Gene Therapy for Fanconi Anemia, Complementation Group A

• ClinicalTrials.gov Identifier: NCT04248439
• Recruitment Status: Recruiting
• First Posted: January 30, 2020
• Last Update Posted: November 24, 2020
• Sponsor: Rocket Pharmaceuticals Inc.
• Information provided by (Responsible Party): Rocket Pharmaceuticals Inc.

Study Description

Brief Summary:

The objective of this study is to assess the therapeutic efficacy of a hematopoietic cell-based gene therapy for patients with Fanconi anemia, subtype A (FA-A).

Hematopoietic stem cells from mobilized peripheral blood of patients with FA-A will be transduced ex vivo (outside the body) with a lentiviral vector carrying the FANCA gene. After transduction, the corrected stem cells will be infused intravenously back to the patient with the goal of preventing bone marrow failure.

Condition or disease	Intervention/treatment	Phase
Fanconi Anemia Complementation Group A	Biological: RP-L102	Phase 2

Detailed Description:

This is a pediatric open-label Phase II clinical trial to assess the efficacy of a hematopoietic gene therapy consisting of autologous CD34+ enriched cells transduced with a lentiviral vector carrying the FANCA gene in subjects with FA-A.

Enriched CD34+ hematopoietic stem cells will be transduced ex vivo with the therapeutic lentiviral vector and infused via intravenous infusion following transduction without any prior conditioning.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Clinical Trial to Evaluate the Efficacy of the Infusion of Autologous CD34+ Cells Transduced With a Lentiviral Vector Carrying the FANCA Gene in Pediatric Subjects With Fanconi Anemia Subtype A
• Actual Study Start Date: July 15, 2020
• Estimated Primary Completion Date: June 2022
• Estimated Study Completion Date: June 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: RP-L102; RP-L102 is CD34+ enriched cells from subjects with Fanconi anemia subtype A transduced ex vivo with a lentiviral vector carrying the FANCA gene	Biological: RP-L102; CD34+ enriched cells from subjects with Fanconi anemia subtype A transduced ex vivo with a lentiviral vector carrying the FANCA gene

Outcome Measures

Primary Outcome Measures :

1. Phenotypic correction of bone marrow colony forming units after infusion of RP-L102 [ Time Frame: 3 years ]
   During months 12-36 post-infusion, the survival of bone marrow colony forming units to 10nM mitomycin C (MMC) increases to over or equal to 10% with respect to values determined at baseline (pretreatment evaluation).

Secondary Outcome Measures :

1. Phenotypic correction of T-lymphocytes in peripheral blood after infusion of RP-L102 [ Time Frame: 3 years ]
   Assessment of the percentage of peripheral blood T-cells with diepoxybutane (DEB)-induced chromosomal aberrations
2. Engraftment of gene-corrected hematopoietic cells after infusion of RP-L102 [ Time Frame: 3 years ]
   The level of gene marking of the FANCA-lentiviral vector (LV) provirus in total peripheral blood cells is at least 0.1 vector copy number (VCN) in peripheral blood cells during months 12-36 post-infusion
3. Prevention or rescue of bone marrow failure after infusion of RP-L102 [ Time Frame: 3 years ]
   Assessment of the need for treatment of bone marrow failure 6-36 months post-infusion.

Eligibility Criteria

• Ages Eligible for Study: 1 Year and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Fanconi anemia as diagnosed by chromosomal fragility assay of cultured lymphocytes in the presence of DEB or a similar DNA-crosslinking agent
2. Patients of the complementation group FA-A
3. Minimum age: 1 year and a minimum weight of 8 kg
4. At least 30 CD34+ cells/μL are determined in one bone marrow (BM) aspiration within 3 months prior to CD34+ cell collection OR (see subsequent criterion)

5. If the number of CD34+ cells/ μL in BM is in the range of 10-29, peripheral blood (PB) parameters should meet two of the three following criteria:

   • Hemoglobin: ≥11g/dL
   • Neutrophils: ≥900 cells/μL
   • Platelets: ≥60,000 cells/μL
6. Provide informed consent in accordance with current legislation
7. 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:

1. Subjects with an available and medically eligible HLA-identical sibling donor.
2. Evidence of myelodysplastic syndrome or leukemia, or cytogenetic abnormalities other than those reported as variant(s) of normal 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.
3. 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 (≥1 NCI CTCAE grade) in at least one blood lineage over time must be documented to enable eligibility, as should <5% resistance of bone marrow colony forming cells (CFCs) to 10nM MMC; whenever possible potential mosaicism should also be evaluated by gene sequencing of MMC-resistant CFCs).
4. Lansky performance status ≤60%.
5. Any concomitant disease or condition that, in the opinion of the Principal Investigator, renders the subject unfit to participate in the study.
6. Pre-existing sensory or motor impairment ≥grade 2 according to the criteria of the NCI.
7. Pregnant or breastfeeding women.

8. Hepatic dysfunction as defined by either:

   • Bilirubin >3.0 × the upper limit of normal (ULN) or
   • Alanine aminotransferase (ALT) > 5.0 × ULN or
   • Aspartate aminotransferase (AST) > 5.0 × ULN

   For subjects with bilirubin, ALT or AST above ULN, a workup to identify the etiology of liver abnormality should be conducted prior to confirmation of eligibility as stipulated in exclusion criterion 5, including evaluation of viral hepatitis, iron overload, drug injury or other causes.

9. Renal dysfunction requiring either hemodialysis or peritoneal dialysis.

10. Pulmonary dysfunction as defined by either:

    • Need for supplemental oxygen during the prior 2 weeks in absence of acute infection or
    • Oxygen saturation by pulse oximetry <90%.
11. Evidence of active metastatic or locoregionally advanced malignancy for which survival is anticipated to be less than 3 years.
12. Subject is receiving androgens (i.e. danazol, oxymetholone).
13. Subject is receiving other investigational therapy for treatment/prevention of FA-associated bone marrow failure.

Contacts and Locations

Contacts

Contact: Clinical Information; 646-627-0033; FAclinicaltrial@rocketpharma.com

Locations

United States, California

Stanford University; Recruiting

Stanford, California, United States, 94304

Contact: Elisabeth Merkel scgt_clinical_trials_office@lists.stanford.edu

United States, Minnesota

University of Minnesota; Active, not recruiting

Minneapolis, Minnesota, United States, 55454

Sponsors and Collaborators

Rocket Pharmaceuticals Inc.

Investigators

• Principal Investigator: Agnieszka Czechowicz, MD; Stanford University
• Principal Investigator: Margaret MacMillan, MD, MSc; University of Minnesota

More Information

• Responsible Party: Rocket Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT04248439
• Other Study ID Numbers: RP-L102-0319
• First Posted: January 30, 2020
• Last Update Posted: November 24, 2020
• Last Verified: January 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rocket Pharmaceuticals Inc.:

anemia; bone marrow failure; gene therapy

Additional relevant MeSH terms:

Fanconi Syndrome; Anemia; Fanconi Anemia; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Hematologic Diseases; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Metabolic Diseases; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases