Gene Therapy for Fanconi Anemia

Gene Transfer for Patients With Fanconi Anemia Complementation Group A (FANCA)

This clinical trial will access the toxicity and efficacy of infusion of gene modified cells for patients with Fanconi anemia (FA). Infusion of autologous patient blood stem cells that have been corrected in the laboratory by introduction of the normal gene may improve blood counts in patients with FA.

Study Overview

• Status: Active, not recruiting
• Conditions: Fanconi Anemia
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Prednisone; Procedure: Leukapheresis; Biological: Filgrastim; Drug: Methylprednisolone; Drug: Plerixafor; Procedure: Bone Marrow Aspiration; Biological: Genetically Engineered Hematopoietic Stem Progenitor Cells

Detailed Description

OUTLINE:

STEM CELL MOBILIZATION FOR CELL COLLECTION: Patients receive filgrastim subcutaneously (SC) twice daily (BID) for up to 6 days (on days 1-6 of mobilization). Patients receive plerixafor SC once daily (QD) on days 4-6 of mobilization. Peripheral blood stem cell (PBSC) count will be checked daily starting on day 4 of mobilization. Patients who have a PBSC count of >= 5 CD34+ cells/mcL will undergo up to 2 apheresis collections on consecutive days.

BONE MARROW HARVEST FOR CELL COLLECTION: Patients with inadequate PBSC counts undergo bone marrow harvest for collection of stem/progenitor cells.

REINFUSION: Patients receive methylprednisolone intravenously (IV) or prednisone orally (PO) on days -1 to 7 followed by a rapid taper over approximately 1 week and undergo reinfusion of genetically modified hematopoietic stem/progenitor cells on day 0.

After completion of study treatment, patients are followed up periodically for 15 years.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• FA demonstrated by a positive test for increased sensitivity to chromosomal breakage with mitomycin C or diepoxybutane performed by a Clinical Laboratory Improvement Amendments (CLIA) or College of American Pathologists (CAP) approved laboratory
• FA complementation group A as determined by somatic cell hybrids, molecular characterization, western blot analysis, acquisition of mitomycin C resistance after in vitro lentiviral transduction with a vector bearing the complementary deoxyribonucleic acid (cDNA) for Fanconi complementation group A, or other clinically certified method of complementation group analysis
• Bone marrow analysis demonstrating normal cytogenetics, and no more than 5% of cells with a single clonal abnormality by fluorescence in situ hybridization (FISH) for myelodysplastic syndrome (MDS) panel within 3 months of stem cell collection
• Signed informed consent by the patient or legally authorized representative
• Absolute neutrophil count >= 0.5 x 10^9/L
• Hemoglobin >= 8 g/dL
• Platelet count >= 20 x 10^9/L and able to achieve a platelet count of >= 50 x 10^9/L with transfusion support
• Adequate hepatic function with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN)
• Adequate renal function with creatinine (Cre) =< 1.5; if greater, then glomerular filtration rate (GFR) > 60 mL/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation
• Adequate pulmonary function with corrected diffusion capacity of carbon monoxide (DLCO) > 50% in those for whom this study can be performed
• For subjects < 17 years of age, Modified Lansky Play-Performance Score of >= 70%; for subjects 17 and older, Karnofsky score of >= 70%

Exclusion Criteria:

• Non-hematopoietic malignancy where the expected survival is less than 2 years
• Myelodysplastic syndrome as defined by World Health Organization (WHO) criteria
• Acute myeloid leukemia as defined by WHO criteria
• Pregnancy or lactation; females of childbearing potential and males who are admitted to the study will be advised that the study procedures and study drugs may be teratogenic, and they will be required to take adequate measures to prevent conception for the duration of the study
• Concurrent enrollment in any other study using an investigational drug
• Physical or emotional status that would prevent informed consent, protocol compliance, or adequate follow-up

• Patients for whom an human leukocyte antigen (HLA) matched sibling donor bone marrow transplant is being actively pursued will not be eligible for study until it is determined that no sibling donor is available or that a stem cell transplant is not feasible during the time the patient might be on study

  • No patient will be included in this study as an alternative to a clinically indicated HLA matched sibling donor stem cell transplant
  • If an HLA matched sibling donor is identified, but stem cell or marrow collection is not feasible (e.g., donor is in utero, is a newborn from whom cord blood was not collected, or is unable to undergo a donation procedure because of ill health), a patient may be included in the study at the discretion of the investigators
• Significant associated diseases including documented human immunodeficiency virus (HIV) infection, uncontrolled hypertension (diastolic blood pressures > 95%ile for age), unstable angina, congestive heart failure (> New York [NY] class II), poorly controlled diabetes (hemoglobin A1c [Hgb A1c] > 7%), coronary angioplasty within 6 months, myocardial infarction within the last 6 months, or uncontrolled atrial or ventricular cardiac arrhythmia, abnormal coagulation, persistent abnormal urinalysis reflecting intrinsic renal disease
• Active ongoing viral, bacterial, or fungal infection

