Gene Therapy for Fanconi Anemia, Complementation Group A

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Fanconi Anemia Complementation Group A
• Intervention / Treatment: Biological: RP-L102

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 Type: Interventional
• Enrollment (Estimated): 5
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Clinical Information; Phone Number: 646-627-0033; Email: FAclinicaltrial@rocketpharma.com

Study Locations

• United States
  • California
    • Stanford, California, United States, 94304
      • Stanford University
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota

Participation Criteria

Eligibility Criteria

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

Description

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. Subject 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

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.

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-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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone Marrow (BM) Colony-Forming Cell (CFC) Mitomycin-C (MMC) resistance	Bone Marrow (BM) colony-forming cell (CFC) mitomycin-C (MMC) resistance ≥20% at 12 months post-infusion with a confirmatory result at 18 or 21 months (MMC at 10 nM concentration)	21 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic Correction	Evidence of genetic correction as demonstrated by ≥0.1 VCN level of FANCA-LV provirus in total PB cells at 18 months post-infusion with a confirmatory result at 21 or 24 months	24 months
Hematologic Stability- Hemoglobin	Hematologic stability demonstrated by hemoglobin levels remaining ≥75% of 6-month post-infusion nadir value, in the absence of Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and/or progressive cytogenetic and/or molecular abnormalities known to be associated with MDS/AML at 18 months post-infusion with a confirmatory result at 21 or 24 months. In settings in which 6-month post-infusion neutrophil or platelet values are demonstrably increased relative to other values during the initial year post-infusion, especially in situations of documented infections or febrile episodes, the value from the most proximate prior visit at which there is no documented infection or febrile episode is used. Levels must exceed the following values at the latest documented assessment (≥18 months post-infusion): hemoglobin ≥8 g/dL (National Cancer Institute-Common Terminology Criteria Adverse Events (NCI-CTCAE) v5 Grade <3).	24 months
Hematologic Stability- Neutrophils	Hematologic stability demonstrated by neutrophil count remaining ≥75% of 6-month post-infusion nadir value, in the absence of Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and/or progressive cytogenetic and/or molecular abnormalities known to be associated with MDS/AML at 18 months post-infusion with a confirmatory result at 21 or 24 months. In settings in which 6-month post-infusion neutrophil or platelet values are demonstrably increased relative to other values during the initial year post-infusion, especially in situations of documented infections or febrile episodes, the value from the most proximate prior visit at which there is no documented infection or febrile episode is used. Levels must exceed the following values at the latest documented assessment (≥18 months post-infusion): neutrophils ≥500/µL (NCI-CTCAE v5 Grade <4).	24 months
Hematologic Stability- Platelets	Hematologic stability demonstrated by Platelet count remaining ≥75% of 6-month post-infusion nadir value, in the absence of Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and/or progressive cytogenetic and/or molecular abnormalities known to be associated with MDS/AML at 18 months post-infusion with a confirmatory result at 21 or 24 months. In settings in which 6-month post-infusion neutrophil or platelet values are demonstrably increased relative to other values during the initial year post-infusion, especially in situations of documented infections or febrile episodes, the value from the most proximate prior visit at which there is no documented infection or febrile episode is used. Levels must exceed the following values at the latest documented assessment (≥18 months post-infusion): platelets ≥25,000/µL (NCI-CTCAE v5 Grade <4).	24 months
Phenotypic Correction	In patients who were not mosaic in Peripheral Blood T-cells prior to gene therapy, the level of phenotypic correction of hematopoietic cells as determined by a T-lymphocyte chromosomal fragility assay targeting a decrease from ≥50% pre-infusion levels to <50% in Peripheral Blood T-cells with DEB-induced aberrations and a ≥20% decrease from pre-treatment levels at ≥182 months post-infusion with a confirmatory result at 21 or 24 months	24 months
Safety of RP-L102	Analysis of Treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs), for the duration of the study.	3 years
Tolerability of RP-L102	Analysis of Treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs), for the duration of the study.	3 years
Overall survival	Survival at end of study	3 years
Bone Marrow Failure Free Survival	Bone Marrow Failure Free at end of study	3 years
Hematological Malignancy Free Survival	Lack of Myelodysplastic Syndrome or Acute Myeloid Leukemia at end of study	3 years

Collaborators and Investigators

• Sponsor: Rocket Pharmaceuticals Inc.
• Investigators: Principal Investigator: Margaret MacMillan, MD, MSc, University of Minnesota; Principal Investigator: Rajni Agarwal, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2020
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: January 24, 2020
• First Submitted That Met QC Criteria: January 28, 2020
• First Posted (Actual): January 30, 2020

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: anemia; gene therapy; bone marrow failure
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Renal Tubular Transport, Inborn Errors; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Anemia; Fanconi Syndrome; Fanconi Anemia
• Other Study ID Numbers: RP-L102-0319

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No