Clinical trial NCT02893189: CAR19 Donor Lymphocytes for Relapsed CD19+ Malignancies Following Allogeneic Transplantation
Official title: Chimeric Antigen Receptor (CAR)19 Donor Lymphocytes for Relapsed Cluster of Differentiation (CD)19+ Malignancies Following Allogeneic Transplantation (CARD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: CD19+ Malignancies: Relapse Post-allogeneic Transplant
Keywords: CD19+
allogeneic transplant
relapse
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2016-09-08
Enrollment: 17
Sex: ALL
Minimum age (years): 16
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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Feasibility of generation of 4G7-CARD T-cells using the ProdigyTM system
timeFrame: Through patient registration and manufacturing period, an average of 18 months from start of trial
measure: Maximum grade for each toxicity type as assessed by CTCAE v4.03, summarized as proportions.
timeFrame: Up to 3 years post final 4G7-CARD T-cell infusion
Secondary outcomes:
measure: Assessment of engraftment, expansion and persistence of the 4G7-CARD T-cells as determined by quantitative polymerase chain reaction (qPCR) or flow cytometry
timeFrame: 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
measure: Assessing the depletion of B cell compartment, as determined by flow cytometry
timeFrame: 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
measure: Assessing the timing and magnitude of cytokine release, evaluated using Cytokine bead arrays
timeFrame: Sampling occurs at days 0, 4, 6, 11, 18, plus 1 month post final 4G7-CARD T-cell infusion
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: University College London Hospital
Study officials:
affiliation: University College London Hospital
name: Karl Peggs
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.