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

Transplant-Related Hematologic Malignancy Clinical Trial

— ITREC  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03131934
• Other study ID #: UCL/16/0529
• Status: Active, not recruiting
• Phase: Early Phase 1
• Start date: May 31, 2019
• Est. completion date: May 15, 2025

Study information

• Verified date: May 2024
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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 (10x7 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 18
• Est. completion date: May 15, 2025
• Est. primary completion date: June 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Hematologic Neoplasms
• Lymphoproliferative Disorders
• Post-transplant Lymphoproliferative Disease
• Transplant-Related Hematologic Malignancy

Intervention

Biological:
• Autologous EBV-CTL transduced with vector SFG-CNA12
Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the retroviral vector SFG-CNA12 conferring resistance to tacrolimus
• Autologous EBV-CTL transduced with control vector SFG-CNA8
Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the control retroviral vector SFG-CNA8

Procedure:
• Leucapheresis
Patients will undergo an unstimulated leucapheresis to isolate the required immune cells to produce the EBV-CTLs

Locations

Country	Name	City	State
United Kingdom	Great Ormond Street Hospital	London
United Kingdom	King's College Hospital	London

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	bluebird bio

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Toxicity at 6 weeks post infusion	Toxicity as assessed by NCI Common toxicity criteria within 6 weeks of infusion	6 weeks
Primary	Persistence and frequency of circulating EBV CTL	Persistence and frequency of circulating EBV CTL transduced with CNA12 compared with control vector CNA8 in the peripheral blood	12 months
Secondary	Disease response	Disease response at 6 weeks	6 weeks
Secondary	Relapse rate	Relapse rate at 1 and 2 years	2 years
Secondary	Disease free survival	Disease free survival at 1 and 2 yrs	2 years
Secondary	Organ graft Rejection	Organ graft Rejection at 1 and 2 yrs	2 years