Clinical trial NCT06736080: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL 3)
Keywords: Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL 3)
Munc13.4
Gene Therapy
Lentiviral Vector
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2024-12-16
Enrollment: 5
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Patient aged from 3 months up to 17 years old.
2. Patient with a FHL caused by mutation of the UNC13D gene.
3. Complete remission is defined by the normalization of clinical and laboratory parameters:

   1. Resolution of fever
   2. Resolution of splenomegaly or reduced and isolated splenomegaly.
   3. Improvement of cytopenia: absolute neutrophil count \> 500/µl AND platelets cout \> 100 000/ µl (unsupported by transfusion)
   4. Normalization of serum fibrinogen level (Fibrinogen ≥1.5g/l)
   5. Resolution of hyperferritinemia (Ferritin level \< 2000µg/l)
   6. Normalization of T-cell activation
4. 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))
5. Parental, guardian's patient signed informed consent.
6. For patients of childbearing age : willing to use an effective method of contraception\* during the trial and for at least 12 months post-infusion
7. Affiliation to Social Security

Exclusion Criteria:

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

Primary outcomes:
measure: Incidence of Transplantation Related Mortality (TRM)
timeFrame: up to 6 months post treatment
measure: Frequency and severity of clinical AEs and laboratory parameters
timeFrame: throughout the whole period of the research, up to 60 months
measure: Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment
timeFrame: At 12 months post treatment
measure: Detection of Replication -Competent Lentivirus (RCL)
timeFrame: at 3, 6 and 12 months post treatment, then yearly up to 60 months
Secondary outcomes:
measure: Neutrophil and platelet recovery
timeFrame: throughout the whole period of the research, up to 60 months
measure: Quantification of the transgene copy number (VCN) on drug substance at time of cryopreservation, on PBMC, sorted T-CD3+ and sorted NK cells
timeFrame: at 1, 2, 3, 6, 9, 12, 18 and 24 months post treatment
measure: Quantification of the UNC13D RNA on PBMC
timeFrame: at 1, 2, 3, 6, 9, 12, 18 and 24 post treatment
measure: 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
timeFrame: at 6, 12 and 24 months post treatment
measure: Determination of the total number of T-cells and distribution of different subpopulations
timeFrame: at 1, 2, 3, 6, 12, 18 and 24 months post treatment
measure: Correction of degranulation function in T-CD3
timeFrame: at 6 months and 24 months post treatment
measure: Integration site analyse study
timeFrame: at 24 months post treatment
measure: Needs of PICU support
timeFrame: up to 24 months post treatment
measure: Endothelial complications
timeFrame: up to 24 months post treatment
measure: Infectious diseases
timeFrame: up to 24 months post treatment
measure: Estimate of the cost of the complete procedure, from mobilisation to transplant
timeFrame: up to 24 months post treatment
measure: stimate of the 24 months total cost
timeFrame: up to 24 months post treatment
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Necker Enfant Malades
Study officials:
affiliation: Assitance publique - Hôpitaux de Paris
name: Jean-Sébastien DIANA, MD, PhD
role: STUDY_DIRECTOR
affiliation: Inserm Institut Imagine
name: Chantal LAGRESLE, PHD
role: STUDY_CHAIR
References: