Gene Therapy for Fanconi Anemia

Phase 1

Terminated

• Conditions: Fanconi Anemia
• Interventions: Procedure: Bone Marrow Aspiration; Biological: Filgrastim; Biological: Genetically Engineered Hematopoietic Stem Progenitor Cells; Other: Laboratory Biomarker Analysis; Procedure: Leukapheresis; Drug: Methylprednisolone; Drug: Plerixafor; Drug: Prednisone

• Registration Number: NCT01331018
• Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary

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.

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 Timeline

• Study First Submitted: 2011-03-16
• Study First Submitted QC: 2011-04-06
• Study First Posted: 2011-04-07
• Study Start: 2012-02-22
• Primary Completion: 2024-02-15
• Study Completion: 2024-02-15
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-15
• Last Update Posted: 2024-05-17

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 3

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (hematopoietic stem progenitor cells)	Bone Marrow Aspiration	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.
Treatment (hematopoietic stem progenitor cells)	Laboratory Biomarker Analysis	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.
Treatment (hematopoietic stem progenitor cells)	Leukapheresis	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.
Treatment (hematopoietic stem progenitor cells)	Filgrastim	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.
Treatment (hematopoietic stem progenitor cells)	Genetically Engineered 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.
Treatment (hematopoietic stem progenitor cells)	Plerixafor	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.
Treatment (hematopoietic stem progenitor cells)	Prednisone	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.
Treatment (hematopoietic stem progenitor cells)	Methylprednisolone	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Detectable levels of transduced cells in blood and marrow	Up to 1 year	Blood and bone marrow samples will be assayed by real-time quantitative polymerase chain reaction.
Transduction efficiency	Day 0	After completion of lentiviral transduction, the percent gene modified cells will be determined by molecular studies.
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
Improved blood counts	Up to 15 years	Complete blood counts will be monitored, initially weekly, then monthly during the first year, then quarterly during the 2nd year after infusion.
Demonstrable functional expression by growth of recipient cells in mitomycin C	3 months	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.

Trial Locations

Locations (1)

Fred Hutch/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States