Evaluation of the Safety and Efficacy of LB-DTK-BKV in Patients With BK Virus-Associated Hemorrhagic Cystitis Following Allogeneic Hematopoietic Stem Cell Transplantation

A Single-Center, Open-Label, Phase 1/2 Clinical Trial to Evaluate the Safety and Efficacy of LB-DTK-BKV in Patients With BK Virus-Associated Hemorrhagic Cystitis Following Allogeneic Hematopoietic Stem Cell Transplantation in Children, Adolescents, and Adults

The goal of this clinical trial is to assess efficacy of BK virus specific T cells (LB-DTK-BKV) to treat pediatric, adolescent, and adult patients with BK virus-associated hemorrhagic cystitis after allogenic hematopoietic stem cell transplantation (allo-HSCT). It will also evaluate the safety of LB-DTK-BKV using treatment-emergent adverse events (TEAEs). The main questions it aims to answer are:

• Does LB-DTK-BKV reduce the number of BKV virus viral load in allo-HSCT patients with hemorrhagic cystitis?
• Do adverse events occur after the second dose? Researchers will compare LB-DTK-BKV to a placebo to see if LB-DTK-BKV works to treat hemorrhagic cystitis in allo-HSCT patients.

Participants will:

• Receive a single intravenous infusion of LB-DTK-BKV at the baseline visit (low dose: 1x10^7/m^2; high dose: 2x10^7/m^2).
• Receive the second dose of LB-DTK-BKV intravenously at the same dose 14 days after the first dose.
• Visit the clinic every week for follow-up for 6 months after the first dose.

Inclusion Criteria:

1. Patients who have undergone allogeneic hematopoietic stem cell transplantation, including pediatric and adolescent patients as well as adults who were 12 years of age or older at the time of transplantation. However, only adults aged 19 years or older are eligible for enrollment in Phase 1.

2. Patients diagnosed with BK virus-associated hemorrhagic cystitis who meet all three of the following criteria.

   • Clinical symptoms and signs of cystitis, such as lower abdominal pain and dysuria
   • Hematuria of grade 2 or higher according to the Bedi criteria
   • Detection of BKV >7log10 copies/mL in urine

3. Subjects confirmed by the investigator to be unresponsive to treatment despite at least 7 days of standard inpatient therapy.

4. Patients with evidence of neutrophil engraftment, defined as an absolute neutrophil count (ANC) maintained at 0.5 × 10³/μL or higher for 3 consecutive days following allogeneic hematopoietic stem cell transplantation.

5. Patients for whom at least 21 days (D+21) have elapsed since allogeneic hematopoietic stem cell transplantation as of the screening date.

6. Patients who are able to reduce their steroid dosage to 0.5 mg/kg/day of prednisolone (or an equivalent dose) or less.

7. For women of childbearing potential, those who tested negative on a pregnancy test (blood test) performed on the screening visit.

8. Female subjects or male subjects with female partners who agree to use the following contraceptive methods during the duration of this clinical trial and who meet the following criteria:

   • Female participants or male participants with female partners who are postmenopausal (diagnosed with non-therapy-induced amenorrhea for 12 months or more or menopause)

   • Female subjects or the female partners of male subjects who are surgically sterile (i.e., lacking ovaries and/or a uterus)

   • Individuals who have agreed to strict abstinence during the clinical trial period [For female participants, intermittent abstinence (e.g., withdrawal during ovulation, the basal body temperature method, or withdrawal after ovulation) does not constitute agreement to abstinence]

   • If the female subject or the female partner of a male subject is a woman of childbearing potential (WOCBP) who has not undergone sterilization, those who meet the following criteria:

     • Hormonal contraceptives (implant, patch, oral)
     • Intrauterine devices
     • Dual barrier method (simultaneous use of the following two contraceptive methods: male condoms, female condoms, cervical caps, contraceptive diaphragms, contraceptive sponges)

9. Individuals who have voluntarily decided to participate in this clinical trial and have provided written consent to comply with the restrictions.

10. Individuals deemed suitable as trial subjects through screening tests (vital signs, physical examination, medical and surgical history, electrocardiogram, laboratory tests, etc.).

Exclusion Criteria:

1. Individuals who have received treatment with ATG (Antithymocyte Globulin), Campath (Alemtuzumab), or other T-cell immunosuppressive monoclonal antibodies within 28 days prior to the first dose.

2. Patients with hemorrhagic cystitis caused by adenovirus (excluded via urine PCR)

3. Patients with bacterial growth in urine culture (excluded via bacterial culture)

4. Individuals who meet any of the following criteria at the time of screening:

   • Uncontrolled hypertension

     • Systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite taking antihypertensive medication.

   • Uncontrolled diabetes: Severe diabetes is defined as follows.

     • Severe hyperglycemia with HbA1C ≥ 10.0%
     • Individuals who have been hospitalized for diabetic ketoacidosis within the past 12 weeks.
     • Individuals who have received emergency treatment or been hospitalized within the past 12 weeks for severe hypoglycemia (glucose <54 mg/dL) accompanied by seizures and loss of consciousness.

   • Human Immunodeficiency Virus (HIV) infection

   • Hepatitis B Virus (HBV) infection. However, individuals who are HBsAg-negative and Anti-HBcAb-positive are not subject to this exclusion criterion.

   • Hepatitis C Virus (HCV) infection

   • Tuberculosis

   • Syphilis

   • Moderate or severe liver damage [Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN)]

   • Patients with other uncontrolled infections. However, the following cases are considered controlled infections and do not meet the exclusion criteria.

     • Bacterial infection Patients must be undergoing definitive antibiotic treatment for the infection and must have shown no signs of progression of the infection for 72 hours prior to enrollment in this clinical trial.
     • Fungal infection The patient must be receiving systemic antifungal therapy and must have shown no signs of infection progression for 1 week prior to enrollment in this clinical trial.

5. Patients who have undergone allogeneic hematopoietic stem cell transplantation within 28 days prior to the scheduled first dose, or who have received donor lymphocyte infusion (DLI) within 28 days prior to enrollment in this clinical trial.

6. Active acute graft-versus-host disease (GvHD) of grade 3 or higher.

7. Patients requiring urgent anticancer therapy due to rapid tumor progression.

8. Patients with a history of substance abuse within 24 weeks prior to administration of the investigational drug, or patients suspected of taking drugs of concern based on medical history and physical examination.

9. Patients requiring vasopressors.

10. Patients who have previously shown hypersensitivity to T-cell therapy.

11. Patients with a history of autoimmune disease.

12. Patients with hemophilia who are at risk of severe bleeding during administration, or patients receiving anticoagulants.

13. Patients who have received another investigational drug within 24 weeks prior to administration of the investigational drug.

14. Patients with a life expectancy of less than 24 hours at the time of the screening visit.

15. Patients deemed ineligible for participation in this clinical trial by the investigator.