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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
PRIMARY OBJECTIVES: To evaluate the feasibility and safety of UCART019 in patients with relapsed or refractory CD19+ leukemia and lymphoma. 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: For patients with detectable disease, measure anti-tumor response due to UCART019 cell infusions. 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.

Official Title
-----------------
Phase I/II Study to Determine the Safety, Tolerability, Biological Activity and Efficacy of Universal CRISPR-Cas9 Gene-Editing CAR-T Cells Targeting CD19(UCART019) in Patients With Relapsed or Refractory CD19+ Leukemia and Lymphoma

Conditions
-----------------
B Cell Leukemia, B Cell Lymphoma

Intervention / Treatment
-----------------
* Biological: UCART019


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female participant 12 Years to 75 Years (Infant, Child, Adult, Senior) Patient with relapsed or refractory CD19 positive B-cell leukemia or lymphoma Estimated life expectancy ≥ 12 weeks (according to investigator's judgement) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Adequate organ function Exclusion Criteria: Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease Diagnosis of Burkitt's leukemia/lymphoma according to WHO classification or chronic myelogenous leukemia lymphoid blast crisis Richter's syndrome Presence of Grade II-IV (Glucksberg) or B-D (IBMTR) acute or extensive chronic GVHD at the time of screening Subjects with any autoimmune disease or any immune deficiency disease or other disease in need of immunosuppressive therapy Severe active infection (uncomplicated urinary tract infections, bacterial pharyngitis is allowed), Prophylactic antibiotic, antiviral and antifungal treatment is permissible Active hepatitis B, active hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening Patient has an investigational medicinal product within the last 30 days prior to screening Previous treatment with investigational gene or cell therapy medicine products Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary Pregnant or nursing women

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (UCART019)<br>The UCART019 will be administered by i.v. injection over 20-30 minutes as a using a split dose approach to dosing: Day 0: 10% of total dose. Day 1: 30% of total dose if patient is stable (no significant toxicity) from prior dose. D2: 60% of total dose if patient is stable (no significant toxicity) from prior dose | Biological: UCART019<br>* Day 0: 10% of total dose Day 1: 30% of total dose if patient is stable (no significant toxicity) from prior dose. D2: 60% of total dose if patient is stable (no significant toxicity) from prior dose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Severe/Adverse Events as a Measure of Safety and Tolerability |  | 24 weeks | 
| Highest dose of UCART019 that is estimated to result in defined DLT with the exception of allowable UCART019 infusion related 'expected' AEs, using CTCAE 4.0, in less than 1/3 patients |  | 8 weeks | 
| Copy numbers of UCAR019 in PB, BM and lymph nodes |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate of complete remission and partial remission.Descriptive statistics will be used |  | 24 weeks | 
| Overall survival.Descriptive statistics will be used |  | 24 weeks | 
| Progression free survival.Descriptive statistics will be used |  | 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CAR-T, Cancer treatment, Immunotherapy, Adoptive cell therapy, Chimeric antigen receptor, Universal CAR-T