A Study of CD19 Targeted CAR T Cell Therapy in Pediatric Patients With Relapsed or Refractory B Cell Acute Lymphoblastic Leukaemia (B ALL) and Aggressive Mature B-cell Non-Hodgkin Lymphoma (B NHL)

Study Overview
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Brief Summary
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This is a Phase Ib study to evaluate the safety and efficacy of autologous T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 in pediatric patients with relapsed or refractory B cell acute lymphoblastic leukemia (B ALL) and relapsed or refractory B cell Non-Hodgkin lymphoma (B NHL)

Detailed Description
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This is a single-arm, open-label, multi-center, Phase Ib study to determine the safety and preliminary efficacy of AUTO1 administered intravenously in pediatric patients with r/r B ALL and with r/r aggressive mature B NHL. This study is designed to evaluate the safety and preliminary efficacy of AUTO1. The safety and tolerability of AUTO1 in pediatric patients will be continually monitored by the Sponsor. Additionally, the Independent Data Monitoring Committee (IDMC) will review the rolling safety data generated after 6 and 12 treated patients have been monitored for at least 28 days and in the event any protocol defined safety stopping criteria are met. If no pre-defined safety events related to AUTO1 are met, and the safety data are consistent with what has previously been observed with AUTO1, the IDMC can recommend continuing the study without or with modifications. Based on emerging data, the study may be stopped early due to excessive toxicity, i.e. certain pre-defined AUTO1-related safety events or deaths. The study will involve consented patients going through the following sequential study periods: screening, leukapheresis, bridging as necessary, pre-conditioning, treatment evaluation, and follow-up.

Official Title
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A Single-Arm, Open-Label, Multi-Centre, Phase Ib Study Evaluating the Safety and Preliminary Efficacy of AUTO1 in Pediatric Patients With CD19-Positive Relapsed/ Refractory (r/r) B Cell Acute Lymphoblastic Leukemia (B ALL) and Aggressive Mature B Cell Non-Hodgkin Lymphoma (B NHL)

Conditions
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Relapsed or Refractory B Cell Acute Lymphoblastic Leukemia, Relapsed or Refractory B Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: AUTO1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients < 18 years old at screening Patients with ≥ 6 kg body weight at screening B ALL Cohort: r/r CD19-positive B ALL defined as: Primary refractory disease defined as: Children's Oncology Group (COG) very high risk first relapse if first remission ≤18 months. Relapsed or refractory disease after two or more lines of systemic therapy. Relapsed or refractory disease after allogeneic transplant provided AUTO1 infusion occurs at least 3 months after stem cell transplant.. Any of the above with Philadelphia chromosome positive disease (Ph+ ALL) where patient is intolerant to or has failed two lines of any tyrosine kinase inhibitor (TKI) or one line of second-generation TKI, or if TKI therapy is contraindicated B NHL Cohort: r/r CD19-positive aggressive mature B NHL defined as: Relapsed after one or more prior therapies (can include allogeneic and autologous hematopoietic stem cell transplant) Primary refractory (have not achieved a complete or partial response after the first line of therapy) with measurable, biopsy-proven disease by radiological criteria at screening including the B NHL subtypes diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, primary mediastinal large B-cell lymphoma (PMBCL) and high-grade B-cell lymphoma (not otherwise specified) Karnofsky (age ≥ 10 years) or Lansky (age < 10 year) performance status score ≥ 50%. Local documentation of CD19 expression on leukemic blasts in the BM, peripheral blood, or cerebrospinal fluid (CSF) or biopsy within 30 days of consent Adequate renal, hepatic, pulmonary, and cardiac function Exclusion Criteria: Diagnosis of chronic myelogenous leukemia lymphoid in blast crisis History or presence of clinically relevant central nervous system (CNS) pathology Presence of CNS 3 disease or CNS 2 disease with neurological changes at screening Presence of active or uncontrolled fungal, bacterial, viral, or other infection requiring systemic antimicrobials for management Patients who had prior (less than 3 months before AUTO 1 infusion) stem cell transplant Prior CD19 targeted therapy other than blinatumomab Patients who have experienced Grade 3 or higher neurotoxicity following blinatumomab

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 18 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: AUTO1<br> | Biological: AUTO1<br>* Following pre-conditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with anti-CD19 chimeric antigen receptor (CAR) T cells<br>* Other names: Obecabtagene autoleucel (obe-cel);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of adverse events (AE) and serious adverse events (SAE) |  | Up to 24 months | 
| Incidence of severe hypogammaglobulinemia |  | Up to 24 months | 
| Duration of severe hypogammaglobulinemia |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall remission rate in B ALL patients | Defined as best response of complete remission or complete remission with incomplete recovery of counts per Investigator assessment occurring at any time after AUTO1 infusion | Up to 24 months | 
| Overall response rate in B NHL patients | Defined as best response of complete response or partial response per Investigator assessment occurring at any time after AUTO1 infusion | Up to 24 months | 
| Duration of remission in B ALL |  | Up to 24 months | 
| Duration of response in B NHL |  | Up to 24 months | 
| Overall survival in B ALL |  | Up to 24 months | 
| Overall survival in B NHL |  | Up to 24 months | 
| Incidence of CD19-negative relapse at any time in B ALL |  | Up to 24 months | 
| Incidence of CD19-negative relapse at any time in B NHL |  | Up to 24 months | 
| Event-free survival in B ALL |  | Up to 24 months | 
| Proportion of patients achieving minimal residual disease (MRD)-negative remission in BM within 3 months of AUTO1 dosing in B ALL |  | Up to 24 months | 
| Proportion of patients achieving complete remission within 3 months per Investigator assessment in B ALL |  | Up to 24 months | 
| Progression-free survival in B NHL |  | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory B cell Non-Hodgkin lymphoma, Pediatric ALL, B cell acute lymphoblastic leukemia, B cell Non-Hodgkin lymphoma, Relapsed B cell acute lymphoblastic leukemia, Relapsed B cell Non-Hodgkin lymphoma, Refractory B cell acute lymphoblastic leukemia, Aggressive mature B cell Non-Hodgkin lymphoma, Pediatric NHL, AUTO1, Obecabtagene autoleucel, CD19-positive CAR T cell