An Early Clinical Study Evaluating the Safety and Efficacy of AcNK-Sup003 Cell Injection in the Treatment of Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma

The purpose of this study is to determine whether AcNK-Sup003 cell injection is safe and effective in the treatment of elapsed or refractory B-cell non-Hodgkin's lymphoma.

Study Overview

• Status: Recruiting
• Conditions: B-cell Non-Hodgkin Lymphoma (B-NHL)
• Intervention / Treatment: Drug: AcNK-Sup003 cell injection solution

Detailed Description

The AcNK technology has successfully achieved the direct, covalent, and directional conjugation of intact antibodies which includes the Fc domain to the surface of NK cells via a one-step enzymatic reaction. This novel approach yields a non-genetically modified NK cell that is conjugated with dual-targeting antibodies, referred to as AcNK. Specifically, AcNK-Sup003 cells are cryopreserved NK cells that have been conjugated with bispecific antibodies target both CD20 and CD19. This clinical trial is an open-label, nonrandomized, investigator-initiated clinical trial to evaluate the safety, tolerability, pharmacokinetics, and efficacy of AcNK-Sup003 cell injection in patients with elapsed or refractory B-cell non-Hodgkin's lymphoma. The treatment cycle in this study is 28 days. A modified "3+3" design principle combined with accelerated titration is used, with three dose cohorts and one alternative dose cohort, each including 1 to 6 subjects (adjustments may be made based on the safety and efficacy results of enrolled subjects). The dose levels are: Dose Level 1: 3×10^8 AcNK-Sup003 cells, Dose Level 2: 1×10^9 AcNK-Sup003 cells, Dose Level 3: 3×10^9 AcNK-Sup003 cells, Dose Level 4 (alternative dose): 9×10^9 AcNK-Sup003 cells (with a flexibility range of ±20%). Treatments are administered up to three times from Day 0 to Day 14 of each cycle (recommended D0/D7/D14, the frequency of infusion per cycle may be adjusted by the investigator based on obtained PK data and the subject's actual situation).

• Study Type: Interventional
• Enrollment (Estimated): 13
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Heng Mei, Ph.D&M.D; Phone Number: 027-8572600; Email: hmei@hust.edu.cn
• Study Contact Backup: Name: Jia Xu; Phone Number: 18274201261; Email: xu_jia@hust.edu.cn

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Recruiting
      • Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Heng Mei, Ph.D&M.D; Phone Number: 027-8572600; Email: hmei@hust.edu.cn
      • Contact: Heng Mei, Ph.D&M.D
      • Contact: Jia Xu; Phone Number: 18274201261; Email: hmei@hust.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Signed an informed consent form in writing and is able to comply with the visits and related procedures specified in the protocol.
2. Age ≥18 years old, with an expected survival of more than 3 months.
3. Confirmed by pathology to have CD20+ relapsed or refractory B-cell non-Hodgkin's lymphoma (according to the WHO 2016 lymphoma classification standards), including but not limited to diffuse large B-cell lymphoma, high-grade B-cell lymphoma, and grade 3b follicular lymphoma.

4. Relapsed or refractory disease, defined by one or more of the following:

   • Relapse, non-response, or progression after hematopoietic stem cell transplantation.
   • Disease stabilization but with a duration of ≤6 months after at least two cycles of second-line therapy (must have received CD20-targeted drugs [excluding CD20-negative tumors] and anthracycline drugs).
   • Disease progression or relapse after second-line therapy (must have received CD20-targeted drugs [excluding CD20-negative tumors] and anthracycline drugs).
5. ECOG performance status of 0-2.
6. Males with fertility potential and women of childbearing age must agree to use effective contraception from the time of signing the informed consent form until 6 months after the last administration of the study drug; women of childbearing age must have a negative pregnancy test at screening.
7. Lymphoma must have at least one measurable lesion according to the Lugano 2014 criteria, that is, lymph node lesions with a long diameter >15 mm or extranodal lesions with a long diameter >10 mm, and positive FDG-PET scan (5PS score of 4 or 5); lesions that have previously received radiotherapy are only considered measurable if there is clear evidence of radiographic disease progression after completion of radiotherapy.
8. Hematological parameters (within 7 days before testing without transfusion or hematopoietic growth factor treatment): Hemoglobin (Hb) ≥80 g/L, Absolute Neutrophil Count (ANC) ≥1×10^9/L, Platelet Count (PLT) ≥50×10^9/L.
9. Coagulation function: International Normalized Ratio (INR) ≤1.5×ULN, and Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN (subjects on prophylactic anticoagulant therapy must have an INR between 2.0-3.0).

10. Hepatic, renal, and pulmonary function must meet the following requirements:

    1. Serum creatinine ≤1.5×ULN, or creatinine clearance ≥50 mL/min (estimated by the Cockcroft-Gault formula).
    2. Total bilirubin ≤1.5×ULN (≤3×ULN for subjects with liver lesions or Gilbert's syndrome).
    3. ALT and AST ≤3×ULN (≤5×ULN for subjects with liver lesions).
    4. Under indoor ventilation conditions and without oxygen supplementation, blood oxygen saturation is ≥92%.

Exclusion Criteria:

1. Primary central nervous system lymphoma, or active central nervous system involvement or symptoms of central involvement.
2. Accompanying active autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren's syndrome, immune thrombocytopenia, etc.), uncontrolled multi-cavity effusions; presence of grade 2-4 acute graft-versus-host disease (GVHD) or moderate to severe chronic GVHD within 4 weeks before screening.

