Clinical trial NCT03131934: Immunotherapy With Tacrolimus Resistant EBV CTL for Lymphoproliferative Disease After Solid Organ Transplant
Official title: Immunotherapy With Tacrolimus Resistant EBV CTL for Lymphoproliferative Disease After Solid Organ Transplant
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Post-transplant Lymphoproliferative Disease
Transplant-Related Hematologic Malignancy
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: bluebird bio
First posted: 2017-04-27
Enrollment: 18
Sex: ALL
Minimum age (years): 1
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).

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 (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.

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

Primary outcomes:
measure: Toxicity at 6 weeks post infusion
timeFrame: 6 weeks
measure: Persistence and frequency of circulating EBV CTL
timeFrame: 12 months
Secondary outcomes:
measure: Disease response
timeFrame: 6 weeks
measure: Relapse rate
timeFrame: 2 years
measure: Disease free survival
timeFrame: 2 years
measure: Organ graft Rejection
timeFrame: 2 years
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
affiliation: Great Ormond Street Hospital
name: Prof. Persis Amrolia
role: PRINCIPAL_INVESTIGATOR
References: