Safety and Efficacy of Gene Therapy of FHL Type 3 Caused by Mutations in the Human UNC13D Gene by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the UNC13D LV Vector Expressing the UNC13D cDNA

Официальное название

A Phase I/II Open Label Non Randomized Study, Monocentric, Single Arm, Evaluating Safety and Efficacy of Gene Therapy of FHL 3 Caused by Mutations in the Human UNC13D Gene by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the UNC13D LV Vector Expressing the UNC13D cDNA

Обзор

The investigators propose to replace HLA- partially compatible allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for FHL type 3 patients, with autologous transplantation of immunoselected gene-modified CD34+ cells, combined with transduced autologous T-cell each time this is possible and also to propose this alternative treatment as salvage in case of failure of a previous allogeneic HSCT. This approach should avoid the severe immunological complications (failure to engraft, acute or chronic graft versus host disease (GVHD)) and conditioning toxicities such as severe Veno-Occlusive Disease (VOD). As the clinical manifestations of FHL type 3 patients are triggered by opportunistic viral infections (often EBV) and can be poorly controlled or only transiently controlled by the available drugs , providing the patient after the conditioning with immediately functional autologous cytotoxic T-cells could be key to maintain the control of the viral infection and hopefully its eradication awaiting for the hematopoietic reconstitution . This procedure should avoid any reactivation of the viral infection and thus improving the patients' overall survival and event-free survival while clearing the ongoing triggering infections.

Вмешательства

• Генная терапия MUNC-CD34
  * Dosage: ≥ 2 x10e6 CD34/kg after thawing, dose limit: 20x10e6 CD34+ cells/kg * Route of administration: intravenous, on D0
• Генная терапия MUNC-T3
  * Dosage: \[1.10e4; 5.10e6\] T-CD3+/kg after thawing, * Route of administration: intravenous, on D14 post-GT +/- D28 In case of persistent circulating T-cell after the HLH remission at inclusion, the MUNC-CD34 will be completed by MUNC-T3 infusion

Первичные конечные точки

• Incidence of Transplantation Related Mortality (TRM) [Срок оценки: up to 6 months post treatment]
• Frequency and severity of clinical AEs and laboratory parameters [Срок оценки: throughout the whole period of the research, up to 60 months]
• Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment [Срок оценки: At 12 months post treatment]
• Detection of Replication -Competent Lentivirus (RCL) [Срок оценки: at 3, 6 and 12 months post treatment, then yearly up to 60 months]

Вторичные конечные точки (12)

• Neutrophil and platelet recovery [Срок оценки: throughout the whole period of the research, up to 60 months]
• Quantification of the transgene copy number (VCN) on drug substance at time of cryopreservation, on PBMC, sorted T-CD3+ and sorted NK cells [Срок оценки: at 1, 2, 3, 6, 9, 12, 18 and 24 months post treatment]
• Quantification of the UNC13D RNA on PBMC [Срок оценки: at 1, 2, 3, 6, 9, 12, 18 and 24 post treatment]
• Quantification of Munc13.4 protein level in the drug substance and on peripheral blood mononuclear cells and on sorted CD3+ and CD56+ cells in function of their number [Срок оценки: at 6, 12 and 24 months post treatment]
• Disease-free survival (DFS). evaluate the Persistent HLH remission [Срок оценки: at M6 and 24 months post treatment.]
• Vector Copy Number (VCN) in Peripheral Blood Mononuclear Cells (PBMC) [Срок оценки: At M6 and 24 months post treatment.]
• Determination of the total number of T-cells and distribution of different subpopulations. [Срок оценки: At 1, 2, 3, 6, 12, 18 and 24 months post treatment]
• Correction of degranulation function in T-CD3 [Срок оценки: at 6 months and 24 months post treatment]
• Integration site analyse study [Срок оценки: at 24 months post treatment]
• Needs of PICU support [Срок оценки: up to 24 months post treatment]
• Endothelial complications [Срок оценки: up to 24 months post treatment]
• Infectious diseases [Срок оценки: up to 24 months post treatment]

Критерии участия

Критерии включения

• Patient aged from 3 months up to 45 years old.
• Patient with a FHL caused by mutation of the UNC13D gene.
• Complete remission is defined by the normalization of clinical and laboratory parameters:

• Resolution of fever
• Resolution of splenomegaly or reduced and isolated splenomegaly.
• Improvement of cytopenia: absolute neutrophil count > 500/µl AND platelets cout > 100 000/ µl (unsupported by transfusion)
• Normalization of serum fibrinogen level (Fibrinogen ≥1.5g/l)
• Resolution of hyperferritinemia (Ferritin level < 2000µg/l)
• Normalization of T-cell activation
• Patient eligible for an allogeneic HSCT in absence of an HLA geno-identical donor (at diagnostic or 6 months after failure of a previous HSCT (rejection or loss of the graft))
• Patint or parental, guardian's patient signed informed consent.
• For patients of childbearing age : willing to use an effective method of contraception\* during the trial and for at least 12 months post-infusion
• Affiliation to Social Security

Критерии исключения

• Active CNS encephalitis related to HLH
• Existence of a matched -sibling donor
• Unwillingness to return for follow-up during the 2 years study and lifelong for off study review.
• HIV-1 or 2 or HTLV1 infections.
• Patient on AME (state medical aid) (unless exemption from affiliation)
• Pregnancy or breast feeding in a post-partum female
• Diagnosis of significant psychiatric disorder of the subject that could seriously impeded the ability to participate in the study
• Known allergies, hypersensitivity, or intolerance to any of busulfan, fludarabine, rituximab, G-CSF, plerixafor or excipients, or similar compounds
• Unable to tolerate general anesthesia and/or apheresis
• Participation in another clinical study with an investigational drug within 30 days of inclusion.
• Uncontrolled HLH manifestation

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• Department of Biotherapy, Hopital Necker Enfants Malades — Paris

Идентификаторы

NCT: NCT06736080 · APHP240201 · 2023-507334-24-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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