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

NCT ID: NCT06736080

Last Updated: 2024-12-16

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-31
• Study Completion Date: 2029-01-31

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.

Conditions

Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL 3)

Keywords

Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL 3); Munc13.4; Gene Therapy; Lentiviral Vector

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

MUNC

Group Type: EXPERIMENTAL

MUNC-CD34

Intervention Type: DRUG

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

MUNC-T3

Intervention Type: DRUG

• 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

Interventions

MUNC-CD34

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jean-Sébastien DIANA, MD, PhD

Role: STUDY_DIRECTOR

Assitance publique - Hôpitaux de Paris

Chantal LAGRESLE, PHD

Role: STUDY_CHAIR

Inserm Institut Imagine

Locations

Hôpital Necker Enfant Malades

Paris, , France

Countries

France

Central Contacts

Marina CAVAZZANA, MD, PhD

Role: CONTACT

Phone: 01 44 49 50 68

Email: m.cavazzana@aphp.fr

Jinmi BAEK, MSc

Role: CONTACT

Email: jinmi.baek@aphp.fr

Facility Contacts

Marina CAVAZZANA, MD, PhD

Role: primary

Other Identifiers

2023-507334-24-00

Identifier Type: CTIS

Identifier Source: secondary_id

APHP240201

Identifier Type: -

Identifier Source: org_study_id