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

This is a Phase Ib study to evaluate the safety and efficacy of autologous T cells engineered with a chimeric antigen receptor (CAR) targeting cluster of differentiation (CD)19 in pediatric patients with relapsed or refractory (r/r) B cell acute lymphoblastic leukemia (B ALL) and r/r B cell Non-Hodgkin lymphoma (B NHL)

This is a single-arm, open-label, multi-center, Phase Ib study to determine the safety and preliminary efficacy of obe-cel 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 obe-cel.

The safety and tolerability of obe-cel 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 every 6 months thereafter, and in the event any protocol defined safety stopping criteria are met. If no pre-defined safety events related to obe-cel are met, and the safety data are consistent with what has previously been observed with obe-cel, 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 obe-cel-related safety events or deaths.

The study will involve consented patients going through the following sequential study periods: screening, leukapheresis, bridging as necessary, lymphodepletion, treatment evaluation, and follow-up.

Eligibility Criteria:
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:

1. Primary refractory disease defined as:

   1. National Cancer Institute high risk (defined as presenting with white blood cell count ≥ 50 × 10\^9 cells/L or aged ≥ 10 years at diagnosis) patients with MRD ≥ 0.01% after first-line induction and consolidation and blinatumomab (if allowed per country specific approvals and treatment guidelines).
   2. Refractory B ALL if BM disease ≥ 25% after first line induction and consolidation.
   3. KMT2A rearranged infant ALL with MRD ≥ 1% after first line induction and blinatumomab (if allowed per country specific approvals and treatment guidelines) or MRD ≥ 0.01% after first line induction and consolidation.
2. First relapse

   1. Children's Oncology Group high risk first relapse involving BM \< 36 months after initial diagnosis or an isolated extramedullary relapse \< 18 months after initial diagnosis.
   2. Patients with Down syndrome and infants with KMT2A rearranged are eligible with first relapse at any time.
   3. Refractory disease with MRD ≥ 0.01% after re-induction for first relapse (with or without blinatumomab, if allowed per country specific approvals and treatment guidelines).
3. Second or greater relapse
4. Relapsed or refractory post-SCT:

   a. Relapsed or refractory disease after allogeneic transplant provided obe cel infusion occurs ≥ 3 months after SCT.
5. Philadelphia chromosome positive (Ph+) ALL:

   1. Any of the above with Ph+ ALL where patient is intolerant to or has failed at least one tyrosine kinase inhibitor (TKI) or if TKI therapy is contraindicated.

B NHL Cohort: r/r CD19-positive aggressive mature B NHL defined as 1 of the following:

1. Relapsed after one or more prior therapies (can include allogeneic and autologous hematopoietic SCT).
2. Primary refractory (have not achieved a CR or PR after the first line of therapy) with measurable, disease by radiological criteria at screening including the B NHL subtypes: (i) diffuse large B-cell lymphoma (DLBCL), (ii) Burkitt's lymphoma, (iii) primary mediastinal large B-cell lymphoma (PMBCL) and (iv) high-grade B-cell lymphoma (not otherwise specified).

   * Karnofsky (age ≥ 10 years) or Lansky (age \< 10 year) performance status score ≥ 50%.
   * In patients with B ALL, local documentation of CD19 expression on leukemic blasts in the BM, peripheral blood, or cerebrospinal fluid (CSF) or biopsy done no more than 30 days prior to consent. In patients treated with blinatumomab, testing should be undertaken after blinatumomab therapy has been stopped. In patients with mature B NHL, CD19 expression must be confirmed in a biopsy after any CD19 targeted therapies.
   * 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 unrelated to CNS leukemia.
* 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 (\< 3 months before obe-cel infusion) stem cell transplant.
* Prior CD19 targeted therapy other than blinatumomab.
* Patients who have experienced Grade ≥ 3 neurotoxicity following blinatumomab.