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

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ClinicalTrials.gov Identifier: NCT02893189
Recruitment Status : Active, not recruiting
First Posted : September 8, 2016
Last Update Posted : May 14, 2020
Sponsor:
Information provided by (Responsible Party):
University College, London

Study Description
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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
CD19+ Malignancies: Relapse Post-allogeneic Transplant Genetic: Infusion of modified CAR19 T-cells (4G7-CARD T-cells) 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:

  • 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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Chimeric Antigen Receptor (CAR)19 Donor Lymphocytes for Relapsed Cluster of Differentiation (CD)19+ Malignancies Following Allogeneic Transplantation (CARD)
Actual Study Start Date : April 27, 2017
Actual Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 2022
Arms and Interventions
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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
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Primary Outcome Measures :
  1. Feasibility of generation of 4G7-CARD T-cells using the ProdigyTM system [ Time Frame: 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

  2. Maximum grade for each toxicity type as assessed by CTCAE v4.03, summarized as proportions. [ Time Frame: 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 :
  1. Assessment of engraftment, expansion and persistence of the 4G7-CARD T-cells as determined by quantitative polymerase chain reaction (qPCR) or flow cytometry [ Time Frame: 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

  2. Assessing the depletion of B cell compartment, as determined by flow cytometry [ Time Frame: 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

  3. Assessing the timing and magnitude of cytokine release, evaluated using Cytokine bead arrays [ Time Frame: 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
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Ages Eligible for Study:   16 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02893189


Locations
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United Kingdom
University College London Hospital
London, United Kingdom
Sponsors and Collaborators
University College, London
Investigators
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Principal Investigator: Karl Peggs University College London Hospital
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT02893189    
Other Study ID Numbers: UCL16/0045
First Posted: September 8, 2016    Key Record Dates
Last Update Posted: May 14, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University College, London:
CD19+
allogeneic transplant
relapse
Additional relevant MeSH terms:
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Neoplasms
Recurrence
Disease Attributes
Pathologic Processes