Clinical trial NCT04557436: TT52CAR19 Therapy for B-cell Acute Lymphoblastic Leukaemia (B-ALL)
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
Overall status: COMPLETED
Phase: PHASE1
Conditions: B Acute Lymphoblastic Leukemia
Keywords: relapsed
refractory
Lead sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University College, London
First posted: 2020-09-21
Enrollment: 9
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: OTHER

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.


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

Primary outcomes:
measure: B-ALL remission
timeFrame: 28 days
Secondary outcomes:
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: UCL GOSH Institute of Child Health
name: Waseem Qasim, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Great Ormond Street Hospital
name: Paul Veys, PhD, MD
role: STUDY_DIRECTOR
affiliation: Great Ormond Street Hospital
name: Kanchan Rao, PhD, MD
role: STUDY_DIRECTOR
affiliation: Great Ormond Street Hospital
name: Ajay Vora, Prof, MD
role: STUDY_DIRECTOR
References: