CD19 /22 CAR T Cells (AUTO3) for the Treatment of B Cell Acute Lymphoblastic Leukemia (ALL)

A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety and Clinical Activity Of AUTO3, a CAR T Cell Treatment Targeting CD19 And CD22 in Paediatric And Young Adult Patients With Relapsed or Refractory B Cell Acute Lymphoblastic Leukaemia

The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment targeting CD19 and CD22 in paediatric or young adult patients with relapsed or refractory B cell acute lymphoblastic leukaemia.

The study will consist of 2 phases, a Phase I or dose escalation phase and a Phase II or expansion phase. Paediatric or young adult patients with relapsed or refractory B cell ALL will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis in order to harvest T cells, which is the starting material for the manufacture of the autologous CAR T product AUTO3 which is a CD19 and CD22 dual targeting CAR T cell product. Following pre-conditioning by a chemotherapeutic regimen, the patient will receive AUTO3 intravenously as a single or split dose and will then enter a 24-month follow-up period.

Key Inclusion Criteria:

1. Male or female patients aged 1-24 years with high risk (HR) relapsed/refractory B-lineage ALL, AND:

   1. Any bone marrow (BM) relapse or central nervous system (CNS) relapse with detectable BM disease after allogeneic stem cell transplant (SCT) and must be ≥6 months from SCT at the time of AUTO3 infusion; OR,

   2. HR first relapse; OR,

   3. Standard risk relapse patients with HR cytogenetics; OR,

   4. Second or greater relapse; OR,

   5. BM minimal residual disease (MRD) ≥10-³ prior to planned SCT; OR,

   6. Any on-treatment relapse in patients aged 16-24 years.

      (Phase II Only - Criteria in addition to those described above:)

   7. Primary refractory disease; OR,

   8. Patients with Philadelphia chromosome positive ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor (TKI) therapy, or if TKI therapy is contraindicated; OR,

   9. Isolated CNS relapse but with ≤CNS Grade 2 disease at time of enrolment.

2. Documentation of CD19 and or CD22 expression on leukaemic blasts in the BM, peripheral blood, or cerebrospinal fluid within 3 months of screening.

3. Detectable disease in the BM at a level ≥10-⁴ (Phase I only).

4. Absolute lymphocyte count ≥0.5 x 10⁹/L.

5. Adequate renal, hepatic, pulmonary, and cardiac function.

6. Karnofsky (age ≥10 years) or Lansky (age <10 years) score ≥50%.

7. Willing and able to give written, informed consent to the current study (patient and/or parent or legal guardian).

Exclusion Criteria:

1. Isolated extra-medullary disease relapse.

2. Active CNS involvement of ALL (CNS Grade 3 per National Comprehensive Cancer Network guidelines).

3. Active infectious bacterial or viral disease requiring IV anti-microbials for treatment.

4. Females who are pregnant or lactating.

5. Females of child-bearing potential and post pubertal male participants who are unwilling to use highly effective methods of contraception for a period of 1 year after the AUTO3 infusion.

6. Inability to tolerate leukapheresis.

7. Prior CD19 or CD22 targeted therapy with Grade 4 toxicity or ≥refractory Grade 3 cytokine release syndrome (CRS) or ≥Grade 3 drug related CNS toxicity.

8. Pre-existing significant neurological disorder.

9. Stem Cell Transplant patients only: active significant acute graft versus host disease (GVHD) or moderate/severe chronic GVHD requiring systemic steroids or other immunosuppressant within 4 weeks of enrolment.

10. The following medications are excluded:

    1. Steroids: Therapeutic doses of steroids must be stopped >72 hours prior to AUTO3 infusion and leukapheresis. However, physiological replacement doses of steroids are allowed: <12 mg/m2/day hydrocortisone or equivalent.
    2. Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed >6 weeks prior to AUTO3 infusion.
    3. Graft versus host disease therapies: Any drug used for GVHD must be stopped >4 weeks prior to AUTO3 infusion.
    4. Chemotherapy: Should be stopped 1 week prior to leukapheresis and 2 days prior to starting pre-conditioning chemotherapy.

11. Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or fludarabine.

For AUTO3 Infusion: Patients meeting any of the following exclusion criteria will not be treated with AUTO3 or treatment will be delayed until they no longer meet these criteria:

1. Severe intercurrent infection.
2. Requirement for supplementary oxygen.
3. Allogeneic transplant recipients with active significant acute GVHD overall Grade ≥II or moderate/severe chronic GVHD requiring systemic steroids.