Study of Base Edited CAR7 T Cells to Treat T Cell Malignancies (TvT CAR7) (TvT CAR7)

• ClinicalTrials.gov Identifier: NCT05397184
• Recruitment Status: Recruiting
• First Posted: May 31, 2022
• Last Update Posted: May 31, 2022
• Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
• Collaborators: UCL Great Ormond Street Institute of Child Health; Medical Research Council
• Information provided by (Responsible Party): Great Ormond Street Hospital for Children NHS Foundation Trust

Study Description

Brief Summary:

T-cell leukaemia is an uncommon type of blood cell cancer that affects white blood cells (T cells). This phase I clinical trial will treat children aged 6 months up to 16 years with T cell leukaemia which has come back (relapsed) after chemotherapy or is not responding to chemotherapy (refractory). The cell therapy is made from white blood cells (T cells) collected from a healthy donor and changed so they can kill other T cells, including leukaemia cells. These 'ready-made' CAR T cells have been made using a new technique called CRISPR base editing to modify them DNA code and have been given the name BE CAR-7. This technique allows them to work after chemotherapy and also disarms them to prevent effects against normal cells. The main aim of this study is to assess the safety of the BE CAR-7 treatment and to see if ready-made CAR T cells can eradicate T cell leukaemia ahead of a planned bone marrow transplant.

Condition or disease	Intervention/treatment	Phase
Relapsed/Refractory T-cell Acute Lymphoid Leukaemia	Biological: Cryopreserved BE CAR7 T cells (BE752TBCCLCAR7PBL)	Phase 1

Detailed Description:

Who can participate? Patients aged 6 months to 16 years with relapsed/refractory T cell leukaemia ahead of a planned bone marrow transplant

What does the study involve? Patients will undergo careful screening to confirm that this treatment is adequate for them. Chemotherapy will be given prior to BE CAR-7 infusion to improve the ability of T-cells to establish and grow. Patients will then receive a single infusion of the BE CAR-7 cells and will be closely monitored in hospital. Patients are expected to be in hospital for 4-6 weeks for the BE CAR-7 treatment and the transplant will be scheduled 2-4 weeks after the end of BE CAR7 if leukaemia cells are no longer detectable. Patients will be monitored on the study for 1 year after transplant and then long term in routine clinics.

What are the possible benefits and risks of participating? Taking part in the study of testing 'ready-made' CAR T cells could help reduce the amount of disease and get the patient into remission before a bone marrow transplant. Leukaemia is less likely to come back after a bone marrow transplant if levels in the bone marrow are undetectable. The ready-made CAR T cells are being used to try and improve the chances of successful transplantation. Side effects may include low blood cell counts, infections, cytokine storm (severe immune reaction), graft versus host disease (where the donated cells attack the body) and other complications.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Phase 1, open label, non randomised
• Masking: None (Open Label)
• Masking Description: Not applicable (Open Label)
• Primary Purpose: Other
• Official Title: Phase 1 Study of Base Edited CAR7 T Cells to Treat T Cell Malignancies (TvT CAR7)
• Actual Study Start Date: April 19, 2022
• Estimated Primary Completion Date: April 1, 2024
• Estimated Study Completion Date: September 30, 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Single-dose intravenous infusion of a banded dose of CAR7+ T cells/kg BECAR7; Single-dose intravenous infusion (weight-based dosing) of CAR7+ T cells/kg BECAR7 Total duration of treatment: 28 days Follow-up: 12 months Patients will undergo careful screening to confirm that this treatment is adequate for them. Chemotherapy will be given prior to BE CAR-7 infusion. Patients will then receive a single infusion of the BE CAR-7 cells and will be closely monitored in hospital via blood and bone marrow tests for safety and to check the levels of BE CAR-7 and leukaemia cells. Patients are expected to be in hospital for 4-6 weeks for the BE CAR-7 therapy and the transplant will be scheduled 2-4 weeks after the end of BE CAR7 if leukaemia cells are no longer detectable. Patients will be monitored on the study for 1 year every month for the first 3 months and then every 6 months and then long term in routine clinics.

Biological: Cryopreserved BE CAR7 T cells (BE752TBCCLCAR7PBL); Single-dose intravenous infusion (weight-based dosing) of a banded dose of CAR7+ T cells/kg BECAR7 Total duration of treatment: 28 days Follow-up: 12 months; Other Name: BECAR7

Outcome Measures

Primary Outcome Measures :

1. Frequency and description of adverse events after BE-CAR7 infusion [ Time Frame: 1 year ]

   Incidence of Grade 3-5 toxicities occurring from infusion up to one year follow-up.

