A Clinical Trial to Evaluate the Safety and Efficacy of RP-L201 in Subjects With Leukocyte Adhesion Deficiency-I

Study Overview
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Brief Summary
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The primary purpose of the Phase I portion of the study is to assess the therapeutic safety and preliminary efficacy of a hematopoietic cell-based gene therapy consisting of autologous CD34+ enriched cells transduced with the therapeutic lentiviral vector, Chim-CD18-WPRE, RP-L201. The primary objectives of the Phase II portion of the study are evaluation of survival, as determined by the proportion of subjects alive at age 2 (24 months) and at least 1-year post-infusion without allogeneic hematopoietic stem cell transplant (HSCT) and characterization of the safety and toxicity associated with the infusion.

Detailed Description
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This is a pediatric non-randomized open-label Phase I/II clinical trial. The Phase I portion will include a safety evaluation and preliminary assessment of the efficacy of hematopoietic gene therapy consisting of autologous CD34+ enriched cells transduced with a lentiviral vector carrying the ITGB2 gene in subjects with severe LAD-I. CD34+ cells will be transduced ex vivo with the therapeutic vector followed by cryopreservation. If the number of CD34+ cells that are available for infusion is at least 2x10e6 total CD34+ cells/kg, subjects will undergo myeloablative conditioning with intravenous busulfan. Subjects will then receive infusion of gene-corrected hematopoietic cells approximately 24 hours following the final busulfan dose. The active agent is a self-inactivating lentiviral vector carrying the therapeutic ITGB2 gene, encoding for the human CD18 receptor (β2 integrin subunit). The therapeutic product is the subject's autologous hematopoietic stem cells that have been transduced with the lentiviral vector.

Official Title
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Gene Therapy for Leukocyte Adhesion Deficiency-I (LAD-I): A Phase I/II Clinical Trial to Evaluate the Safety and Efficacy of the Infusion of Autologous Hematopoietic Stem Cells Transduced With a Lentiviral Vector Encoding the ITGB2 Gene

Conditions
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Leukocyte Adhesion Defect - Type I

Intervention / Treatment
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* Biological: RP-L201


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A confirmed diagnosis of severe LAD-I as demonstrated by flow cytometry indicating CD18 expression on <2% neutrophils (polymorphonuclear neutrophils (PMNs)). Subjects in which CD18+ PMNs are >2% will be considered eligible with <2% CD11a or CD11b expressing PMNs and if there is a documented ITGB2 mutation and clinical history consistent with LAD-I (or known family history). At least one (1) prior significant bacterial or fungal infection US NCI CTCAE, v5.0, Grade ≥2). This criterion is not required for subjects with documented family history who meet the above inclusion criteria. Age ≥3 months. Considered to be an appropriate candidate for autologous transplantation of hematopoietic stem cells. A competent custodial parent with legal capacity to execute an institutional review board (IRB)/ethics committee (EC)-approved consent form must be available to participate in the consent process. (Informed assent will be sought from capable subjects, in accordance with the directive of the IRB/EC and with local requirements). Ability to comply with trial procedures including investigational therapy and follow-up evaluations. Exclusion Criteria: Availability of a medically-eligible human leukocyte antigen (HLA)-identical sibling donor transplant. Subjects may not be included in this trial as an alternative to a clinically-indicated and feasible HLA-matched sibling donor hematopoietic stem cell transplant. If an HLA-identical sibling is identified, but mobilized peripheral blood or bone marrow hematopoietic stem cell collection is not feasible (for example: donor is in utero, is a newborn from whom cord blood was not collected, or is unable to undergo donation procedure because of medical impairments), then inclusion may be permitted per Investigator discretion. Hepatic dysfunction as defined by either: Bilirubin >1.5× the upper limit of normal (ULN) or Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5×ULN. Renal dysfunction as defined by either Grade 3 or higher abnormalities in serum sodium, potassium, calcium, magnesium or phosphate as defined by NCI CTCAE v5.0, or the requirement for either peritoneal dialysis or hemodialysis. Pulmonary dysfunction as defined by either: Need for supplemental oxygen during the prior 2 weeks (in absence of acute infection). Oxygen saturation (by pulse oximetry) <90%. Evidence of active metastatic or locoregionally advanced malignancy (including hematologic malignancy) for which survival is anticipated to be less than 3 years. Serious infections with persistent bloodstream pathogens at time of trial entry. (Subjects with active infections (e.g., unresolved ulcerative lesions, skin or oral infections) are permitted as long as appropriate antibiotic therapy has been (or is being) administered). Any medical or other contraindication for both leukapheresis and bone marrow harvest procedure, as determined by the treating Investigator. Any medical or other contraindication for the administration of conditioning therapy, as determined by the treating Investigator. Significant medical conditions, including documented human immunodeficiency virus (HIV) infection, poorly-controlled diabetes, poorly-controlled hypertension, poorly-controlled cardiac arrhythmia or congestive heart failure; or arterial thromboembolic events (including stroke or myocardial infarction) within the 6 prior months. Any medical or psychiatric condition that in the opinion of the Investigator renders the subject unfit for trial participation or at higher than acceptable risk for participation.

