MUNC13.4 - 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

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Decision date (initial)

2024-10-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS _ ministère de la santé _ RHU

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

assessing the initial safety of treatment with MUNC-CD34 and MUNC-T3, including the mobilisation procedure, conditioning regimen and transplantation with LV-EF1a-UNC13D lentiviral vector gene modified autologous hematopoietic stem cells combined with transduced autologous T-cell in Munc 13.4 deficient patients.

Secondary objectives 4

1. 1. Characterized the engraftment of DPs through hematopoietic reconstitution after IV infusion of MUNC-CD34:
2. 2. Assess the initial efficacy of treatment :
3. 3. Assess the long-term safety and efficacy
4. 4. Estimate of the cost of the complete procedure, from mobilisation to transplant and estimate of the 24 months total cost.

Conditions and MedDRA coding

Familial Hemophagocytic Lymphohistiocytosis (FHL)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1. Patient aged from 3 months up to 17 years old
2. 2. Patient with a FHL caused by mutation of the UNC13D gene.
3. 3. Complete remission is defined by the normalization of clinical and laboratory parameters:
4. 4. Patient eligible for an allogeneic HSCT in absence of an HLA geno-identical donor (at diagnostic or after failure of a previous HSCT (rejection or loss of the graft))
5. 5. Parental, guardian’s patient signed informed consent.
6. 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. 7. Affiliation to Social Security

Exclusion criteria 9

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 1. Incidence of Transplantation Related Mortality (TRM) up to M3 post treatment.
2. 2. Frequency and severity of clinical AEs and laboratory parameters throughout the whole period of the research. Adverse event will be measured using CTCAE.
3. 3. Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment M12 (Bone marrow analysis and VISA) Detection of Replication –Competent Lentivirus (RCL) at M12.

Secondary endpoints 4

1. 1. Characterized the engraftment of DPs through hematopoietic reconstitution after IV infusion of MUNC-CD34: a. Neutrophil and platelet recovery (ANC> 500/µl, Platelets > 20.000/µl on two consecutive days without transfusion)
2. 2. Assess the initial efficacy of treatment : a. The Persistent HLH remission evaluated by the Disease-free survival (DFS) at M6. b. VCN in PBMC > 0.2 at M6.
3. 3. Assess the long-term safety and efficacy. a. The Persistant HLH remission evaluated by the Disease-free survival (DFS) at M24 b. VCN in PBMC > 0.2 at M24. c. Correction of degranulation function in T-CD3 at M24.
4. 4. Estimate of the cost of the complete procedure, from mobilisation to transplant and estimate of the 24 months total cost.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Marina CAVAZZANA

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Marina CAVAZZANA

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Application history

2 submissions — initial application plus substantial / non-substantial modifications