Universal CNK-UT Therapy for Refractory aGVHD

Phase 1

Recruiting

• Conditions: Acute Graft-versus-Host Disease
• Interventions: Biological: Chimeric Natural Killer Receptor Universal T-cells (CNK-UT)

• Registration Number: NCT06750133
• Lead Sponsor: First Affiliated Hospital of Zhejiang University

Brief Summary

This is a single arm, open-label, multi-center, pilot studies (Investigator Initiated Trial, IIT) to evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of universal T-cells engineered with chimeric natural killer receptor (CNK-UT) to treat the patients with steroid-refractory/resistant or steroid-dependent aGVHD.

Detailed Description

This is a single arm, open-label, multi-center, pilot studies (Investigator Initiated Trial, IIT) to evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of universal T-cells engineered with chimeric natural killer receptor (CNK-UT) to treat the patients with steroid-refractory/resistant or steroid-dependent acute graft-versus-host disease (aGvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Study Timeline

• Status Verified: 2024-12
• Study Start: 2024-12-14
• Study First Submitted: 2024-12-20
• Study First Submitted QC: 2024-12-25
• Last Update Submitted: 2024-12-25
• Study First Posted: 2024-12-27
• Last Update Posted: 2024-12-27
• Primary Completion: 2025-12-14
• Study Completion: 2026-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

1. Aged 14-70 years, male or female;
2. Participants diagnosed with grade II~IV steroid-refractory/resistant or steroid-dependent aGVHD after allogeneic hematopoietic stem cell transplantation.
3. ECOG physical status score 0~3;
4. Estimated life expectancy > 12 weeks;
5. Female participants of childbearing age must undergo a serum or urine pregnancy test before enrollment, and the results must be negative, and agree to take acceptable measures to minimize the possibility of pregnancy during the trial; For female participants of childbearing age or male participants whose sexual partners are women of childbearing age, effective contraceptive measures should be taken during the study and for at least 6 months following the last dose of the study cells infusion.
6. Participants voluntarily participate in clinical trial; Understand and know this study, sign an informed consent form, and be willing to follow all experimental procedures.

Exclusion Criteria

1. Suffering from malignant tumors or diagnosed within 5 years before enrollment, excluding radical skin basal cell carcinoma, skin squamous cell carcinoma, thyroid cancer, breast cancer (ductal carcinoma in situ) and / or radical resection of carcinoma in situ.
2. Participants with a history of organ transplantation;
3. Participants who have previously undergone more than one allogeneic hematopoietic stem cell transplantation.
4. Uncontrolled hypertension as determined by principal investigator, a history of hypertensive crisis or hypertensive encephalopathy; symptomatic congestive heart failure (New York Heart Association classification III-IV); symptomatic or poorly controlled arrhythmias; a history of congenital long QT syndrome or a corrected QT interval (QTc) > 500 ms at screening (calculated using the Fridericia method)..
5. Systemic diseases deemed unstable by principal investigator include, but are not limited to, severe pulmonary, hepatic, renal, or metabolic disorders that require pharmacological intervention (excluding complications related to allogeneic hematopoietic stem cell transplantation).
6. Active pulmonary tuberculosis (TB), who is receiving anti-tuberculosis treatment or has received anti-tuberculosis treatment within 1 year before enrollment; human immunodeficiency virus (HIV) infection, known syphilis infection.
7. Severe infections that are active or poorly controlled clinically.
8. Participants who have received treatment from other clinical trials within 12 weeks prior to the initiation of the study.
9. Participants who have previously used any gene therapy products prior to the initiation of the study.
10. Allergic to components of CNK-UT injection.
11. Participants suffer from known mental or substance abuse disorders, which may interfere with their ability to comply with research requirements.
12. Women who are pregnant or breastfeeding, as well as male or female participants who have planned for birth within 1 year after receiving medication.
13. Uncontrolled/uncorrectable metabolic disorders or other non-malignant organ diseases or systemic diseases or secondary reactions to cancer, which can lead to higher medical risk and/or uncertainty in survival assessments.
14. Other situations that the participant is identified by the investigator as unsuitable to participate in the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
CNK-UT cell Therapy	Chimeric Natural Killer Receptor Universal T-cells (CNK-UT)	1. Dose Escalation：Single-dose intravenous injection of CNK-UT cells (3×10\^7 CNK+ cells/kg). 2. Dose Expansion：Multiple-dose intravenous injection of CNK-UT cells (6-10×10\^7 CNK+ cells/kg)according to the results of dose escalation.

Primary Outcome Measures

Name	Time	Method
Incidence of Treatment Related adverse events (AEs)	up to 1 year	Incidence of Treatment Related AEs, AEs of special interest and serious adverse events (SAEs) assessed by NCI-CTCAE v5.0 criteria
Identification of Maximum Tolerated Dose (MTD) & incidence of Dose-limiting Toxicities (DLTs)	up to 21 days since first infusion of CNK-UT cells	Incidence of dose-limiting toxicities (DLTs)

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Overall response is defined as either a complete or partial response (CR+PR), the response should be confirmed no less than 4 weeks after the first evaluation.	Overall response is defined as either a complete or partial response (CR+PR), the response should be confirmed no less than 4 weeks after the first evaluation.
Best Overall Response (BOR)	6 months	The best efficacy recorded from the beginning of treatment to the progression or recurrence of the disease.
Duration of Response (DOR)	6 months	The period from the first evaluation of CR or PR to the first evaluation of PD or death of any cause.
Progression-free Survival (PFS)	6 months	The period from the day when the participant receives the cell therapy to the first recorded disease progression (whether treated or not) or death of any cause, which occurs first.
Overall survival (OS)	6 months	The period from the first infusion to any cause of death.
Pharmacokinetics (PK) (Cmax)	up to 48 weeks	The Peak Plasma concentration (Cmax) of amplified CNK-UT DNA in peripheral blood after infusion.
Pharmacokinetics (PK) (Tmax)	up to 48 weeks	The time to reach the maximum concentration (Tmax)
Pharmacokinetics (PK)	up to 48 weeks	The Area under the plasma concentration versus time curve (AUC) of amplified CNK-UT DNA in peripheral blood after infusion.
Levels of peripheral blood lymphocyte subsets	up to 48 weeks	Percentage of CD45+CD3+TCR+T cell、CD3+CD8+ CD25+ CD69+T cell、CD3+CD4+CD25+ CD69+ T cell and Treg（CD4+CD25+FoxP3+）cell in peripheral blood detected by FCM after infusion.

Trial Locations

Locations (2)

First Affiliated Hospital of Fujian Medical University; 🇨🇳 Fuzhou, Fujian, China

The first affiliated hospital of zhejiang university, school of medicine.; 🇨🇳 Hangzhou, Zhejiang, China