A Gene Transfer Study Inducing Fetal Hemoglobin in Sickle Cell Disease (GRASP, BMT CTN 2001)

NCT05353647 | Active Not Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: P000380821OT2HL154815CLIN2-12031
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 9

Brief Summary

A promising approach for the treatment of genetic diseases is called gene therapy. Gene therapy is a relatively new field of medicine in which genetic material (mostly DNA) in the patient is changed to treat his or her own disease. In gene therapy, we introduce new genetic material in order to fix or replace the patient's disease gene, with the goal of curing the disease. The procedure is similar to a bone marrow transplant, in that the patient's malfunctioning blood stem cells are reduced or eliminated using chemotherapy, but it is different because instead of using a different person's (donor) blood stem cells for the transplant, the patient's own blood stem cells are given back after the new genetic material has been introduced into those cells. This approach has the advantage of eliminating any risk of graft versus host disease (GVHD), reducing the risk of graft rejection, and may also allow less chemotherapy to be utilized for the conditioning portion of the transplant procedure. To introduce new genetic material into the patient's own blood stem cells we use a modified version of a virus (called a 'vector') that efficiently inserts the "correcting" genetic material into the cells. The vector is a specialized biological medicine that has been formulated for use in human beings. Fetal hemoglobin (HbF) is a healthy, non-sickling kind of hemoglobin. The investigators have discovered a gene that is very important in controlling the amount of HbF. Decreasing the expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin in their blood, specifically the amount in red blood cells where sickle hemoglobin causes damage to the cell, and therefore potentially cure or significantly improve the condition. The gene we are targeting for change in this study that controls the level of fetal hemoglobin is called BCL11A. In summary, the advantages of a gene therapy approach include: 1) it can be used even if the patient does not have a matched donor available; 2) it may allow a reduction in the amount of chemotherapy required to prepare the patient for the transplant; and 3) it will avoid certain strong medicines often required to prevent and treat GVHD and rejection. Our lab studies with normal mice, mice that have a form of SCD, and with cells from the bone marrow of SCD patients who have donated bone marrow for research purposes show this approach is very effective in reducing the amount of sickle hemoglobin in red cells. Our pilot trial testing this approach in 10 patients with SCD has shown that the treatment has not caused any unexpected safety problems, and that it increases HbF within the red blood cells. Our goal is to continue to test whether this approach is safe, and whether using gene therapy to change the expression of BCL11A will lead to decreased episodes of vaso-occlusive crisis pain in people with SCD.

Conditions

Sickle Cell Disease

Keywords

gene therapy; lentivirus vector; BCL11A; fetal hemoglobin

Outcome Measures

Primary Outcomes (1)

• Occurrence of VOEs by Month 24 post-infusion

  Each patient will be classified as either a success or a failure (binary endpoint). Success is defined as a complete absence of severe VOEs (defining VOE as a painful event or ACS with no medically determined cause other than a vaso-occlusion, requiring a ≥24-hour hospital or emergency room (ER) observation unit visit or at least 2 visits to a day unit or ER over 72 hours with both visits requiring parenteral opioids) in the period from Month 6 to Month 24 after gene therapy. Patients with one or more severe VOEs from Month 6 to Month 24 after gene therapy, or who experience engraftment failure, or who initiate disease modifying agent(s) for prevention or management of severe VOEs, or who have less than 24 months of follow-up post-infusion, will be classified as 'failures'. For the purpose of this primary endpoint analysis, the first 6 months after infusion of the gene therapy product will be excluded from the VOE observation period.

  Month 6 to Month 24 post-infusion of gene modified cells

Secondary Outcomes (7)

• Hemoglobin Function

  Baseline through Month 24 post-infusion of gene modified cells

• Hemolysis

  up to 18 months post-infusion of gene modified cells

• Hemolysis

  up to 18 months post-infusion of gene modified cells

• Hemolysis

  up to 18 months post-infusion of gene modified cells

• Toxicities and Adverse Events

  Study enrollment through Month 24 post-infusion of gene modified cells

Study Arms (1)

Treatment Arm

EXPERIMENTAL

Open-label, non-randomized, single arm study of a single infusion of autologous CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a.

