CAR19 Donor Lymphocytes for Relapsed CD19+ Malignancies Following Allogeneic Transplantation

Phase 1

Completed

• Conditions: CD19+ Malignancies: Relapse Post-allogeneic Transplant
• Interventions: Genetic: Infusion of modified CAR19 T-cells (4G7-CARD T-cells)

• Registration Number: NCT02893189
• Lead Sponsor: University College, London

Brief Summary

Eligible patients will receive escalating doses of 4G7-CARD T-cells paralleling clinical standard of care with unmanipulated donor lymphocytes. There are 3 intra-patient dose levels planned.

Patients will be followed up regularly during the interventional phase of the study until 12 months post-final 4G7-CARD T-cell infusion. Thereafter patients will be followed up annually for years 2 and 3.

Detailed Description

Patients will receive escalating doses of 4G7-CARD T-cells (after pre-conditioning with Fludarabine and Cyclophosphamide), paralleling clinical standard of care with unmanipulated donor lymphocytes. Intra-patient dose escalation will proceed at intervals of not less than 8 weeks, dependent on development of toxicity or evidence of efficacy and confirmation by the Trial Management Group.

Three dose cohorts levels are planned, and dosing will be according to total CD3+ T- cell dose as this correlates with toxicity in the unmanipualated donor lymphocyte setting:

* Dose Level 1: 1x10\^6 CD3+ T-cells/kg (starting dose for all patients)

* Dose Level 2: 3x10\^6 CD3+ T-cells/kg

* Dose Level 3: 1x10\^7 CD3+ T-cells/kg

The inter-patient dosing for the first 3 patients was at least 28 days, following TMG confirmation.

Patients will be followed up regularly during the interventional phase of the study until 12 months post-final 4G7-CARD T-cell infusion. During the long term follow up phase of the study (years 2-3 post-final 4G7-CARD T-cell infusion) patients will be followed-up annually for overall survival, disease status and safety.

All patients will enter long term follow up until 3 years post-final 4G7-CARD T-cell infusion.

Study Timeline

• Study First Submitted: 2016-05-17
• Study First Submitted QC: 2016-09-01
• Study First Posted: 2016-09-08
• Study Start: 2017-04-27
• Primary Completion: 2019-12-31
• Study Completion: 2022-12-31
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-21
• Last Update Posted: 2023-06-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 17

Inclusion Criteria

1. Age 16-70 years
2. Confirmed diagnosis of CD19+ malignancy relapsing following allogeneic transplantation
3. Agreement to have a pregnancy test, use adequate contraception for 12 months post-final 4G7-CARD T-cell infusion
4. Karnofsky performance status >60
5. Written informed consent

Exclusion Criteria

1. Women who are pregnant or lactating
2. Prior history of ischaemic heart disease, dysrhythmias, abnormal ECG (LBBB), Multi Gated Acquisition Scan (MUGA) left ventricular ejection fraction (LVEF<40%) (if performed)
3. Known involvement of the central nervous system or cerebral vascular accident within prior 3 months
4. Patients receiving corticosteroids at a dose of > 10mg prednisolone per day (or equivalent)
5. Active graft versus host disease requiring immunosuppression
6. Use of rituximab within the last 2 months prior to ATIMP infusion
7. Known allergy to albumin or dimethyl sulfoxide (DMSO)
8. Patients who have experienced significant neurotoxicity following blinatumomab treatment

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
4G7-CARD T-cells	Infusion of modified CAR19 T-cells (4G7-CARD T-cells)	All patient will receive modified CAR19 T-cells.

Primary Outcome Measures

Name	Time	Method
Maximum grade for each toxicity type as assessed by CTCAE v4.03, summarized as proportions.	Up to 3 years post final 4G7-CARD T-cell infusion	Toxicity evaluation following 4G7-CARD T-cell administration as evaluated by the occurrence of adverse events per studied dose using CTCAE v4.03, defined as \>grade 2 events that are causally related to study treatment or procedure or Serious Adverse Reactions that require withdrawal of the patient from the study; development and severity of graft-versus-host-disease (GvHD) following cell infusion will also be evaluated as a potential toxicity, as well as development and severity of cytokine release syndrome / macrophage activation syndromes assessed by 'University of Pennsylvania' criteria
Feasibility of generation of 4G7-CARD T-cells using the ProdigyTM system	Through patient registration and manufacturing period, an average of 18 months from start of trial	The number of ATIMP successfully manufactured would be assessed for all registered patients

Secondary Outcome Measures

Name	Time	Method
Assessing the timing and magnitude of cytokine release, evaluated using Cytokine bead arrays	Sampling occurs at days 0, 4, 6, 11, 18, plus 1 month post final 4G7-CARD T-cell infusion	Data on timing (kinetic of change) and magnitude of cytokine levels can be summarised using means (medians) and plots for each patients
Assessment of engraftment, expansion and persistence of the 4G7-CARD T-cells as determined by quantitative polymerase chain reaction (qPCR) or flow cytometry	Sampling occurs at days 0, 4, 6, 11, 18, plus months 1, 2, 3, 6, 9 and 1 year post final 4G7-CARD T-cell infusion	Data for engraftment and expansion would be summarised by mean, median or interquartile ranges and a Kaplan Meier plot for persistence
Assessing the depletion of B cell compartment, as determined by flow cytometry	Sampling occurs at days 0, 4, 6, 11, 18, plus months 1, 2, 3, 6, 9 and 1 year post final 4G7-CARD T-cell infusion	Data would be summarised using means (medians) and as the percentage reduction from baseline

Trial Locations

Locations (1)

University College London Hospital; 🇬🇧 London, United Kingdom