CAR19 Donor Lymphocytes for Relapsed CD19+ Malignancies Following Allogeneic Transplantation

Study Overview
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Brief Summary
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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
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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.

Official Title
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Chimeric Antigen Receptor (CAR)19 Donor Lymphocytes for Relapsed Cluster of Differentiation (CD)19+ Malignancies Following Allogeneic Transplantation (CARD)

Conditions
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CD19+ Malignancies: Relapse Post-allogeneic Transplant

Intervention / Treatment
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* Genetic: Infusion of modified CAR19 T-cells (4G7-CARD T-cells)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 16-70 years Confirmed diagnosis of CD19+ malignancy relapsing following allogeneic transplantation Agreement to have a pregnancy test, use adequate contraception for 12 months post-final 4G7-CARD T-cell infusion Karnofsky performance status >60 Written informed consent Exclusion Criteria: Women who are pregnant or lactating Prior history of ischaemic heart disease, dysrhythmias, abnormal ECG (LBBB), Multi Gated Acquisition Scan (MUGA) left ventricular ejection fraction (LVEF<40%) (if performed) Known involvement of the central nervous system or cerebral vascular accident within prior 3 months Patients receiving corticosteroids at a dose of > 10mg prednisolone per day (or equivalent) Active graft versus host disease requiring immunosuppression Use of rituximab within the last 2 months prior to ATIMP infusion Known allergy to albumin or dimethyl sulfoxide (DMSO) Patients who have experienced significant neurotoxicity following blinatumomab treatment

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4G7-CARD T-cells<br>All patient will receive modified CAR19 T-cells. | Genetic: Infusion of modified CAR19 T-cells (4G7-CARD T-cells)<br>* The original stem cells donor (or if not available the patient) will undergo unstimulated leucapheresis for generation of the Advanced Therapy Interventional Medicinal Product (ATIMP) 4G7-CARD T-cells. Escalating doses of the ATIMP will then be infused to the patient depending on outcome and any experienced side effects.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of generation of 4G7-CARD T-cells using the ProdigyTM system | The number of ATIMP successfully manufactured would be assessed for all registered patients | Through patient registration and manufacturing period, an average of 18 months from start of trial | 
| Maximum grade for each toxicity type as assessed by CTCAE v4.03, summarized as proportions. | 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 | Up to 3 years post final 4G7-CARD T-cell infusion | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD19+, allogeneic transplant, relapse