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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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B Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Refractory Childhood Acute Lymphoblastic Leukemia, B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: AUTO3 (CD19/22 CAR T cells


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female patients aged 1-24 years with high risk (HR) relapsed/refractory B-lineage ALL, AND: 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, HR first relapse; OR, Standard risk relapse patients with HR cytogenetics; OR, Second or greater relapse; OR, BM minimal residual disease (MRD) ≥10-³ prior to planned SCT; OR, Any on-treatment relapse in patients aged 16-24 years. (Phase II Only - Criteria in addition to those described above:) Primary refractory disease; OR, 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, Isolated CNS relapse but with ≤CNS Grade 2 disease at time of enrolment. Documentation of CD19 and or CD22 expression on leukaemic blasts in the BM, peripheral blood, or cerebrospinal fluid within 3 months of screening. Detectable disease in the BM at a level ≥10-⁴ (Phase I only). Absolute lymphocyte count ≥0.5 x 10⁹/L. Adequate renal, hepatic, pulmonary, and cardiac function. Karnofsky (age ≥10 years) or Lansky (age <10 years) score ≥50%. Willing and able to give written, informed consent to the current study (patient and/or parent or legal guardian). Exclusion Criteria: Isolated extra-medullary disease relapse. Active CNS involvement of ALL (CNS Grade 3 per National Comprehensive Cancer Network guidelines). Active infectious bacterial or viral disease requiring IV anti-microbials for treatment. Females who are pregnant or lactating. 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. Inability to tolerate leukapheresis. 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. Pre-existing significant neurological disorder. 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. The following medications are excluded: 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. Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed >6 weeks prior to AUTO3 infusion. Graft versus host disease therapies: Any drug used for GVHD must be stopped >4 weeks prior to AUTO3 infusion. Chemotherapy: Should be stopped 1 week prior to leukapheresis and 2 days prior to starting pre-conditioning chemotherapy. 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: Severe intercurrent infection. Requirement for supplementary oxygen. Allogeneic transplant recipients with active significant acute GVHD overall Grade ≥II or moderate/severe chronic GVHD requiring systemic steroids.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AUTO3<br>Paediatric patients with relapse or refractory B-cell ALL | Biological: AUTO3 (CD19/22 CAR T cells<br>* Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with 1 to 5.0 x 10⁶/kg CD19/CD22 Chimeric Antigen Receptor (CAR) positive T cells as a single or split dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion |  | Within 30 days (+/- 3 days) after the last dose of AUTO3. | 
| Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3 | DLT was defined as i) any new non-hematological adverse event (AE) of Grade 3 or higher toxicity using the NCI CTCAE (version 5.0), which was probably or definitely related to AUTO3 therapy, which occurred within the DLT evaluation period, and which failed to resolve to Grade 2 or better within 14 days, despite appropriate supportive measures; ii) Grade 4 cytokine release syndrome (CRS) or neurotoxicity, cerebral edema, or Grade 3 neurotoxicity (including cerebral edema) that lasted >72 hours; iii) Grade >3 disseminated intravascular coagulation; iv) Grade >2 infusion reaction; v) Any other fatal event (Grade 5) or life-threatening event (Grade 4) that could not be managed with conventional supportive measures or which in the opinion of the Safety Evaluation Committee (SEC) necessitated dose reduction or other modification to trial treatment to avoid a similar hazard in future patients. | Within 30 days (+/- 3 days) after the last dose of AUTO3. | 
| Number of Patients Achieving Morphological Remission (Complete Response(CR) or Complete Response With Incomplete Count Recovery (CRi) and Minimal Residual Disease (MRD)-Negative Response in the Bone Marrow (PCR)). | Morphological response evaluations were based on the response criteria for ALL according to the NCCN guidelines version 2.2014. Minimal residual disease-negative status was achieved if MRD was <10^-4 (0.01%) by PCR amplification of individual rearrangements of Ig genes and/or flow cytometry MRD testing. | Within 30 days (+/- 3 days) post AUTO3 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis | Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients screened). | Up to 8 weeks post leukapheresis | 
| Event-Free Survival (EFS) by Morphological Analysis | Time from date of first AUTO3 infusion until the earliest of treatment failure (defined as not achieving CR/CRi post AUTO3 infusion / no response), morphological relapse, or death due to any cause, whichever occurred first. | Up to 2 years | 
| Number of Patients With CD19- and/or CD22-negative Relapse |  | Up to 2 years | 
| Relapse-Free Survival (RFS) by Morphological Analysis | Time from first achievement of morphological CR/CRi post AUTO3 treatment until the earliest of morphological relapse, or death due to any cause, whichever occurred first. | Up to 2 years | 
| Overall Survival (OS) | Calculated from the date of AUTO3 treatment to the date of death anytime post AUTO3 infusion. Patients who had not died were censored at the date of last contact. | Up to 2 years after the last patient was infused | 
| Expansion of AUTO3 Following Adoptive Transfer | Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion | Up to 2 years | 
| Persistence of AUTO3 Following Adoptive Transfer | Persistence of AUTO3 was measured by quantitative polymerase chain reaction (qPCR) and/or flow cytometry at a range of time points in the peripheral blood and the bone marrow. Persistence was defined as the timepoint in days of last detectable CAR T cell by qPCR or last assessment if zero copies per μg DNA (whichever occurred later) before morphological relapse (Tlast). | Up to 2 years | 
| Duration of B Cell Aplasia | Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lymphoblastic Leukaemia, CD19 Positive, CD22 Positive, Relapsed Acute Lymphoblastic Leukaemia, Refractory Acute Lymphoblastic Leukaemia, AUTO3