A Study Evaluating UCART019 in Patients With Relapsed or Refractory CD19+ Leukemia and Lymphoma

Overview

Autologous T cells engineered to express chimeric antigen receptors (CARs) against leukemia antigens such as CD19 on B cells have shown promising results for the treatment of relapsed or refractory B-cell malignancies. However, a subset of cancer patients especially heavily pretreated cancer patients could be unable to receive this highly active therapy because of failed expansion. Moreover, it is still a challenge to manufacture an effective therapeutic product for infant cancer patients due to their small blood volume. On the other hand, the inherent characters of autologous CAR-T cell therapy including personalized autologous T cell manufacturing and widely "distributed" approach result in the difficulty of industrialization of autologous CAR-T cell therapy. Universal CD19-specific CAR-T cell(UCART019),derived from one or more healthy unrelated donors but could avoid graft-versus-host-disease (GVHD) and minimize their immunogenicity, is undoubtedly an alternative option to address above-mentioned issues. We have generated gene-disrupted allogeneic CD19-directed BBζ CAR-T cells (termed UCART019) by combining the lentiviral delivery of CAR and CRISPR RNA electroporation to disrupt endogenous TCR and B2M genes simultaneously and will test whether it can evade host-mediated immunity and deliver antileukemic effects without GVHD. The main goal of the phase 1 portion of this phase 1/2 trial is to evaluate the safety and tolerability of several doses of UCART019 in patients with relapsed or refractory CD19+ leukemia and lymphoma, so as to establish the recommended dose and/or schedule of UCART019 for phase 2 portion. The recommended Phase 2 dose will be defined as the highest dose level of UCART019 that induced DLT in fewer than 33% of patients (i.e., one dose level below that which induced DLT in at least two of six patients). Phase 2 portion of the trial will not be initiated until the recommended Phase 2 dose is determined. In the phase 2 portion of this trial, we will mainly determine if UCART019 help the body's immune system eliminate malignant B-cells. Safety of UCART019 and impact of this treatment on survival will also be observed.

PRIMARY OBJECTIVES: 1. To evaluate the feasibility and safety of UCART019 in patients with relapsed or refractory CD19+ leukemia and lymphoma. 2. To evaluate the duration of in vivo persistence of adoptively transferred T cells, and the phenotype of persisting T cells. Real Time polymerase chain receptor (RT-PCR) analysis of peripheral blood(PB), bone marrow(BM) and lymph node will be used to detect and quantify survival of UCART019 over time. SECONDARY OBJECTIVES: 1. For patients with detectable disease, measure anti-tumor response due to UCART019 cell infusions. 2. Determine if cellular or humoral host immunity develops against the murine anti-CD19, and assess correlation with loss of detectable UCART019 (loss of engraftment). OUTLINE: This is a phase I, dose-escalation study of allogeneic CD19 CAR-T-cells followed by a phase II study. The UCART019 will be administered by i.v. injection over 20-30 minutes as a using a "split dose" approach to dosing: 10% on day 0, 30% on day 1 and 60% on day 2.