precursor frequency and without
      the need for T-cell priming. As approximately 50% of adult individuals have been previously
      infected with CMV, there are significant numbers of CMV 'mismatched' Allo-HSCT performed,
      where the donor is CMV seronegative and the recipient CMV seropositive. The proposed study
      will test the feasibility of generating donor-derived CMV-specific T cells via the ex vivo
      introduction of a CMV-specific T cell receptor using a GMP grade retroviral vector.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Determination of the frequency of transduced donor-derived cells expressing the CMV-specific TCR by flow cytometry.
time frame: 5 years
description: CMV-TCR transduced cells express vbeta13 and murine constant beta chain (mCb), both of which can be easily detected by flow cytometry. The frequency of vbeta13+/mCb+ is used to calculate the efficiency of transduction of donor-derived cells.
measure: Evaluation of treatment toxicity according to the NCI Common Toxicity Criteria Scale (v4.03).
time frame: 5 years
measure: Documentation of anti-CMV responses post CMV-TCR transduced cell infusion using quantitative PCR to determine viral copy numbers in peripheral blood.
time frame: 5 years
measure: Evaluation of GvHD post CMV-TCR transduced cell infusion following allo-HSCT using standardised international criteria.
time frame: 5 years
measure: Evaluation of immune reconstitution post CMV-TCR transduced cell infusion following allo-HSCT.
time frame: 5 years
description: Flow cytometry and TCR repertoire analysis can be used to evaluate overall T-cell subset reconstitution.
measure: Assessment of the number of CMV-TCR transduced cells that are able to persist post-infusion using quantitative real-time PCR.
time frame: 5 years
description: Quantitative real-time PCR using primers specifically targeting nucleotide sequences that are only present in the introduced CMV-TCR can be used to determine the number of circulating CMV-TCR transduced cells post infusion.
measure: Phenotypic characterisation of CMV-TCR transduced cells by flow cytometry in terms of relative expression of markers associated with cell differentiation, proliferation and intracellular cytokine production.
time frame: 5 years
description: Flow cytometry can be used to further characterise CMV-TCR transduced cells in terms of naive/memory subsets (based on the expression of CD45RO and CD62L differentiation markers), proliferation status (assessed by Ki-67) and ability to produce cytokines (such as IFN-gamma and TNF-alpha).
arm group label: Cohort 1 - 10^4 transduced cells/kg
arm group type: Experimental
description: The first 3 patients will receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10^4 T cells/kg recipient weight
arm group label: Cohort 2 - 10^5 transduced cells/kg
arm group type: Experimental
description: If no cases grade III-IV GVHD in Cohort 1 the remaining patients (N=7) each receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10^5 T cells/kg recipient weight
arm group label: Cohort 1a - 10^3 transduced cells/kg
arm group type: Experimental
description: If 1 case grade III-IV GVHD in Cohort 1, next three patients to be treated with a single infusion of bulk CMV-TCR transduced donor-derived T cells of 1 x 10^3 T cells/kg recipient weight
intervention type: Genetic
intervention name: CMV-TCR transduced donor-derived T cells
description: Dose escalation
arm group label: Cohort 1 - 10^4 transduced cells/kg
arm group label: Cohort 1a - 10^3 transduced cells/kg
arm group label: Cohort 2 - 10^5 transduced cells/kg
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Emma Morris, Prof
role: Principal Investigator
affiliation: University College, London
last name: Hans Stauss, Prof
role: Study Chair
affiliation: University College, London
facility: 
facility: 
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Cytomegalovirus Infections
mesh term: Hematologic Neoplasms
sharing ipd: Undecided