Ages Eligible for Study
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Minimum Age: 3 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RP-L201<br>RP-L201 is a gene therapy product containing autologous genetically modified CD34+ hematopoietic cells transduced with Chim-CD18-WPRE lentiviral vector administered as a single intravenous infusion | Biological: RP-L201<br>* CD34+ enriched hematopoietic stem cells from subjects with severe LAD-I transduced ex vivo with lentiviral vector carrying the ITGB2 gene, Chim-CD18-WPRE.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 | Evaluation of safety associated with treatment with RP-L201 | 2 years | 
| Phase II: Survival following infusion of RP-L201 | , as determined by the proportion of subjects alive at least 1-year post investigational product infusion without allogeneic HSCT and alive at age 2 (24 months) without allogeneic HSCT for subjects less than 1 year of age at study enrollment. | 2 years | 
| Phase II: Number of participants with treatment-related adverse events as assessed by CTCAE v.5.0 | Evaluation of safety associated with treatment with RP-L201 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD18 expression after infusion of RP-L201 | Determination of the percentage of subjects in whom infusion of RP-L201 results in a change in the percentage of neutrophils expressing CD18 to at least 10% | 2 years | 
| Genetic correction after infusion of RP-L201 | Determination of the percentage of subjects in whom infusion of RP-L201 results in at least 10% of peripheral blood neutrophils carrying the therapeutic Chim-CD18-WPRE lentiviral vector provirus at 6 months post-infusion | 2 years | 
| Incidence of infections after infusion of RP-L201 | Determination of the incidence of significant infections, infection-related hospitalizations, and prolonged infection-related hospitalizations, comparing the incidences prior to investigational product infusion and subsequent to hematopoietic reconstitution. | 2 years | 
| Assessment of LAD-I-associated neutrophilia after infusion of RP-L201 | Evaluation of change to partially normal or to normal levels of LAD-I-associated neutrophilia | 2 years | 
| Assessment of LAD-I-associated leukocytosis after infusion of RP-L201 | Evaluation of change to partially normal or to normal levels of LAD-I-associated leukocytosis | 2 years | 
| Assessment of skin rash or periodontal abnormalities after infusion of RP-L201 | Evaluation of resolution (partial or complete) of any underlying skin rash or periodontal abnormalities | 2 years | 
| Assessment of overall survival after infusion of RP-L201 | Assessment of event-free survival (EFS) defined as survival without graft failure (GF) and without acute graft-versus-host disease (aGVHD) grade 2 to 4. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukocyte Adhesion Deficiency- Type I, LAD-I, ITGB2 mutation, CD18 deficiency