Natural Killer(NK) Cell Therapy Targeting CLL1 in Acute Myeloid Leukemia

Clinical Study to Evaluate the Safety and Efficacy of iPSC NK Cells Targeting CLL1 in Patients With Relapsed/Refractory AML

This is a phase 1, first-in-human (FIH), open-label, multicohort study to evaluate the safety, tolerability and preliminary efficacy of CLL1 target CAR iPSC NK cells in patients with relapsed/refractory AML

Study Overview

• Status: Recruiting
• Conditions: AML, Adult
• Intervention / Treatment: Drug: CLL1 CAR-NK cell injection

Detailed Description

Acute myelogenous leukemia (AML) is a potentially cur-able disease; 70% of newly diagnosed patients achievecomplete remission with first-line therapy, but prognosisworsens for relapsed disease in both pediatric and adultpatients. CLL-1 has attracted the researchers' attention due to its high expression in AML while being absent in normal hematopoietic stem cell. Accumulating evidence have demonstrated CLL-1 is an ideal target for AML.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: He Huang, MD; Phone Number: +8613605714822; Email: hehuangyu@126.com
• Study Contact Backup: Name: Yongxian Hu, MD; Phone Number: +8615957162012; Email: huyongxian2000@aliyun.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Recruiting
      • Clinical research ethics committee of the first affiliated hospital, college of medicine, zhejiang University
      • Contact: He Huang; Phone Number: 0571-87233772; Email: hehuang@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥18 years old.
2. Confirmed diagnosis of r/r AML
3. CLL1 expression is positive in AML blasts.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and life expectancy greater than 12 weeks.

5. Adequate organ and marrow function, as defined below:

   1. Blood creatinine (Cr) ≤ 2 x ULN or calculated creatinine clearance (Cockcroft- Gault formula) ≥ 50 mL/min;
   2. Total bilirubin (TBIL) ≤ 2 x the ULN;
   3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN;
   4. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
6. Females of childbearing potential must have a negative serum pregnancy test.
7. Donor specific antibody (DSA) is negative: MFI <= 2000.
8. Provision of signed and dated informed consent form (ICF).

Exclusion Criteria:

1. Allergic to drug used in this study.

2. Subjects received any antitumor therapy as follows, prior to first NK infusion:

   1. Systemic steroid therapy within 3 days (except physiological replacement therapy);
   2. Systemic antitumor therapy within 2 weeks or at least 5 half-lives, whichever is less;
   3. Radiotherapy within 4 weeks;
   4. Donor lymphocyte infusion within 6 weeks;
   5. Intrathecal treatment within 1 week;
   6. CAR-T therapy, CAR-NK therapy, or any other genetically modified cell therapy product within 6 months;
3. History of allogeneic stem cell transplantation.
4. Received the vaccine within 4 weeks prior to the first infusion and/or expected to require vaccination from the study period to 12 weeks after the last infusion.
5. Active central nervous system Leukemia.
6. Acute Promyelocytic Leukemia (APL).
7. History of other malignant tumors, except for those who have achieved complete remission more than 5 years after radical treatment without any signs of recurrence.
8. Active autoimmune diseases.
9. History of central nervous system disease or meningeal involvement such as epilepsy, paralysis, aphasia, stroke, etc.

10. Serious cardiovascular and cerebrovascular diseases:

    1. Severe heart rhythm or conduction abnormalities, corrected QT interval (QTc)≥480 ms;
    2. Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events within 6 months prior to first infusion;
    3. New York Heart Association (NYHA) class II or above congestive heart failure or left ventricular ejection fraction (LVEF) <50% in color Doppler echocardiography;
    4. Hypertension that cannot be controlled by drug.
11. Active pulmonary infection; SpO2 ≤90%; Pulmonary embolism, chronic obstructive pulmonary disease, or interstitial lung disease.
12. Uncontrolled bacterial, fungal, or viral infection. Known HIV infection, active Hepatitis B (HBV) or Hepatitis C (HCV) infection.
13. History of substance abuse.
14. Toxicity induced by previous therapy not recovered to ≤ grade 2(NCI-CTCAE v5.0).
15. Large surgical treatment within 4 weeks prior to first infusion, not including diagnostic biopsy.
16. Pregnant/breastfeeding women.
17. Investigator-assessed presence of any medical or social issues that are likely to interfere with study conduct or may cause increased risk to subject.

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 cell therapy in Adult subjects with r/r AML	Drug: CLL1 CAR-NK cell injection; Drug: CLL1 NK cell therapy Drug: Cyclophosphamid Lympho-conditioning Agent Drug: Fludarabine Lympho-conditioning Agent Drug: VP-16 Lympho-conditioning Agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Safety and Tolerability	28 Days from first dose of iPSC NK cell infusion
Incidence of subjects with Dose Limiting Toxicities within each dose level cohort	Tolerability	28 Days from first dose of iPSC NK cell infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the pharmacokinetics (PK) of iPSC NK cells in peripheral blood	The PK of iPSC NK in peripheral blood will be reported as the relative percentage of product DNA versus patient DNA (% chimerism) measured from blood samples at the specified time points	Up to approximately 2 years after last dose of iPSC NK cell infusion

Collaborators and Investigators

• Sponsor: Zhejiang University
• Collaborators: Hangzhou Qihangene Biotech Co.,Ltd.
• Investigators: Principal Investigator: He Huang, MD, First Affiliated Hospital of Zhejiang University

Study record dates

Study Major Dates

• Study Start (Estimated): September 10, 2023
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: August 30, 2023
• First Submitted That Met QC Criteria: August 30, 2023
• First Posted (Actual): September 7, 2023

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: QH-CLL1-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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