Department of Biotherapy, Hopital Necker Enfants Malades
Paris, 75015, France
Not Yet Recruiting
NCT Number: 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
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.
Not Yet Recruiting
Trial opening soon.
Get NotifiedKey information
Age range
3 month–45 year
Sex eligibility
All sexes
Study type
Interventional
Phase
Phase 1 / Phase 2
Primary location
Who can participate
Healthy volunteers accepted: No
Only the study team can determine whether someone qualifies for participation.
Inclusion criteria
- 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
Exclusion criteria
- 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
Treatment and study plan
MUNC-CD34
Genetic- Dosage: ≥ 2 x10e6 CD34/kg after thawing, dose limit: 20x10e6 CD34+ cells/kg
- Route of administration: intravenous, on D0
MUNC-T3
Genetic- 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
Primary outcomes
-
Incidence of Transplantation Related Mortality (TRM)
Time frame: up to 6 months post treatment
-
Frequency and severity of clinical AEs and laboratory parameters
Time frame: throughout the whole period of the research, up to 60 months
Adverse event will be measured using CTCAE
-
Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment
Time frame: At 12 months post treatment
Bone marrow analysis and VISA
-
Detection of Replication -Competent Lentivirus (RCL)
Time frame: at 3, 6 and 12 months post treatment, then yearly up to 60 months
Secondary outcomes
-
Neutrophil and platelet recovery
Time frame: throughout the whole period of the research, up to 60 months
ANC> 500/µl, Platelets > 20.000/µl on two consecutive days without transfusion
-
Quantification of the transgene copy number (VCN) on drug substance at time of cryopreservation, on PBMC, sorted T-CD3+ and sorted NK cells
Time frame: at 1, 2, 3, 6, 9, 12, 18 and 24 months post treatment
-
Quantification of the UNC13D RNA on PBMC
Time frame: at 1, 2, 3, 6, 9, 12, 18 and 24 post treatment
by Q-PCR
-
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
Time frame: at 6, 12 and 24 months post treatment
by western blot
-
Disease-free survival (DFS). evaluate the Persistent HLH remission
Time frame: at M6 and 24 months post treatment.
Disease-free survival (DFS).
-
Vector Copy Number (VCN) in Peripheral Blood Mononuclear Cells (PBMC)
Time frame: At M6 and 24 months post treatment.
> 0.2.
-
Determination of the total number of T-cells and distribution of different subpopulations.
Time frame: At 1, 2, 3, 6, 12, 18 and 24 months post treatment
Naïve and memory CD4+ and CD8+ T cells will be evaluated using CCR7/CD45RA/RO markers, and the quantification of activation marker will be performed by the expression of DR+, by flow cytometry.
-
Correction of degranulation function in T-CD3
Time frame: at 6 months and 24 months post treatment
-
Integration site analyse study
Time frame: at 24 months post treatment
-
Needs of PICU support
Time frame: up to 24 months post treatment
-
Endothelial complications
Time frame: up to 24 months post treatment
-
Infectious diseases
Time frame: up to 24 months post treatment
-
Estimate of the cost of the complete procedure, from mobilisation to transplant
Time frame: up to 24 months post treatment
-
Estimate of the 24 months total cost.
Time frame: up to 24 months post treatment
Study contacts
Contact information is provided by the study sponsor or research team.
Aline DECHANET, Project Manager
CONTACT
01 71 19 61 69 ext. +33
Marina CAVAZZANA, MD, PhD
CONTACT
01 44 49 50 68 ext. +33
Sponsors and collaborators
Lead sponsor
Assistance Publique - Hôpitaux de Paris
Other
Collaborators
- URC-CIC Paris Descartes Necker Cochin
Registry information
Official study 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
Acronym: MUNC13-4
Important dates
- Study start
- 2026
- Primary completion
- 2029
- Study completion
- 2030
- First posted
- Dec 16, 2024
- Registry last updated
- May 22, 2026
OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.
View the official ClinicalTrials.gov record (opens in a new tab)This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.