3. Severe cardiovascular and cerebrovascular history, including but not limited to:

   • Serious cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, second- or third-degree atrioventricular block, etc.
   • Prolonged QT interval corrected by the Fridericia formula (QTcF), >450 ms for males; >470 ms for females.
   • Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurring within 6 months before screening.
   • Heart failure with a New York Heart Association (NYHA) functional classification of ≥II or left ventricular ejection fraction (LVEF) <50%.
   • Clinically uncontrollable hypertension, with systolic blood pressure still ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg after standardized drug treatment.
4. Received autologous hematopoietic stem cell transplantation or other autologous cell therapy products within 3 months before lymphodepletion; received allogeneic hematopoietic stem cell transplantation or other allogeneic cell therapy products within 6 months before lymphodepletion; subjects who have undergone other organ transplants.
5. Received anti-tumor drug treatment or participated in other interventional clinical studies within 4 weeks before lymphodepletion or within 5 half-lives (whichever is shorter), including but not limited to chemotherapy drugs, small molecule targeted drugs, monoclonal antibodies, antibody-drug conjugates, etc.
6. Received live attenuated vaccine immunization or major surgery within 4 weeks before lymphodepletion, or subjects who require live attenuated vaccine immunization or major surgery during the study period.
7. Requires long-term (≥3 days) systemic corticosteroid treatment during the study period (dose ≥10 mg/day prednisone or equivalent corticosteroids), excluding inhaled or topical use; as determined by the investigator.
8. History of other malignant tumors (except for cervical carcinoma in situ, non-invasive basal cell or squamous cell skin cancer, or localized prostate cancer treated with radical therapy, and ductal carcinoma in situ after radical surgery) in the past or concurrently; suffering from severe diabetes or other severe underlying diseases.
9. Subjects with fungal, bacterial, viral, tuberculosis, or other infections requiring systemic anti-infective treatment within 14 days before lymphodepletion.
10. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with HBV DNA copies above the lower limit of detection; positive for hepatitis C virus (HCV) antibody with HCV RNA copies above the lower limit of detection; positive for human immunodeficiency virus (HIV) antibody; positive for syphilis spirochete antibody.
11. Has life-threatening hypersensitivity reactions or other intolerable conditions to the drugs used in the study, or severe allergic constitution.
12. Pregnant or breastfeeding women.
13. The investigator deems that the subject has other conditions that may affect compliance or is not suitable for participating in this 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: AcNK-Sup003 cell injection solution; The AcNK technology has successfully achieved the direct, covalent, and directional conjugation of intact antibodies which includes the Fc domain to the surface of NK cells via a one-step enzymatic reaction. This novel approach yields a non-genetically modified NK cell that is conjugated with dual-targeting antibodies, referred to as AcNK. Specifically, AcNK-Sup003 cells are cryopreserved NK cells that have been conjugated with bispecific antibodies target both CD20 and CD19.

Drug: AcNK-Sup003 cell injection solution; The AcNK technology has successfully achieved the direct, covalent, and directional conjugation of intact antibodies which includes the Fc domain to the surface of NK cells via a one-step enzymatic reaction. This novel approach yields a non-genetically modified NK cell that is conjugated with dual-targeting antibodies, referred to as AcNK. Specifically, AcNK-Sup003 cells are cryopreserved NK cells that have been conjugated with bispecific antibodies target both CD20 and CD19.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicities (DLTs)		up to Day 28 post-infusion
serious adverse events (SAEs)	The incidence, severity, and relationship to the study drug of all adverse events (AEs), including serious adverse events (SAEs). Adverse events would be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0)	Through study completion, an average of 2 years
Maximum tolerated dose		Through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Clinical efficacy would be evaluated according to 2014 Lugano criteria.	up to 1 year after treatment of AcNK-Sup003
Duration of response (DOR)	Clinical efficacy would be evaluated according to 2014 Lugano criteria.	Through study completion, an average of 2 years
Progression-free survival (PFS)	PFS is defined as the interval between a subject's receipt of the first dose of AcNK-Sup003 cell infusion and the first assessment of disease progression or death.	Through study completion, an average of 2 years
Overall survival (OS)	OS is defined as the interval between a subject's receipt of first AcNK-Sup003 cell infusion and death from any cause.	Through study completion, an average of 2 years
Cmax	Cmax is the peak expansion value of NK cells in peripheral blood.	up to Day 28 post-infusion
Tmax	Tmax is the time to maximum concentration in peripheral blood.	up to Day 28 post-infusion
AUC (0- day 28)	Area under the curve (0- day 28) refers to the area under curve of NK cell expansion between infusion and day 28 post infusion. They all reflect the pharmacokinetics.	up to Day 28 post-infusion

Other Outcome Measures

Outcome Measure	Time Frame
Changes in CD19 and/or CD20-positive B cells	Through study completion, an average of 2 years
Donor-specific HLA antibodies in the blood	Through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: Wuhan Union Hospital, China
• Collaborators: SupermAb (BeiJing) Biotech Co., Ltd

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2023
• Primary Completion (Estimated): January 13, 2026
• Study Completion (Estimated): January 13, 2026

Study Registration Dates

• First Submitted: November 13, 2024
• First Submitted That Met QC Criteria: November 15, 2024
• First Posted (Estimated): November 19, 2024

Study Record Updates

• Last Update Posted (Estimated): November 19, 2024
• Last Update Submitted That Met QC Criteria: November 15, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: CD19; CD20; NK cells
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin
• Other Study ID Numbers: Supermab01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data obtained through this study may be provided to qualified researchers with academic interest in cell therapy. Data or samples shared will be coded, with no PHI included. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party.
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• IPD Sharing Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No