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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: CAR-NK-CD19 Cells

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Hebei
    • Sanhe, Hebei, China
      • Hebei Yanda Ludaopei Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CAR-NK-CD19 Cells; After preconditioning with chemotherapy, CAR-NK-CD19 Cells will be evaluated.	Biological: CAR-NK-CD19 Cells; 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.

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

Collaborators and Investigators

• Sponsor: Shanghai Simnova Biotechnology Co.,Ltd.
• Collaborators: Hebei Yanda Ludaopei Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2022
• Primary Completion (Actual): November 25, 2022
• Study Completion (Actual): November 25, 2022

Study Registration Dates

• First Submitted: September 26, 2022
• First Submitted That Met QC Criteria: September 29, 2022
• First Posted (Actual): October 3, 2022

Study Record Updates

• Last Update Posted (Actual): November 28, 2022
• Last Update Submitted That Met QC Criteria: November 24, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: NK; CD19 positive; Acute B lymphoblastic leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
• Other Study ID Numbers: XB-NK-1003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No