Leukocyte Adhesion Deficiency-I (LAD-I) MedDRA version: 20.0 Level: LLT Classification code 10018137 Term: Genetic anomalies of leukocytes System Organ Class: 100000004850
Conditions
Interventions
Product Name: LADICell
Product Code: RP-L201
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: CD34+CELLS
Other descriptive name: CD34+CELLS
Concentration unit: IU/kg international un
Sponsors
Rocket Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. A confirmed diagnosis of severe LAD-I as demonstrated by flow cytometry indicating CD18 expression on 2% will be considered eligible with =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Availability of a medically-eligible human leukocycte antigen (HLA)-identical sibling donor transplant. Patients may not be included in this trial as an alternative to a clinically-indicated and feasible HLA-matched sibling donor HSC transplant. If an HLA-identical sibling is identified, but mPB or BM HSC 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 the Principal Investigator discretion. 2. Hepatic dysfunction as defined by either: • Bilirubin > 1.5 × the upper limit of normal (ULN) or • Alanine aminotransferase (ALT) or asparate aminotransferase (AST) >2.5×ULN 3. 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. 4. 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%. 5. Evidence of active metastatic or locoregionally advanced malignancy (including hematologic malignancy) for which survival is anticipated to be less than 3 years. 6. Serious infections with persistent bloodstream pathogens at time of trial entry. (Patients 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). 7. Any medical or other contraindication for both leukopheresis and BM harvest procedure, as determined by the treating investigator. 8. Any medical or other contraindication for the administration of conditioning therapy, as determined by the treating investigator. 9. 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. 10. Any medical or psychiatric condition that in the opinion of the Investigator renders the patient unfit for trial participation or at higher than acceptable risk for participation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): The primary efficacy endpoint is the proportion of patients alive at age 2 (24 months) and at least 1 year post-IMP infusion without allogeneic HSC transplant post-IMP infusion;Timepoint(s) of evaluation of this end point: Up to 2 years after infusion;Main Objective: The primary objective is the characterization of the safety and toxicity associated with infusion of investigational product: autologous CD34+ enriched cells transduced with the therapeutic LV (Chim.hCD18-LV). A second primary objective is the survival, as determined by the proportion of patients which are alive at age 2 (24 months) and at least 1 year post-IMP infusion without allogeneic HSC transplant post-IMP infusion.;Secondary Objective: Determination whether infusion of IMP results in increase in the percentage of neutrophils expressing CD18 to at least 10%. • Determination of whether infusion of IMP results in VCN/cell of at least 0.1 in peripheral blood (PB) neutrophils carrying the therapeutic Chim.hCD18-LV provirus at 6 months post-infusion. • Determination of the incidence and severity of bacterial or other infections (subsequent to hematopoietic reconstitution). • Evaluation of decreases (partial or to normal levels) of LAD-I-associated neutrophilia. Evaluation of resolution (partial or complete) of any underlying skin rash or periodontal abnormalities. • Assessment of overall survival (beyond age 24 months and beyond the initial year subsequent to investigational therapy). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Determination of whether at least 10% of PB neutrophils show CD18 expression, and evaluation of increased expression of additional beta-2 integrin components CD11a and CD11b in PB neutrophils, as determined by flow cytometry. . • Decrease from pre-infusion (partial or to normal levels) of LAD-I-associated neutrophilia. • Incidence of hospitalizations or outpatient-based treatments for systemic bacterial, fungal, or viral infections (including, but not limited to, CMV infections). Insertional mutagenesis: Evaluation of gene modified clonal repertoire and lentiviral insertion site analysis in blood and, if feasible, bone marrow cells via MGS-PCR • Replication competent lentivirus (RCL) (if necessary in settings where there is clinical suspicion of unexplained viral illness, or where otherwise required) in blood. • Immunogenicity: evidence of antibodies against CD18 (or other B2-integrin components CD11a or CD11b) in blood (serum) (if necessary in settings where there is clinical suspicion of immunogenic response or evidence of decreasing CD18 expression) • Incidence of respiratory complications (including but not limited to pneumonitis) • Incidence of hepatic complications (including, but not limited to, veno-occlusive disease (VOD);Timepoint(s) of evaluation of this end point: Up to 2 years after infusion | — |
Countries
Spain
Contacts
Public ContactTeresa Bricio
Alpha Bioresearch, S.L.
Outcome results
None listed