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

Официальное название

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

Обзор

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.

Вмешательства

• Биопрепарат LB-DTK-BKV
  LB-DTK-BKV derived from a designated donor determined based on the type of allogeneic hematopoietic stem cell transplant the subject is undergoing. A pale yellow cell suspension filled in a colorless, transparent freeze-dried vial that is stored frozen until thawed into liquid before administration. Study participants will receive a single intravenous infusion of the assigned cell dose (low dose: 1x10\^7/m\^2;high dose: 2x10\^7/m\^2) on Visit 2 and 14 days after the initial dose.
• Другое Standard-of-care
  Standard-of-care therapy for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation will be administered according to the participant's clinical status by the principal investigator. Participants in the placebo group will not receive LB-DTK-BKV during the clinical trial.

Первичные конечные точки

• BK virus viral load [Срок оценки: From enrollment through 24 weeks after treatment initiation.]
• Immunogenicity Testing [Срок оценки: From enrollment through 24 weeks after treatment initiation.]
• Adverse Events [Срок оценки: From enrollment through 24 weeks after treatment initiation.]

Вторичные конечные точки (1)

• BK virus viral load [Срок оценки: From enrollment through 24 weeks after treatment initiation.]

Критерии участия

Критерии включения

• 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.
• 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
• Subjects confirmed by the investigator to be unresponsive to treatment despite at least 7 days of standard inpatient therapy.
• 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.
• Patients for whom at least 21 days (D+21) have elapsed since allogeneic hematopoietic stem cell transplantation as of the screening date.
• Patients who are able to reduce their steroid dosage to 0.5 mg/kg/day of prednisolone (or an equivalent dose) or less.
• For women of childbearing potential, those who tested negative on a pregnancy test (blood test) performed on the screening visit.
• 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)
• Individuals who have voluntarily decided to participate in this clinical trial and have provided written consent to comply with the restrictions.
• Individuals deemed suitable as trial subjects through screening tests (vital signs, physical examination, medical and surgical history, electrocardiogram, laboratory tests, etc.).

Критерии исключения

• 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.
• Patients with hemorrhagic cystitis caused by adenovirus (excluded via urine PCR)
• Patients with bacterial growth in urine culture (excluded via bacterial culture)
• 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.
• 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.
• Active acute graft-versus-host disease (GvHD) of grade 3 or higher.
• Patients requiring urgent anticancer therapy due to rapid tumor progression.
• 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.
• Patients requiring vasopressors.
• Patients who have previously shown hypersensitivity to T-cell therapy.
• Patients with a history of autoimmune disease.
• Patients with hemophilia who are at risk of severe bleeding during administration, or patients receiving anticoagulants.
• Patients who have received another investigational drug within 24 weeks prior to administration of the investigational drug.
• Patients with a life expectancy of less than 24 hours at the time of the screening visit.
• Patients deemed ineligible for participation in this clinical trial by the investigator.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

South Korea · 9 центров

• Seoul National University Hospital — Seoul
• Severance Hospital — Seoul
• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul
• Kyungpook National University Chilgok Hospital — Daegu
• National Cancer Center Korea — Goyang-si
• Chonnam National University Hwasun Hospital — Hwasun
• Ewha Womans University Seoul Hospital — Seoul
• … и ещё 1 центр

Публикации

• Jahangiri, V., et al., Post-Transplantation Cyclophosphamide (PTCY) Is Associated with Increased Risk of BK Virus-Associated Hemorrhagic Cystitis (BKHC) in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant (HSCT). Biology of Blood and Marrow Transplantation, 2019.25 (3): p. S359-S360.
• Cho SG, Kim N, Sohn HJ, Lee SK, Oh ST, Lee HJ, Cho HI, Yim HW, Jung SE, Park G, Oh JH, Choi BO, Kim SW, Kim SW, Chung NG, Lee JW, Hong YS, Kim TG. Long-term Outcome of Extranodal NK/T Cell Lymphoma Patients Treated With Postremission Therapy Using EBV LMP1 and LMP2a-specific CTLs. Mol Ther. 2015 Aug;23(8):1401-1409. doi: 10.1038/mt.2015.91. Epub 2015 May 28. PMID 26017177
• Simmons HZ, Bazzell AF, Dains JE. Adverse Effects of Virus-Specific T-Cell Therapy: An Integrative Review. J Adv Pract Oncol. 2019 Mar;10(2):120-131. Epub 2019 Mar 1. PMID 31538024
• Cruz CR, Hanley PJ, Liu H, Torrano V, Lin YF, Arce JA, Gottschalk S, Savoldo B, Dotti G, Louis CU, Leen AM, Gee AP, Rooney CM, Brenner MK, Bollard CM, Heslop HE. Adverse events following infusion of T cells for adoptive immunotherapy: a 10-year experience. Cytotherapy. 2010 Oct;12(6):743-9. doi: 10.3109/14653241003709686. PMID 20429793
• Green A, Rubinstein JD, Grimley M, Pfeiffer T. Virus-Specific T Cells for the Treatment of Systemic Infections Following Allogeneic Hematopoietic Cell and Solid Organ Transplantation. J Pediatric Infect Dis Soc. 2024 Feb 28;13(Supplement_1):S49-S57. doi: 10.1093/jpids/piad077. PMID 38417086
• Martits-Chalangari K, Spak CW, Askar M, Killian A, Fisher TL, Atillasoy E, Marshall WL, McNeel D, Miller MD, Mathai SK, Gottlieb RL. ALVR109, an off-the-shelf partially HLA matched SARS-CoV-2-specific T cell therapy, to treat refractory severe COVID-19 pneumonia in a heart transplant patient: Case report. Am J Transplant. 2022 Apr;22(4):1261-1265. doi: 10.1111/ajt.16927. Epub 2021 Dec 27. PMID 34910857
• Vasileiou S, Hill L, Kuvalekar M, Workineh AG, Watanabe A, Velazquez Y, Lulla S, Mooney K, Lapteva N, Grilley BJ, Heslop HE, Rooney CM, Brenner MK, Eagar TN, Carrum G, Grimes KA, Leen AM, Lulla P. Allogeneic, off-the-shelf, SARS-CoV-2-specific T cells (ALVR109) for the treatment of COVID-19 in high-risk patients. Haematologica. 2023 Jul 1;108(7):1840-1850. doi: 10.3324/haematol.2022.281946. PMID 36373249
• Dadwal SS, Bansal R, Schuster MW, Yared JA, Myers GD, Matzko M, Adnan S, McNeel D, Ma J, Gilmore SA, Vasileiou S, Leen AM, Hill JA, Young JH. Final outcomes from a phase 2 trial of posoleucel in allogeneic hematopoietic cell transplant recipients. Blood Adv. 2024 Sep 10;8(17):4740-4750. doi: 10.1182/bloodadvances.2023011562. PMID 38593233

Идентификаторы

NCT: NCT07638332 · LB-DTK-BKV-DD-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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