Anti-CD19 CAR-Engineered NK Cells in the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia

Study Overview
=================
Brief Summary
-----------------
This study is a single arm clinical study to observe the safety ，dose tolerance and pharmacokinetic characteristics of CAR NK-CD19 in patients with recurrent or refractory CD19 positive acute lymphoblastic leukemia, and preliminarily evaluate the effectiveness, the immunogenicity of the product and the correlation between the changes of cytokines after infusion and CRS , ICANS.

Detailed Description
-----------------
It is planned to select 9-21 patients with recurrent or refractory CD19 positive acute lymphoblastic leukemia （ALL）, from the lowest dose group. It is expected that 3-6 cases will be enrolled in each dose group. The protocol will be performed into screening period (-30 -10 days), prophase of lymophodepletion (-10 -5 days), Lymophodepletion (-5 -3 days), pre-infusion evaluation (-2 -1 days), infusion (day 0), and follow-up period (1-720 days). The incidence of DLT is observed after infusion. There are three preset dose groups in this clinical trial. The initial dose is 1.0 × 107 CAR positive NK cells/kg (body weight). Subsequent dose groups included 2.0 × 107 and 3.0 × 107 CAR positive NK cells/kg (body weight). The specific dose is determined by SRC based on the patient safety data and PK data. The maximum sample size of this study is tentatively 21 cases.

Official Title
-----------------
A Phase Ⅰ Clinical Study on the Safety and Efficacy of Chimeric Antigen Receptor Gene Modified NK Cells Targeting CD19 in Patients With Recurrent or Refractory CD19 Positive Acute Lymphoblastic Leukemia

Conditions
-----------------
Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Biological: CAR-NK-CD19 Cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥12 years in the single-dose exploration phase, age ≥3 years in the dose exploration phase, both sexes; Meet the diagnostic criteria for recurrent or refractory CD19 positive acute lymphoblastic leukemia. The main organs have good organ function. The estimated survival time is ≥12 weeks. Blood pregnancy tests for women of childbearing age are negative. The patient himself/herself , and/or his/her legal guardian, agree to participate in the trial and sign the informed consent form. Exclusion Criteria: Central nervous system involvement； Simple extramedullary leukemia or simple extramedullary recurrence； Received hematopoietic stem cell transplantation within the last 3 months and had graft-versus-host disease (GVHD) in the last 2 weeks, requiring immunosuppressive agents； Treated with high-dose corticosteroids in the last 1 week； Allogeneic cell therapy, major surgery, and live or attenuated vaccine had been received within 4 weeks prior to CAR NK-CD19 infusion； Had received other antitumor therapy or had an uncontrolled infection within 2 weeks prior to CAR NK-CD19 infusion； Systemic steroids were used within 3 days before CAR NK-CD19 infusion； Toxicity caused by previous treatment do not fully recover or do not stabilize to grade 1； Concomitant autoimmune diseases, central nervous system diseases, other active malignancies, infectious diseases, severe cardiovascular diseases, etc； Known allergies to study drugs or drugs that may be used in the study； Other conditions determined by Investigator which are not suitable for participation in the study

Ages Eligible for Study
-----------------
Minimum Age: 3 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: CAR-NK-CD19 Cells<br>After preconditioning with chemotherapy, CAR-NK-CD19 Cells will be evaluated. | Biological: CAR-NK-CD19 Cells<br>* CAR-NK-CD19 Cells, 1-3×10^7 /KG, treatment follows a lymphodepletion. Drug: Fludarabine Recommendation: 25-30 mg/m2 (D-5 D-3), determined by tumor burden at baseline. Drug: Cyclophosphamide Recommendation: 250-300 mg/m2 (D-5 D-3), determined by tumor burden at baseline.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of CAR NK-CD19 Cell | Incidence of adverse events associated with CAR NK-CD19 treatment, abnormal clinically significant laboratory findings, including dose-limiting toxicity (DLT) and maximum-tolerated Dose (MTD). | Up to 3 months after cell infusion | 
| Cell count of CAR NK-CD19 | CAR NK-CD19 cell count | From 1 to 720 days after infusion | 
| Cmax of CAR NK-CD19 | CAR gene copy number maximum (Cmax) | From 1 to 720 days after infusion | 
| Tmax of CAR NK-CD19 | Time to maximum (Tmax) | From 1 to 720 days after infusion | 
| AUC of CAR NK-CD19 | Area under curve (AUC) | From 1 to 720 days after infusion | 
| Other pharmacokinetic of CAR NK-CD19 Cell | Other related pharmacokinetic parameters in peripheral blood and bone marrow | From 1 to 720 days after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The overall response rate (ORR) | Total response rate (ORR) in 12 weeks (inclusive) after infusion of CAR NK-CD19 cells. CR/CRi ratio at 4 and 12 weeks; Duration of response (DOR); Progression free survival (PFS); Minimal residual disease (MRD) negative rate and duration at 4 and 12 weeks; Overall survival (OS) | Up to 3 months after cell infusion | 
| Concentration of anti-drug antibody (ADA) | Detection of anti-drug antibody (ADA) in CAR NK-CD19 cells | From 14 to 720 days after infusion | 
| The changes of cytokines | Detect the changes of cytokines in peripheral blood before and after CAR NK-CD19 cell infusion and the recovery time | Up to 3 months after cell infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NK, CD19 positive, Acute B lymphoblastic leukemia