Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A

NCT04418414 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: ET3-201
• Study Type: interventional
• Target: 7
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a first-in-human, non-randomized, open label, single treatment, Phase 1 study in approximately 7 patients with severe hemophilia A. The study will evaluate gene therapy by transplantation of autologous CD34+ hematopoietic stem cells transduced ex vivo with the CD68-ET3 lentiviral vector.

Conditions

Hemophilia A

Keywords

Hematopoietic stem cell transplant; Gene therapy

Outcome Measures

Primary Outcomes (3)

• Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.

  As assessed by physical examination, vital signs, clinical labs, and FVIII inhibitor levels (Bethesda assay). Serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly.

  12 weeks

• Severity of serious adverse events following administration of CD68-ET3-LV CD34+ as assessed by NCI Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0.

  Serious adverse events

  12 weeks

• Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.

  As assessed by stop and end dates of the SAEs

  12 weeks

Secondary Outcomes (7)

• Time to absolute neutrophil count (ANC) recovery.

  Measured up to 5 years.

• Time to platelet recovery.

  Measured up to 5 years.

• Anti-human factor VIII inhibitor titer

  Measured up to 5 years.

• Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into fVIII-deficient plasma

  Measured up to 5 years.

• Vector copy number of circulating genetically modified cells as determined by real time PCR

  Measured up to 5 years.

Other Outcomes (3)

• Factor VIII (fVIII) Activity Level following autologous HSCT

  Measured up to 5 years.

• Annualized bleed rate (ABR) assessed by number of bleeding episodes and in comparison to before gene therapy.

  Measured through long term follow-up (up to 15 years).

• Consumption of exogenous Factor VIII by evaluating historical clotting factor usage versus usage post-transplant.

  Historical data from prior to study enrollment versus post-transplant (up to 15 years).

Study Arms (1)

Autologous HSCT CD68-ET3-LV gene therapy

EXPERIMENTAL

G-CSF/Plerixafor mobilization and apheresis will be used for collection of hematopoietic stem cells and subjects will receive transplantation of autologous CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector encoding the human factor VIII gene.

Drug: Gene therapy; Other: Biological

Interventions

Gene therapy DRUG

CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector (encoding human factor VIII gene) is administered by IV infusion following conditioning regimen with busulfan and anti-thymocyte globulin.

Also known as: CD68-ET3-LV CD34+

Autologous HSCT CD68-ET3-LV gene therapy

Biological OTHER

G-CSF and Plerixafor are administered by subcutaneous injection prior to apheresis.

Autologous HSCT CD68-ET3-LV gene therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to provide informed consent for the protocol approved by the Institutional Review Board.
• Male subjects who are \>= 18 years of age.
• Diagnosis of severe hemophilia A (\<1 IU/dL factor VIII activity) based on one-stage coagulation assay.
• Documented history of more than 150 days of factor VIII treatment.
• Average of at least 4 bleeds requiring treatment per year over the prior three years, or at least 4 bleeds per year during the 3 years preceding the initiation of prophylaxis, or evidence of joint damage (knee, elbow or ankle) on physical or radiographic examination thought to be related to hemophilia.
• Performance status (Karnofsky score) of at least 70.
• Willingness to use effective barrier contraception or limit sexual intercourse to postmenopausal, surgically sterilized, or contraception-practicing partners, for 12 weeks (3 months) after transplantation.
• Willing and able to comply with the requirements of the protocol.

You may not qualify if:

• History of spontaneous central nervous system bleeding within the last 5 years.
• Significant functional deficits in major organs which would interfere with successful outcome following autologous stem cell transplant, the following guidelines will be utilized:
• Cardiac: There should be no evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of \< 50%) and no marked cardiomegaly. There should not be uncontrollable hypertension.
• Renal: GFR \< 60 mL/min/1.73m2 per local institutional standard such as CKD-EPI creatinine equation or equivalent.
• Hepatic: There should be no evidence of hepatic dysfunction which is defined as a serum total bilirubin of \> 1.5 mg/dL and AST/ALT \> 3X the upper limit of normal.
• Hematologic: Absolute neutrophil counts (ANC) \<1000/ µL or platelets counts \< 150,000/µL.
• Pulmonary function with a corrected carbon monoxide diffusing capacity (cDLCO) \< 50% predicted.
• History of a fVIII inhibitor (\> 0.4 Bethesda Units/mL) including at least 2 measurements done at least a week apart or any single titer \> 5 BU/mL.
• Subjects who have had prior cellular based therapy or gene editing/ gene therapy including a previous stem cell transplant.
• Subjects with any evidence of active infection or any immunosuppressive disorder, including currently detectable HIV viral load
• Subjects who are RPR, anti-HTLV-1 and II antibody, CMV PCR, VZV antibody and HSV PCR positive at screening.
• Subjects who have allergic reactions or hypersensitivity to any of the drugs used in the study (i.e., anti-thymocyte globulin, plerixafor, G-CSF, busulfan, levetiracetam) or to the constituents of the investigational product formulation.
• Evidence of hepatitis B active infection or chronic carrier based on a positive Hepatitis B DNA testing at screening.
• Positive (detectable viral load per local institutional standard) for the presence of Hepatitis C virus (HCV). Subjects who are positive for anti-HCV antibody are eligible as long as they have a negative undetectable HCV viral load at screening.
• Subjects diagnosed with any history of clinically relevant coagulation or bleeding disorder other than hemophilia A.

Sponsors & Collaborators

• Expression Therapeutics, LLC: lead

MeSH Terms

Conditions

Hemophilia A

Interventions

Genetic Therapy; Biological Products

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics; Genetic Engineering; Genetic Techniques; Investigative Techniques; Complex Mixtures

Central Study Contacts

Study Coordinator

CONTACT

404-850-0123; clinicaltrials@expressiontherapeutics.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2020
• First Posted: June 5, 2020
• Study Start: September 1, 2024
• Primary Completion (Estimated): August 1, 2029
• Study Completion (Estimated): August 1, 2039
• Last Updated: February 20, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share