CAR19 Donor Lymphocytes for Relapsed CD19+ Malignancies Following Allogeneic Transplantation (CARD)

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

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.

Study Overview

• Status: Completed
• Conditions: CD19+ Malignancies: Relapse Post-allogeneic Transplant
• Intervention / Treatment: Genetic: Infusion of modified CAR19 T-cells (4G7-CARD T-cells)

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 Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • University College London Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Principal Investigator: Karl Peggs, University College London Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2017
• Primary Completion (Actual): December 31, 2019
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: May 17, 2016
• First Submitted That Met QC Criteria: September 1, 2016
• First Posted (Estimated): September 8, 2016

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 21, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: relapse; allogeneic transplant; CD19+
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Neoplasms; Recurrence
• Other Study ID Numbers: UCL16/0045

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No