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

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.

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.

Eligibility Criteria:
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.