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TT52CAR19 Therapy for B-cell Acute Lymphoblastic Leukaemia (B-ALL) (PBLTT52CAR19)

Primary Purpose

B Acute Lymphoblastic Leukemia

Status
Active
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
PBLTT52CAR19
Sponsored by
Great Ormond Street Hospital for Children NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for B Acute Lymphoblastic Leukemia focused on measuring relapsed, refractory

Eligibility Criteria

6 Months - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with relapsed (second or subsequent bone marrow relapse or bone marrow relapse after allo-SCT) or refractory (not achieving an initial complete response (CR) after 2 cycles of standard chemotherapy) CD19-positive B-acute lymphoblastic leukaemia
  • Morphologically confirmed with leukemic blasts in the bone marrow or a quantifiable MRD load of 1x10-4 (by multiparameter flow cytometry and/or quantitative polymerase chain reaction)
  • Eligible and fit for allogeneic hematopoietic stem cells transplantation with suitable donor available
  • Estimated life expectancy ≥ 12 weeks
  • Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age ≥ 16 years at the time of assent/consent) performance status ≥ 50 Eastern Cooperative Oncology Group ECOG performance status < 2

Exclusion Criteria:

  • Patients/parents unwilling to undergo a follow-up for 15 years
  • Foreseeable poor compliance to the study procedures
  • CD19-negative B-cell leukaemia
  • Evidence of disease progression after cytoreduction
  • Uncontrollable CNS leukaemia or neurological symptoms defined as CNS grade 3 (per National Comprehensive Cancer National guidelines). Patients developing grade 3 CNS disease at any time after enrolment will be excluded.
  • Absence of suitable HLA matched or mismatched donor
  • Weight < 6 kgs
  • Presence of donor-specific anti-HLA antibodies directed against PBLTT52CAR19
  • GvHD requiring systemic therapy
  • Systemic steroid therapy prednisolone >0.5mg/kg/day
  • Known hypersensitivity to any of the test materials or related compounds
  • Active bacterial, fungal, or viral infection not controlled by a 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 anti-fungal therapy.
  • Uncontrolled viraemia is defined as rising viral loads on two consecutive occasions despite antiviral therapy.
  • 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.
  • Lactating female participants unwilling to stop breastfeeding
  • Intrathecal methotrexate within 4 weeks or intrathecal chemotherapy (e.g Ara-C) within 2 weeks of lymphodepletion
  • Less than 2 half-lives from prior therapy with immune checkpoint pathway modifiers to lymphodepletion
  • Prior CAR19 therapy known to be associated with ≥Grade 3 cytokine release syndrome (CRS) or ≥Grade 3 drug-related CNS toxicity

Sites / Locations

  • Great Ormond Street Hospital

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Standard of care

Arm Description

Follow-up period: For patients achieving molecular remission by day 28, allo-HSCT will be scheduled as soon as practicable. Routine transplant care for 24 months will incorporate the disease monitoring and recording of adverse events of special interest and document elimination of PBLTT52CAR19 through the transplant conditioning period. For patients with refractory disease at Day 56, the monitoring of adverse events of special interest, the disease outcome will be monitored monthly up to 24 months or until a palliative therapy approach is adopted. Assessments will be carried out after the treatment period at the following time points: 1m, 2m, 3m, 6m, and 12m, 24m Physical examination, ECOG Laboratory tests Vital signs (temperature, BP, HR, respiratory rate, weight) Persistence of PBLTT52CAR19, VCN by qPCR in blood and bone marrow (if sampled) Chimerism and MRD in blood and bone marrow (if sampled) Adverse events Concomitant treatments

Outcomes

Primary Outcome Measures

B-ALL remission
The main benefit expected from PBLTT52CAR19 for anti-CD19 activity leading to anti-leukemic effect and induction of remission in children with refractory/relapsed B-ALL. Patients who achieve molecular remission will become eligible to receive an allo-HSCT that would otherwise be considered futile.Remission of B-cell acute lymphoblastic leukaemia (B-ALL) in anticipation of a haematopoietic stem cell transplant (HSCT that would otherwise be considered futile.

Secondary Outcome Measures

Full Information

First Posted
September 15, 2020
Last Updated
May 30, 2023
Sponsor
Great Ormond Street Hospital for Children NHS Foundation Trust
Collaborators
University College, London
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1. Study Identification

Unique Protocol Identification Number
NCT04557436
Brief Title
TT52CAR19 Therapy for B-cell Acute Lymphoblastic Leukaemia (B-ALL)
Acronym
PBLTT52CAR19
Official Title
Phase 1, Open Label Study of CRISPR-CAR Genome Edited T Cells (PBLTT52CAR19) in Relapsed /Refractory B Cell Acute Lymphoblastic Leukaemia
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 12, 2020 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Great Ormond Street Hospital for Children NHS Foundation Trust
Collaborators
University College, London