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: Treatment (hematopoietic stem progenitor cells); STEM CELL MOBILIZATION FOR CELL COLLECTION: Patients receive filgrastim SC BID for up to 6 days (on days 1-6 of mobilization). Patients receive plerixafor SC QD on days 4-6 of mobilization. PBSC count will be checked daily starting on day 4 of mobilization. Patients who have a PBSC count of >= 5 CD34+ cells/mcL will undergo up to 2 apheresis collections on consecutive days. BONE MARROW HARVEST FOR CELL COLLECTION: Patients with inadequate PBSC counts undergo bone marrow harvest for collection of stem/progenitor cells. REINFUSION: Patients receive methylprednisolone IV or prednisone PO on days -1 to 7 followed by a rapid taper over approximately 1 week and undergo reinfusion of genetically modified hematopoietic stem/progenitor cells on day 0.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Prednisone; Given PO; Other Names: Deltasone; Orasone; .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Panafcort; Panasol-S; Paracort; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisonum; Prednitone; Promifen; Servisone; SK-Prednisone; Procedure: Leukapheresis; Undergo leukapheresis; Other Names: Leukocytopheresis; Therapeutic Leukopheresis; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; FILGRASTIM, LICENSE HOLDER UNSPECIFIED; Drug: Methylprednisolone; Given IV; Other Names: Medrol; Wyacort; Adlone; Caberdelta M; DepMedalone; Depo Moderin; Depo-Nisolone; Duralone; Emmetipi; Esametone; Firmacort; Medlone 21; Medrate; Medrol Veriderm; Medrone; Mega-Star; Meprolone; Methylprednisolonum; Metilbetasone Solubile; Metrocort; Metypresol; Metysolon; Predni-M-Tablinen; Prednilen; Radilem; Sieropresol; Solpredone; Summicort; Urbason; Veriderm Medrol; Drug: Plerixafor; Given SC; Other Names: Mozobil; AMD 3100; JM-3100; SDZ SID 791; Procedure: Bone Marrow Aspiration; Undergo bone marrow harvest; Biological: Genetically Engineered Hematopoietic Stem Progenitor Cells; Undergo infusion of genetically modified hematopoietic progenitor cell therapy; Other Names: Genetically Engineered HSPCs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of gene transfer	Adverse events will be graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4.	Up to 15 years
Hematological and non-hematological organ toxicity	Adverse events will be graded by CTCAE, version 4.	Up to 15 years
Development of insertional mutagenesis or hematologic malignancy	Adverse events will be graded by CTCAE, version 4.	Up to 15 years
Development of replication competent lentivirus	Adverse events will be graded by CTCAE, version 4.	Up to 15 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of G-CSF and plerixafor mobilization in Fanconi anemia (FA) patients		Up to 6 days
Efficacy of lineage depletion of bone marrow or mobilized cell product		Up to 15 years
Transduction efficiency	After completion of lentiviral transduction, the percent gene modified cells will be determined by molecular studies.	Day 0
Detectable levels of transduced cells in blood and marrow	Blood and bone marrow samples will be assayed by real-time quantitative polymerase chain reaction.	Up to 1 year
Improved blood counts	Complete blood counts will be monitored, initially weekly, then monthly during the first year, then quarterly during the 2nd year after infusion.	Up to 15 years
Demonstrable functional expression by growth of recipient cells in mitomycin C	Blood and bone marrow cells will be assayed for viability of cultured cells and hematopoietic colonies in the presence of the chemotherapy drug and deoxyribonucleic acid crosslinking agent, mitomycin C.	3 months

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Rocket Pharma Limited
• Investigators: Principal Investigator: Hans-Peter Kiem, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2012
• Primary Completion (Estimated): July 17, 2032
• Study Completion (Estimated): July 17, 2032

Study Registration Dates

• First Submitted: March 16, 2011
• First Submitted That Met QC Criteria: April 6, 2011
• First Posted (Estimated): April 7, 2011

Study Record Updates

• Last Update Posted (Actual): July 11, 2023
• Last Update Submitted That Met QC Criteria: July 10, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• 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; Physiological Effects of Drugs; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Adjuvants, Immunologic; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Lenograstim; Prednisone; Cortisone; Plerixafor
• Other Study ID Numbers: 2097.00; NCI-2011-00202 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RG9212015 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)