Hemophilia A
Conditions
Keywords
Gene Therapy
Brief summary
This is a Phase I study. This research study is being conducted to find new ways to treat severe hemophilia A. This study is a gene therapy study. Gene therapy is an experimental way to introduce, into a person's cells, specific genetic material. A gene can be delivered/introduced into a cell using a carrier known as a "vector." In this study, a virus (lentivirus), the "vector", is used to introduce or deliver a gene that creates and stores a protein Factor VIII (FVIII) in your platelets. These platelets are made from stem cells (mother cells for your bone marrow) that are removed from your blood by a procedure called apheresis. This research study will take some of the patient's own stem cells, from the apheresis procedure, and genetically modify them using the vector in order to make them produce FVIII in platelets that arise from the stem cells. They will then give the genetically modified stem cells back to the patient so that they can possibly create platelets that produce and store Factor VIII on their own.
Detailed description
This is an open label, nonrandomized, single center, phase I cohort study, involving reduced intensity conditioning, followed by a single infusion of autologous CD34+PBSC, transduced with a lentiviral vector (-889ITGA2B-BDDFVIII-WPTS (MUT6)(VSVg)) also known as (Pleightlet(MUT6)) encoding the B domain deleted from of human coagulation factor VIII (BDDFVIII) in up to five hemophilia A patients with a history of FVIII inhibitors (≥0.6BU) .
Interventions
BIOLOGICALAuto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII
Reduced intensity conditioning with melphalan and fludarabine, followed by a single infusion of autologous CD34+PBSC, transduced with a lentiviral vector (-889ITGA2B-BDDFVIII-WPTS(MUT6)(VSVg)) also known as (Pleightlet(MUT6)) encoding the B domain deleted from of human coagulation factor VIII (BDDFVIII) in up to five hemophilia A patients with a history of FVIII inhibitors (≥0.6BU). The infusion volume of transduced cells will not exceed 20 ml/kg body weight.
Sponsors
Medical College of Wisconsin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, nonrandomized, single-center phase I cohort study
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Study population will include: adult males \>18 years of age with a diagnosis of severe hemophilia A and currently active or a history of FVIII inhibitors (≥0.6 BU). Females will be excluded because hemophilia A is an X-linked disorder that is extremely rare in females. 1. Confirmed diagnosis of severe hemophilia A by undetectable plasma factor VIII:C by a one-stage PTT-based assay and coatest chromogenic factor VIII assay. Subjects with currently active or a history of positive FVIII inhibitor titers (≥0.6 BU) irrespective of their titer or current inhibitor status will be included for enrollment. 2. Subject may be prescribed prophylactic therapy with factor VIII bypassing agents or factor VIII mimetics prior to referral for inclusion in the study. 3. Subjects who are treated on demand using factor VIII bypassing agents must have a history of four or more bleeding episodes requiring treatment in the six-month period prior to referral for inclusion in the study. 4. Adequate bone marrow reserve as demonstrated by ANC \>1.5/cu.mm; Hemoglobin \>9g/dL; Platelets \>100,000/microliter. 5. Adequate renal function, defined as creatinine clearance\>60 ml/min (Cockroft-Gault formula) 6. Adequate liver function, defined as defined as total bilirubin ≤1.5 times the upper limit of normal (ULN) (excluding Gilbert's syndrome), both AST and ALT ≤3 times ULN at the time of screening, and no clinical signs or known laboratory/radiographic evidence consistent with cirrhosis. 7. Subject must sign an informed consent after explanation of the study and having questions answered. 8. Subject must be willing and able to document type of bleeding episodes and treatment in a paper or electronic diary during the study. 9. Subject must be willing to return for regular follow-up visits during the 15-year study.
Exclusion criteria
* A potential subject who meets any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of enrolled participants with adequate gene transduced hematopoietic stem cells for FVIII gene therapy infusion | Through study completion, an average of 4 years | Assessed by availability of ≥4x106 transduced clinical grade CD34+PBSC per kg meeting release criteria for infusion; undetectable microbiological contamination and cell viability ≥70%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of toxicity from gene therapy | Within 3 months of gene therapy infusion | Number of events meeting CTCAE criteria grade 3 or 4 toxicity |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMary Eapen, MD
Froedtert Hosptial and Medical College of Wisconsin
Outcome results
None listed