   Severe Adverse Reactions of special interest will be CRS, ICANS and GvHD. American Society of Bone Marrow Transplantation grading scales for CRS/ICANS and National Institute of Health criteria for GVHD will be applied. Commo Terminology Criteria nomenclature will be used to grade other adverse events.

Secondary Outcome Measures :

1. Number of patients achieving disease remission ahead of allo-SCT [ Time Frame: 28 days ]
   Remission rate will be assessed by bone marrow and CNS evaluation after 28 days. Disease remission is defined as morphological complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) with MRD <10e-3 by flow and/or PCR.

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 16 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Demographic characteristics:

1. Male or female patients
2. Age ranging between 6 months and <16 years

Medical and therapeutic criteria:

1. Relapsed/refractory T cell malignancy ahead of planned allogeneic haematopoietic stem cell transplantation (allo-SCT). Morphologically confirmed with leukemic blasts in the bone marrow (>5%) or a quantifiable MRD load (by multiparameter flow cytometry and/or quantitative polymerase chain reaction)
2. CD7+ (>99%) leukaemia associated immunophenotype (LAIP)
3. Eligible and fit for allogeneic hematopoietic stem cells transplantation with suitable donor available
4. Estimated life expectancy ≥12 weeks
5. Lansky (age <16 years at the time of assent/consent) or Karnofsky (age ≥16 years at the time of assent/consent) performance status ≥70; Eastern Cooperative Oncology Group ECOG performance status < 2

Exclusion Criteria:

1. Patients/parents unwilling to undergo a follow-up for 15 years
2. Foreseeable poor compliance to the study procedures
3. Evidence of disease progression after cytoreduction
4. Uncontrollable CNS leukaemia or neurological symptoms defined as CNS grade 3 (per National Comprehensive Cancer Network guidelines)
5. Absence of suitable HLA matched or mismatched donor
6. Weight <6 kg
7. Presence of donor-specific anti-HLA antibodies directed against BE-CAR7
8. GvHD requiring systemic therapy
9. Systemic steroid therapy prednisolone >0.5 mg/kg/day
10. Known hypersensitivity to any of the test materials or related compounds
11. Active bacterial, fungal or viral infection not controlled by standard of care anti-microbial or anti-viral treatment. Uncontrolled bacteraemia/ fungaemia is defined as the ongoing detection of bacteria/fungus on blood cultures despite antibiotic or antifungal therapy. Uncontrolled viraemia is defined as rising viral loads on two consecutive occasions despite antiviral therapy.
12. Risk of pregnancy or non-compliance with contraception (if applicable). Girls of childbearing potential must have been tested negative in a pregnancy test within 14 days prior to inclusion.
13. Lactating female participants unwilling to stop breastfeeding
14. Prior CAR therapy known to be associated with ≥Grade 3 cytokine release syndrome (CRS) or ≥Grade 3 drug-related CNS toxicity

Contacts and Locations

Contacts

Contact: Robert Chiesa, Dr; 020 7405 9200 ext 8434; Robert.Chiesa@gosh.nhs.uk

Contact: Agnieszka B Kubat, MSc; 07502269573; a.kubat@ucl.ac.uk

Locations

United Kingdom

Ilyas Ali; Recruiting

London, United Kingdom, WC1N 1EH

Contact: Ilyas Ali, MSc +44 (0)207 905 2863 Ilyas.Ali@gosh.nhs.uk

Contact: Vanshree Patel, Dr +44 (0)207 905 2863 Vanshree.Patel@gosh.nhs.uk

Principal Investigator: Waseem Qasim, Professor

Sub-Investigator: Robert Chiesa, Dr

Sub-Investigator: Ajay Vora, Professor

Sponsors and Collaborators

Great Ormond Street Hospital for Children NHS Foundation Trust

UCL Great Ormond Street Institute of Child Health

Medical Research Council

Investigators

• Principal Investigator: Waseem Qasim, Professor; Great Ormond Street Hospital

More Information

• Responsible Party: Great Ormond Street Hospital for Children NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT05397184
• Other Study ID Numbers: 19IC17
• First Posted: May 31, 2022
• Last Update Posted: May 31, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasms; Leukemia; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases