CARD: CAR19 Donor Lymphocytes for Relapsed CD19+ Malignancies Following Allogeneic Transplantation
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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:
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Dose Level 1: 1x10^6 CD3+ T-cells/kg (starting dose for all patients)
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Dose Level 2: 3x10^6 CD3+ T-cells/kg
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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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 4G7-CARD T-cells All patient will receive modified CAR19 T-cells. |
Genetic: Infusion of modified CAR19 T-cells (4G7-CARD T-cells)
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.
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
Secondary Outcome Measures
- 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
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age 16-70 years
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Confirmed diagnosis of CD19+ malignancy relapsing following allogeneic transplantation
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Agreement to have a pregnancy test, use adequate contraception for 12 months post-final 4G7-CARD T-cell infusion
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Karnofsky performance status >60
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Written informed consent
Exclusion Criteria:
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Women who are pregnant or lactating
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Prior history of ischaemic heart disease, dysrhythmias, abnormal ECG (LBBB), Multi Gated Acquisition Scan (MUGA) left ventricular ejection fraction (LVEF<40%) (if performed)
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Known involvement of the central nervous system or cerebral vascular accident within prior 3 months
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Patients receiving corticosteroids at a dose of > 10mg prednisolone per day (or equivalent)
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Active graft versus host disease requiring immunosuppression
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Use of rituximab within the last 2 months prior to ATIMP infusion
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Known allergy to albumin or dimethyl sulfoxide (DMSO)
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Patients who have experienced significant neurotoxicity following blinatumomab treatment
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University College London Hospital | London | United Kingdom |
Sponsors and Collaborators
- University College, London
Investigators
- Principal Investigator: Karl Peggs, University College London Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- UCL16/0045