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
PBLTT52CAR19 modified T cells are allogenic engineered human T cells (defined as TT52CAR19 +TCRαβ-) prepared for the treatment of CD19+ B cell leukaemia. The cells are from healthy adult volunteer donors and are not HLA-matched. They have been transduced to express and anti-CD19 chimeric antigen receptor (CAR19) using a lentiviral vector that also incorporates CRISPR guides for genome editing of CD52 and TRAC loci in the presence of transiently provided Cas9. Recognition by TT52CAR19 T cells mediates eradication of CD19+ leukaemia and other CD19+ B cells through T cell mediated cytotoxicity. This study aims to apply PBLTT52CAR19 T cells to secure molecular remission in children with relapsed/refractory B-ALL ahead of programmed allogeneic stem cell transplantation. The cells are to be used in a time-limited manner for their anti-leukaemia effects and then depleted by standard pre- transplant conditioning.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B Acute Lymphoblastic Leukemia
Keywords
relapsed, refractory

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
This is an open label, single-centre, phase I, cohort study using genome edited T cells to bring patients with relapsed or refractory B-cell acute lymphoblastic leukaemia (B-ALL) into remission in anticipation of a haematopoietic stem cell transplant (HSCT) that will hopefully prevent the leukaemia from returning. It involves a single infusion of allogenic T cells transduced with a self-inactivating (SIN) lentiviral vector in up to 10 subjects aged from 6 months to 18 years. The primary objective in this study is to test the safety and secondary objective will test the efficacy of this gene therapy procedure in this population. Patients will be enrolled following diagnosis and referral to GOSH, and will receive TT52CAR19 cells at GOSH after lymphodepleting conditioning. They will be followed on this protocol for 12 months post IMP infusion.
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard of care
Arm Type
Other
Arm Description
Follow-up period: For patients achieving molecular remission by day 28, allo-HSCT will be scheduled as soon as practicable. Routine transplant care for 24 months will incorporate the disease monitoring and recording of adverse events of special interest and document elimination of PBLTT52CAR19 through the transplant conditioning period. For patients with refractory disease at Day 56, the monitoring of adverse events of special interest, the disease outcome will be monitored monthly up to 24 months or until a palliative therapy approach is adopted. Assessments will be carried out after the treatment period at the following time points: 1m, 2m, 3m, 6m, and 12m, 24m Physical examination, ECOG Laboratory tests Vital signs (temperature, BP, HR, respiratory rate, weight) Persistence of PBLTT52CAR19, VCN by qPCR in blood and bone marrow (if sampled) Chimerism and MRD in blood and bone marrow (if sampled) Adverse events Concomitant treatments
Intervention Type
Drug
Intervention Name(s)
PBLTT52CAR19
Intervention Description
gene therapy
Primary Outcome Measure Information:
Title
B-ALL remission
Description
The main benefit expected from PBLTT52CAR19 for anti-CD19 activity leading to anti-leukemic effect and induction of remission in children with refractory/relapsed B-ALL. Patients who achieve molecular remission will become eligible to receive an allo-HSCT that would otherwise be considered futile.Remission of B-cell acute lymphoblastic leukaemia (B-ALL) in anticipation of a haematopoietic stem cell transplant (HSCT that would otherwise be considered futile.
Time Frame
28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with relapsed (second or subsequent bone marrow relapse or bone marrow relapse after allo-SCT) or refractory (not achieving an initial complete response (CR) after 2 cycles of standard chemotherapy) CD19-positive B-acute lymphoblastic leukaemia Morphologically confirmed with leukemic blasts in the bone marrow or a quantifiable MRD load of 1x10-4 (by multiparameter flow cytometry and/or quantitative polymerase chain reaction) Eligible and fit for allogeneic hematopoietic stem cells transplantation with suitable donor available Estimated life expectancy ≥ 12 weeks Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age ≥ 16 years at the time of assent/consent) performance status ≥ 50 Eastern Cooperative Oncology Group ECOG performance status < 2 Exclusion Criteria: Patients/parents unwilling to undergo a follow-up for 15 years Foreseeable poor compliance to the study procedures CD19-negative B-cell leukaemia Evidence of disease progression after cytoreduction Uncontrollable CNS leukaemia or neurological symptoms defined as CNS grade 3 (per National Comprehensive Cancer National guidelines). Patients developing grade 3 CNS disease at any time after enrolment will be excluded. Absence of suitable HLA matched or mismatched donor Weight < 6 kgs Presence of donor-specific anti-HLA antibodies directed against PBLTT52CAR19 GvHD requiring systemic therapy Systemic steroid therapy prednisolone >0.5mg/kg/day Known hypersensitivity to any of the test materials or related compounds Active bacterial, fungal, or viral infection not controlled by a 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 anti-fungal therapy. Uncontrolled viraemia is defined as rising viral loads on two consecutive occasions despite antiviral therapy. 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. Lactating female participants unwilling to stop breastfeeding Intrathecal methotrexate within 4 weeks or intrathecal chemotherapy (e.g Ara-C) within 2 weeks of lymphodepletion Less than 2 half-lives from prior therapy with immune checkpoint pathway modifiers to lymphodepletion Prior CAR19 therapy known to be associated with ≥Grade 3 cytokine release syndrome (CRS) or ≥Grade 3 drug-related CNS toxicity
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Waseem Qasim, Prof
Organizational Affiliation
UCL GOSH Institute of Child Health
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Paul Veys, PhD, MD
Organizational Affiliation
Great Ormond Street Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Kanchan Rao, PhD, MD
Organizational Affiliation
Great Ormond Street Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Ajay Vora, Prof, MD
Organizational Affiliation
Great Ormond Street Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Great Ormond Street Hospital
City
London
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

TT52CAR19 Therapy for B-cell Acute Lymphoblastic Leukaemia (B-ALL)

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