A Phase I Clinical Study of KSD-101 in Patients With Relapsed or Refractory EBV-associated Hematological Malignancies

A Single-arm, Open-label, Multi-center Phase I Clinical Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of KSD-101 in Patients With Relapsed or Refractory EBV-associated Hematological Malignancies

The main purpse of this study is to evaluate the safety and tolerability of KSD-101 in the treatment of relapsed or refractory EBV-associated hematological malignancies,to preliminarily explore the clinical efficacy ,evaluate the immune response to KSD-101 for the treatment in Patients with EBV-associated hematological diseases and the improvement in subjects' quality of life (QOL) after KSD-101 treatment.

This is a multi-center, single-arm, open-label, dose confirmation and expansion Phase I clinical study to evaluate the safety, tolerability, immune response, and preliminary clinical efficacy of KSD-101 in the treatment of relapsed or refractory EBV-associated hematological malignancies. The study is divided into three stages by age.

Inclusion Criteria:

1. Subjects and/or their legal guardians agree to participate and sign the ICF.

2. Male or female subjects who are 2-70 (inclusive,If the age exceeds 70 years, the decision will be made jointly by the investigator and the sponsor.) years old.

3. Subjects with histologically and/or cytologically confirmed EBV-associated hematological diseases, including but not limited to EBV-positive diffuse large B-cell lymphoma, EBV-positive NK/T-cell lymphoma, EBV-positive Hodgkin's lymphoma, EBV-positive Burkitt lymphoma, EBV-positive nodal T follicular helper (TFH) cell lymphoma (angioimmunoblastic-type), and EBV-positive primary cutaneous T-cell lymphoma, and meeting the following conditions

4. Positive for EBER by in situ hybridization (ISH or FISH) .

5. Eastern Cooperative Oncology Group (ECOG) score of 0-1.

6. The EBV-associated lymphoma population must have at least one measurable lesion (lymph node lesion with a longest diameter > 15 mm, or extranodal lesion with a longest diameter > 10 mm).

7. Eligible for leukapheresis and has no other contraindications for cell collection.

8. Must have adequate organ function (have not received blood transfusion or hematopoietic stimulating factor therapy within 28 days):

   • Hematology test: Monocyte count ≥ 0.1 × 10^9/L, neutrophil count ≥ 1.2 × 10^9/L, hemoglobin ≥ 90 g/L, platelet count ≥ 90 × 10^9/L
   • Liver function: ALT, AST ≤ 2.5 × ULN and TBIL ≤ 1.5 × ULN [for patients with liver metastases: ALT, AST ≤ 5 × ULN and TBIL≤ 2 × ULN]
   • Kidney function: Creatinine ≤ 1.5 × ULN (if creatinine > 1.5 ULN, creatinine clearance > 60 mL/mins is required) (The Cockcroft-Gault formula)
   • Pulmonary function: pulse oximetry ≥94%
   • Coagulation function: Fibrinogen ≥ 1.0 g/L, activated partial thromboplastin time (APTT) ≤ 1.5 × ULN, prothrombin time (PT) ≤ 1.5 × ULN
   • Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% during the screening period

9. Male and female subjects of reproductive age agree to take non-pharmacological contraceptive measures from signing the ICF until 6 months after the last dose.

Exclusion Criteria:

1. Received chemotherapy or immunosuppressive therapy within 4 weeks prior to leukapheresis or radiotherapy within 2 weeks prior to leukapheresis.

2. Underwent allogeneic transplantation prior to enrollment.

3. Received (attenuated) live vaccines within 4 weeks prior to enrollment.

4. Participated in other clinical studies within 4 weeks prior to enrollment and received at least one dose of the investigational product.

5. Underwent therapeutic surgery within 4 weeks prior to enrollment, or plan to undergo major surgery during the study, except diagnostic, biopsy and drainage procedures.

6. Presence of uncontrolled infectious disease within 4 weeks prior to enrollment, except EBV infection.

7. Receiving systemic corticosteroid therapy prior to screening and require long-term systemic corticosteroids during the treatment period (except inhalation or topical application) as judged by the investigator, or received systemic corticosteroid therapy (except inhalation or topical application) within 72 hours prior to administration.

8. Active central nervous system metastases/lesions (e.g., brain edema requiring hormone intervention or brain metastases).

9. Severe cardiovascular diseases:

   • Grade ≥ 3 cardiovascular diseases according to the New York Heart Association (NYHA) classification within 6 months prior to enrollment.
   • Unstable angina or severe arrhythmias requiring medication.
   • Other significant ECG abnormalities, including second-degree type 2 atrioventricular block, third-degree atrioventricular block, bradycardia (ventricular rate < 50 beats/min with clinical symptoms), etc.

10. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and increased peripheral blood hepatitis B virus (HBV) DNA titer above the ULN; positive for hepatitis C virus (HCV) antibody and peripheral blood HCV RNA; positive for human immunodeficiency virus (HIV) antibody; positive for syphilis-specific antibodies.

11. Have not recovered to normal or Grade ≤ 1 from prior treatment-induced AEs prior to enrollment, except alopecia (any grade) and peripheral neuropathy (Grade ≤ 2).

12. Other active malignancies within the past 3 years, except for curable cancers that have been markedly cured, such as basal or squamous cell carcinoma, cervical or breast cancer in situ.

13. Prior history of severe drug allergies or history of penicillin allergy.

14. Substance abuse/addiction.

15. Women who are pregnant or nursing.

16. Other serious medical conditions, including liver disease, kidney disease, neurological/psychiatric disorders, endocrine disorders, hematologic disorders, and immune system disorders, which will render a subject unsuitable for participation in the study as judged by the investigator.

17. Other conditions that render a subject unsuitable for enrollment as judged by the investigator.