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

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

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.

Study Overview

• Status: Completed
• Conditions: Leukocyte Adhesion Defect - Type I
• Intervention / Treatment: Biological: RP-L201

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Niño Jesús (HIUNJ)
• United Kingdom
  • London, United Kingdom
    • University College London Great Ormond Street Institute of Child Health
• United States
  • California
    • Los Angeles, California, United States, 90095-1489
      • University of California, Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RP-L201; 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; CD34+ enriched hematopoietic stem cells from subjects with severe LAD-I transduced ex vivo with lentiviral vector carrying the ITGB2 gene, Chim-CD18-WPRE.

What is the study measuring?

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: 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
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

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
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 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
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 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 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

Collaborators and Investigators

• Sponsor: Rocket Pharmaceuticals Inc.
• Collaborators: California Institute for Regenerative Medicine (CIRM)
• Investigators: Principal Investigator: Donald B Kohn, MD, University of California, Los Angeles; Principal Investigator: Claire Booth, MBBS, PhD, MSc, University College London Great Ormond Street Institute of Child Health; Principal Investigator: Julián Sevilla Navarro, MD, PhD, Hospital Infantil Universitario Niño Jesús

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2019
• Primary Completion (Actual): September 12, 2023
• Study Completion (Actual): September 12, 2023

Study Registration Dates

• First Submitted: January 18, 2019
• First Submitted That Met QC Criteria: January 18, 2019
• First Posted (Actual): January 23, 2019

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Leukocyte Adhesion Deficiency- Type I; LAD-I; ITGB2 mutation; CD18 deficiency
• Additional Relevant MeSH Terms: Pathologic Processes; Fibrosis; Cicatrix; Tissue Adhesions
• Other Study ID Numbers: RP-L201-0318

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No