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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 4G7-CARD T-cells | Experimental | All patient will receive modified CAR19 T-cells. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Infusion of modified CAR19 T-cells (4G7-CARD T-cells) | Genetic | 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Karl Peggs | University College London Hospitals | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University College London Hospital | London | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40643148 | Derived | Roddie C, Dias J, O'Reilly MA, Abbasian M, Cadinanos-Garai A, Vispute K, Bosshard-Carter L, Mitsikakou M, Charalambous E, Mehra V, Roddy H, Cheung GW, Hartley JA, Mahmoud N, Ensell L, Patel Y, Marzolini MAV, Farzaneh F, Nickolay L, Himoudi N, Syed F, Popova B, Galani S, Day A, Lowdell MW, Peggs KS. Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion. Blood. 2025 Oct 2;146(14):1664-1676. doi: 10.1182/blood.2025028790. | |
| 32135121 |
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| ID | Term |
|---|---|
| D012008 | Recurrence |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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|
| 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 |
| Derived |
| O'Reilly M, Roddie C, Marzolini MAV, Rodriguez-Justo M, Pomplun S, Pule M, Peggs KS. Trafficking of CAR T cells to sites of subclinical leukaemia cutis. Lancet Oncol. 2020 Mar;21(3):e179. doi: 10.1016/S1470-2045(19)30861-7. No abstract available. |