Biological: Autologous CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a

Interventions

Autologous CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a BIOLOGICAL

A single infusion of autologous CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a

Treatment Arm

Eligibility Criteria

• Age: 13 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• A diagnosis of sickle cell disease with genotype HbSS or HbS/β0 thalassemia.
• Between the age of 13-40 years.
• Clinically severe disease, defined as at least 4 vaso-occlusive events (VOEs) within the past 24 months prior to consent.
• Adequate hematologic parameters (regardless of therapy) including white blood cell (WBC) count within the range of 2.5 - 25.0 x 10\^9 /L, hemoglobin within the range of 5 - 11 g/dL, and platelet count above 150 x 10\^9 /L
• Adequate organ function and performance status:
• Karnofsky/Lansky performance status ≥80%.
• Serum creatinine \</= 1.5 times the upper limit of normal for age, and calculated creatinine clearance or GFR \>/= 60 mL/min/1.73 m2.
• Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value \<3× the upper limit of normal (ULN).
• DLCO, FEV1, and FVC \>50% of predicted
• Left ventricular ejection fraction \>40% or shortening fraction \>25%
• No HLA-genotypically identical related bone marrow donor available.
• Parental/guardian/patient signed informed consent.

You may not qualify if:

• Concomitant condition or illness including: ongoing or active infection, active malignancy, major surgery in the past 30 days, medical/psychiatric illness/social situations that would limit compliance with study requirements as determined by the treating physician.
• Receiving a chronic transfusion regimen for primary or secondary stroke prophylaxis. (Note: patients with a history of abnormal TCD who have transitioned from transfusions to hydroxyurea for stroke prophylaxis are also not eligible for the study.)
• Patients with history of abnormal TCD (measured with a timed average maximum mean velocity of ≥200 cm/second in the terminal portion of the internal carotid or proximal portion of middle cerebral artery or if the imaging TCD method is used, \>185 cm/second plus evidence of intracranial vasculopathy) who were ever on transfusions and subsequently transitioned to hydroxyurea.
• History of overt stroke or any neurologic event lasting \>24 hours. (Note: patients with imaging evidence of silent stroke but not on a chronic transfusion regimen are not excluded.)
• Contraindication to administration of conditioning medication (busulfan)
• Prior allogeneic hematopoietic stem cell transplant
• Known myelodysplasia of the bone marrow or abnormal bone marrow cytogenetics
• Severe cerebral vasculopathy
• Liver MRI (≤ 180 days prior to initiation of BU conditioning) to document hepatic iron content is required for participants who have received ≥20 packed red blood cell transfusions (cumulative); participants who have hepatic iron content ≥ 9 mg Fe/g liver dry weight by liver MRI must have a liver biopsy and histological examination/documentation of the absence of cirrhosis, bridging fibrosis, and active hepatitis (≤ 180 days prior to initiation of transplant conditioning); the absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues (1995) as described in the Manual of Operations (MOO);
• Evidence of HIV infection, HTLV infection, active hepatitis B infection or active hepatitis C infection.
• Known acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on prior biopsy
• Receipt of an investigational study drug or procedure within 90 days of study enrollment
• Either or both of the following findings on screening bone marrow aspirate/biopsy: a) diagnosis of myelodysplastic syndrome (MDS) based on morphology and/or cytogenetics (based on WHO definitions) OR b) pathogenic mutation in any gene on the Rapid Heme Panel (RHP), a next-generation sequencing clinical assay for gene mutations associated with hematologic malignancies performed at Brigham and Women's Hospital.
• Pregnancy or breastfeeding
• Presence of a genetically-determined hypercoagulable state or personal history of prior VTE (deep vein thrombosis or pulmonary embolism) that would represent a contraindication to proceed with central line placement and study events.

Sponsors & Collaborators

• David Williams: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• California Institute for Regenerative Medicine (CIRM): collaborator
• Genetix Biotherapeutics Inc.: collaborator
• Blood and Marrow Transplant Clinical Trials Network: collaborator

Study Sites (9)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

UCSF Benioff Children's Hospital Oakland

Oakland, California, 94609, United States

Location

UC Davis Medical Center

Sacramento, California, 95817, United States

Location

Children&#39;s Healthcare of Atlanta/Emory University

Atlanta, Georgia, 30322, United States

Location

Lurie Children&#39;s Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Boston Children&#39;s Hospital

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute/Brigham and Women&#39;s Hospital

Boston, Massachusetts, 02115, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Anemia, Sickle Cell; beta-Thalassemia

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Thalassemia

Study Officials

• David Williams

  Boston Children&#39;s Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief - Division of Hematology/Oncology

Model Details: Open-label, non-randomized, multi-center, phase 2, single arm study

Study Record Dates

• First Submitted: April 21, 2022
• First Posted: April 29, 2022
• Study Start: July 12, 2022
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027
• Last Updated: April 18, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)