Clinical trial NCT03814408: A Clinical Trial to Evaluate the Safety of RP-L102 in Pediatric Subjects With Fanconi Anemia Subtype A
Official title: A Phase I Clinical Trial to Evaluate the Safety of the Infusion of Autologous CD34+ Cells Transduced With a Lentiviral Vector Carrying the FANCA Gene in Pediatric Subjects With Fanconi Anemia Subtype A
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Fanconi Anemia Complementation Group A
Keywords: FANCA, FA-A, Fanconi Anemia Subtype A
Lead sponsor: Rocket Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2019-01-24
Enrollment: 2
Sex: ALL
Minimum age (years): 1
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The objective of this 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 a lentiviral vector carrying the FANCA gene in subjects with Fanconi anemia subtype A (FA-A).

Detailed description: This is a pediatric open-label Phase 1 clinical trial and 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 FANCA gene in subjects with FA-A. CD34+ cells will be transduced ex vivo with the therapeutic lentiviral vector and infused following transduction, without any prior conditioning. After transduction, product quality control evaluations will be carried out in aliquots of the transduced population. Investigational product will be infused via intravenous infusion with no upper or lower limit; a dose of ≥5 x 105 CD34+ cells/kg body weight will be considered optimal.

The active agent is a self-inactivating lentiviral vector carrying the therapeutic FANCA gene and the therapeutic product is subject's autologous HSCs that have been transduced with the lentiviral vector. The vector contains the functional FANCA gene.

Eligibility criteria: Inclusion Criteria:

* Fanconi anemia, as diagnosed by chromosomal fragility assay of cultured T-lymphocytes in the presence of DEB or a similar DNA-crosslinking agent.
* Subjects of Fanconi Anemia complementation group A.
* Minimum age: 1 year and a minimum of 8 kg.
* Maximum age: 12 years.
* At least one of the following hematologic parameters below lower limits of normal:

  * Hemoglobin
  * Absolute neutrophils
  * Platelets
* At least 30 CD34+ cells/μL are determined in one BM aspiration within 3 months prior to initiation of CD34+ cell collection.
* If the number of C34+ cells/ μL in BM is in the range of 10-29, PB parameters should meet two of the three following criteria:

  * Hemoglobin: ≥11g/dL
  * Neutrophils: ≥900 cells/μL
  * Platelets: ≥60,000 cells/μL
* Provide informed consent in accordance with current legislation.
* Women of childbearing age must have a negative urine pregnancy test at the baseline visit and accept the use of an effective contraception method during participation in the trial.

Exclusion Criteria:

* Subjects with an available and medically eligible human leukocyte antigen (HLA)-identical sibling donor.
* Evidence of myelodysplastic syndrome or leukemia, or cytogenetic abnormalities predictive of these conditions in BM aspirate analysis. This assessment should be made by valid studies conducted within the 3 months before the subject commences the stem cell mobilization/collection procedures of the clinical trial.
* Subjects with somatic mosaicism associated with stable or improved counts in all PB cell lineages. (If T-lymphocyte chromosomal fragility analysis indicates potential mosaicism, a medically significant decrease in at least one blood lineage over time must be documented to enable eligibility).
* Lansky performance status ≤60%.
* Any concomitant disease or condition that, in the opinion of the Principal Investigator, renders the subject unfit to participate in the study.
* Pre-existing sensory or motor impairment ≥grade 2 according to the NCI CTCAE v5.0 criteria.
* Pregnant or breastfeeding women.
* Hepatic dysfunction as defined by either:

  * Bilirubin \>3.0 × upper limit of normal (ULN) or
  * Alanine aminotransferase (ALT) \> 5.0 × ULN or
  * Aspartate aminotransferase (AST) \> 5.0 × ULN
* Renal dysfunction requiring either hemodialysis or peritoneal dialysis.
* 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 for which survival is anticipated to be less than 3 years.
* Subject is receiving androgens (i.e. danazol, oxymethalone).

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v.5.0
timeFrame: 3 years
Secondary outcomes:
measure: Phenotypic correction of T-lymphocytes in peripheral blood after infusion of RP-L102
timeFrame: 3 years
measure: Phenotypic correction of hematopoietic cells in bone marrow after infusion of RP-L102
timeFrame: 3 years
measure: Engraftment of gene-corrected hematopoietic cells after infusion of RP-L102
timeFrame: 3 years
measure: Prevention or rescue of bone marrow failure after infusion of RP-L102
timeFrame: 3 years
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University Institute for Stem Cell Biology and Regenerative Medicine Lucille Packard Children's Hospital, Stanford University
state: California
Study officials:
affiliation: Stanford University, Stem Cell Transplantation and Regenerative Medicine
name: Agnieszka Czechowicz, MD
role: PRINCIPAL_INVESTIGATOR
References: