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Not yet recruiting 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

Phase I / Phase II Interventional Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL 3)

For patients and families

In plain language

An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied
The protocol lists: MUNC-CD34, MUNC-T3.
Who it may be relevant to
Registry conditions: Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL 3). Basic parameters: 3 months — 45 years · All.
What needs checking
Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place
France
Next step
Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

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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

Overview

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.

Interventions

  • Genetic MUNC-CD34
    * Dosage: ≥ 2 x10e6 CD34/kg after thawing, dose limit: 20x10e6 CD34+ cells/kg * Route of administration: intravenous, on D0
  • Genetic 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

Primary outcome measures

  • 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]
  • Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment [Time frame: At 12 months post treatment]
  • Detection of Replication -Competent Lentivirus (RCL) [Time frame: at 3, 6 and 12 months post treatment, then yearly up to 60 months]
Secondary outcome measures (12)
  • Neutrophil and platelet recovery [Time frame: 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 [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]
  • 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]
  • Disease-free survival (DFS). evaluate the Persistent HLH remission [Time frame: at M6 and 24 months post treatment.]
  • Vector Copy Number (VCN) in Peripheral Blood Mononuclear Cells (PBMC) [Time frame: At M6 and 24 months post treatment.]
  • 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]
  • 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]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation
N/A
Model
Single group
Masking
Open label
Primary purpose
Treatment

Study locations

France · 1 center
  • Department of Biotherapy, Hopital Necker Enfants Malades — Paris

Identifiers

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

Primary sources (government registries)

View this study on ClinicalTrials.gov ↗