Gene Therapy for Fanconi Anemia

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Terminated

Phase 1

Conditions

Fanconi Anemia

Treatments

Biological: Filgrastim

Biological: Genetically Engineered Hematopoietic Stem Progenitor Cells

Procedure: Bone Marrow Aspiration

Drug: Plerixafor

Drug: Methylprednisolone

Drug: Prednisone

Other: Laboratory Biomarker Analysis

Procedure: Leukapheresis

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01331018

2097.00

RG9212015 (Other Identifier)

NCI-2011-00202 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

3 patients

Sex

All

Ages

4+ years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

3 participants in 1 patient group

Treatment (hematopoietic stem progenitor cells)

Experimental group

Description:

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: