Clinical Trials /

Immunotherapy With Tacrolimus Resistant EBV CTL for Lymphoproliferative Disease After Solid Organ Transplant

NCT03131934

Description:

This is an open label, non-randomised, multicentre Phase I to determine the safety of tacrolimus-resistant autologous EBV-specific cytotoxic T-cells (EBV CTL) and compare their expansion/persistence with control EBV CTL in solid organ transplant patients with post-transplant lymphoproliferative disease (PTLD). Each patient will receive an infusion of two ATIMPs - autologous EBV CTL retrovirally transduced with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8).

Related Conditions:
  • Post-Transplant Lymphoproliferative Disorder
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

    <li>Brief Title: Immunotherapy With Tacrolimus Resistant EBV CTL for Lymphoproliferative Disease After Solid Organ Transplantli><li>Official Title: Immunotherapy With Tacrolimus Resistant EBV CTL for Lymphoproliferative Disease After Solid Organ Transplantli>

Clinical Trial IDs

    <li>ORG STUDY ID: UCL/16/0529li><li>NCT ID: NCT03131934li>

Conditions

    <li>Post-transplant Lymphoproliferative Diseaseli><li>Transplant-Related Hematologic Malignancyli>

Interventions

<td>AutologousEBV-CTL transduced with vector SFG-CNA12td><td/><td>AutologousEBV-CTL transduced with SFG-CNA12/SFG-CNA8td><td>AutologousEBV-CTL transduced with control vector SFG-CNA8td><td/><td>AutologousEBV-CTL transduced with SFG-CNA12/SFG-CNA8td>
DrugSynonymsArms

Purpose

This is an open label, non-randomised, multicentre Phase I to determine the safety of tacrolimus-resistant autologous EBV-specific cytotoxic T-cells (EBV CTL) and compare their expansion/persistence with control EBV CTL in solid organ transplant patients with post-transplant lymphoproliferative disease (PTLD). Each patient will receive an infusion of two ATIMPs - autologous EBV CTL retrovirally transduced with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8).

Detailed Description

      This is a multi-centre, non-randomised, open label Phase 1 clinical trial of Advanced Therapy
      Investigational Medicinal Products (ATIMPs) in adult and paediatric (age 1-70 years) solid
      organ transplant recipients with histologically proven B-lineage EBV+ post-transplant
      lymphoproliferative disease (PTLD).

      The ATIMPs for this study are autologous EBV CTL transduced with the (a) the retroviral
      vector SFG-CNA12 encoding a calcineurin A mutant (CNA12) that confers resistance to
      tacrolimus and (b) the retroviral vector SFG-CNA8 encoding a control calcineurin A mutant
      (CNA8).

      Following informed consent and registration to the trial, patients will undergo an
      unstimulated leucapheresis for generation of both ATIMPs. Patients will receive an equal dose
      of each ATIMP (107 CNA8+ or CNA12+ CTL/m2) which will be administered intravenously.

      Other immunosuppressants (e.g. MMF) will be reduced, but tacrolimus will be maintained at
      therapeutic levels.The trial will evaluate the safety of the ATIMPs in organ transplant
      recipients developing EBV+ PTLD and compare the persistence and frequency of circulating
      CNA12 and CNA8 CTL in the peripheral blood.

      Our hypothesis is that in the presence of ongoing immunosuppression with tacrolimus, CNA12
      CTL will show preferential expansion and prolonged persistence compared with CNA8 CTL. If
      successful this will result in durable clearance of PTLD without the need to reduce
      tacrolimus, thus reducing the risk of graft rejection.

      Patients will be followed up regularly during the interventional phase of the study until 1
      year post EBV CTL infusion. During the long-term follow-up phase of the study (from 1-5 years
      post EBV CTL infusion) patients will be followed up annually.
    

Trial Arms

<td>AutologousEBV-CTL transduced with SFG-CNA12/SFG-CNA8td><td>Experimentaltd><td>All patients will receive the autologousEBV CTL retrovirally transduced with with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8). For each patient two ATIMPs will be generated: AutologousEBV-specific cytotoxic T-cells (CTL) transduced with the retroviral vector SFG-CNA12 AutologousEBV-specific cytotoxic T-cells (CTL) transduced with the control retroviral vector SFG-CNA8 An equal dose (10x7/m2) of CNA12+ EBV CTL and CNA8+ EBV CTL will be administered intravenously on day 0. While awaiting ATIMP generation, patients may receive a single dose of Rituximab and otherimmunosuppressants (e.g. MMF) will be reduced, but tacrolimus will be maintained at therapeutic levels.td><td>
    td>
NameTypeDescriptionInterventions

Eligibility Criteria

        Inclusion Criteria:

          1. Adult and paediatric (age 1-70 years) solid organ transplant recipients with
             histologically proven B-lineage EBV+ post-transplant lymphoproliferative disease
             (PTLD) either de novo or resistant to Rituximab

          2. EBV viraemia at enrolment

          3. On immunosuppression with tacrolimus

          4. Agreement to have a pregnancy test and use of contraception for duration of trial (if
             applicable)

          5. Written informed consent

        Exclusion Criteria:

          1. Fulminant disease

          2. Requirement for supplemental oxygen

          3. Burkitt's lymphoma/Mature B-acute lymphoblastic leukaemia with IgH-Myc rearrangement

          4. T-lineage PTLD

          5. Bilirubin > 3 x upper limit of normal

          6. Creatinine > 3 x upper limit of normal

          7. Active hepatitis B, C or HIV infection

          8. Women who are pregnant or breast-feeding

          9. ECOG performance score ≥ 4

         10. Inability to tolerate leucapheresis
      
<td>Maximum Eligible Age:td><td>70 Yearstd><td>Minimum Eligible Age:td><td>1 Yeartd><td>Eligible Gender:td><td>Alltd><td>Healthy Volunteers:td><td>Notd>

Primary Outcome Measures

<td>Measure:td><td>Toxicity at 6 weeks post infusiontd><td>Time Frame:td><td>6 weekstd><td>Safety Issue:td><td/><td>Description:td><td>Toxicity as assessed by NCI Common toxicity criteria within 6 weeks of infusiontd>

Secondary Outcome Measures

<td>Measure:td><td>Disease responsetd><td>Time Frame:td><td>6 weekstd><td>Safety Issue:td><td/><td>Description:td><td>Disease response at 6 weekstd>
<td>Measure:td><td>Relapse ratetd><td>Time Frame:td><td>2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>Relapse rate at 1 and 2 yearstd>
<td>Measure:td><td>Disease free survivaltd><td>Time Frame:td><td>2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>Disease free survival at 1 and 2 yrstd>
<td>Measure:td><td>Organ graft Rejectiontd><td>Time Frame:td><td>2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>Organ graft Rejection at 1 and 2 yrstd>

Details

<td>Phase:td><td>Early Phase 1td><td>Primary Purpose:td><td>Interventionaltd><td>Overall Status:td><td>Not yet recruitingtd><td>Lead Sponsor:td><td>University College, Londontd>

Last Updated

<p/>