Study of Gene Therapy Using a Lentiviral Vector to Treat X-linked Chronic Granulomatous Disease

NCT02234934 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: G1XCGD2P01HL073104
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 3

Brief Summary

Chronic Granulomatous Disease (CGD) is an inherited immunodeficiency disorder which results from defects that prevent white blood cells from effectively killing bacteria, fungi and other microorganisms. Chronic granulomatous inflammation may compromise vital organs and account for additional morbidity. CGD is thought to affect approximately 1 in 200,000 persons, although the real incidence might be higher due to under-diagnosis of milder phenotypes. The first gene therapy approaches in X-CGD have shown that effective gene therapy requires bone-marrow (BM) conditioning with chemotherapy to make space for the gene-modified cells to engraft. These studies demonstrated that transplantation of gene modified stem cells led to production of white blood cells that could clear existing infections. However, some trials using mouse-derived retroviral vectors were complicated by the development of myelodysplasia and leukemia-like growth of blood cells. This trial will evaluate a new lentiviral vector that may be able to correct the defect, but have much lower risk for the complication. This study is a two-part, prospective non-controlled, non-randomized Phase I/II clinical trial to assess the safety, feasibility and efficacy of cellular gene therapy in patients with chronic granulomatous disease using transplantation of autologous bone marrow CD34+ cells transduced ex vivo by the G1XCGD lentiviral vector containing the human CGD gene. Primary objectives include evaluation of safety and evaluation of efficacy by biochemical and functional reconstitution in progeny of engrafted cells and stability at 12 months. Secondary objectives include evaluation of clinical efficacy, longitudinal evaluation of clinical effect in terms of augmented immunity against bacterial and fungal infection, transduction of CD34+ hematopoietic cells from X-CGD patients by ex vivo lentivirus-mediated gene transfer, and evaluation of engraftment kinetics and stability. Approximately 3-6 patients will be treated per site with a goal of 16 total patients to be treated with G1XCGD lentiviral vector.

Conditions

Granulomatous Disease, Chronic, X-linked

Keywords

Gene Therapy; X-Linked Chronic Granulomatous Disease (X-CGD); Lentiviral Vector

Outcome Measures

Primary Outcomes (2)

• The incidence of adverse events assessed by CTCAE v4

  Record clinical significant adverse events, laboratory abnormalities, monitor overall adverse events for the study as a whole, including serious adverse events

  up to 2 years

• Measuring percentage of subjects who have ≥ 10% oxidase positive granulocytes

  Oxidase positive granulocytes for each subject will be assessed by DHR flow cytometry

  At month 12 after transplant

Other Outcomes (2)

• Concentration of gp91 protein produced in response to the corrected gene

  up to 2 years

• Characterization of drug product immunophenotype

  up to 2 years

Study Arms (2)

Lentiviral G1XCGD Gene Therapy, Part A

EXPERIMENTAL

Transplantation with autologous CD34+ stem cells corrected with X1XCGD lentiviral vector after myeloreductive conditioning

Biological: Lentiviral G1XCGD Gene Therapy

Lentiviral G1XCGD Gene Therapy, Part B

EXPERIMENTAL

Transplantation with autologous CD34+ stem cells corrected with X1XCGD lentiviral vector after modified myeloreductive conditioning including increased monitoring and rescue treatment

Biological: Lentiviral G1XCGD Gene Therapy

Interventions

Lentiviral G1XCGD Gene Therapy BIOLOGICAL

The investigational product is patient-specific and corresponds to autologous CD34+ cells transduced ex vivo with the G1XCGD vector in their final suspension. The starting materials used for the production of the investigational product consist of the viral vector and the patient's CD34+ cells. The G1XCGD vector is used to transduce autologous CD34+ cells ex vivo. These transduced cells are then frozen, and an aliquot tested and characterized for quality. If the cell product passes release criteria, it is thawed at bedside and infused into the patient after the patient has received myelo-ablative conditioning. The cell/product dose will consist of at least 3 x 10\^6 cells per kg of body weight transduced ex vivo with 1 x 10\^8 IG/mL of lentiviral vector to achieve \> 0.3 integrated copies per cell.

Also known as: G1XCGD (pCCLChimGp91/VSVg lentiviral vector)

Lentiviral G1XCGD Gene Therapy, Part A; Lentiviral G1XCGD Gene Therapy, Part B

Eligibility Criteria

• Age: 23 Months+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• (Part A \& B)
• Male X-CGD patients \> 23 months of age
• Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or reduction \> 95% of the biochemical activity of the NADPH-oxidase
• At least one prior, ongoing or refractory severe infection and/or inflammatory complications requiring hospitalization despite conventional therapy
• No 10/10 HLA-matched donor available after initial search of NMDP registries
• No co-infection with Human Immunodeficiency Virus (HIV)-1 or -2, hepatitis B virus or hepatitis C virus, adenovirus, parvovirus B 19 or toxoplasmosis, or active infection with CMV
• Written informed consent for adult patient, and assent for pediatric subjects seven years or older.
• Parental/guardian and, where appropriate, child's signed consent/assent

You may not qualify if:

• Age \< 23 months
• /10 HLA identical (A,B,C,DR,DQ) family or unrelated or cord blood donor unless there is deemed to be an unacceptable risk associated with an allogeneic procedure
• Contraindication for leukapheresis or bone marrow harvest (anemia Hb \<8g/dl, cardiovascular instability, severe coagulopathy)
• Appropriate organ function as outlined below must be observed within 8 weeks of entering this trial.
• Hematologic
• Anemia (hemoglobin \< 8 g/dL).
• Neutropenia (absolute granulocyte count \<1,000/mm3)
• Thrombocytopenia (platelet count \< 150,000/mm3).
• PT or PTT \> 2X the upper limits of normal (patients with a correctable deficiency controlled on medication will not be excluded).
• Cytogenetic abnormalities known to be associated with hematopoietic defect on peripheral blood or bone marrow.
• Infectious
• a. Evidence of co-infection with HIV-1, HIV-2, hepatitis B, Hepatitis C, adenovirus, parvovirus B19, toxoplasmosis. CMV infection is allowable as long as the infection is under control.
• Pulmonary
• a. Resting O2 saturation by pulse oximetry \< 90% on room air.
• Cardiac

Sponsors & Collaborators

• University of California, Los Angeles: lead
• Boston Children's Hospital: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Genethon: collaborator
• California Institute for Regenerative Medicine (CIRM): collaborator

Study Sites (3)

University of California, Los Angeles (UCLA)

Los Angeles, California, 90095, United States

Location

National Institutes of Health

Bethesda, Maryland, 20892, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 90095, United States

Location

Related Publications (2)

• Santilli G, Almarza E, Brendel C, Choi U, Beilin C, Blundell MP, Haria S, Parsley KL, Kinnon C, Malech HL, Bueren JA, Grez M, Thrasher AJ. Biochemical correction of X-CGD by a novel chimeric promoter regulating high levels of transgene expression in myeloid cells. Mol Ther. 2011 Jan;19(1):122-32. doi: 10.1038/mt.2010.226. Epub 2010 Oct 26.

  PMID: 20978475 BACKGROUND

• Brendel C, Rothe M, Santilli G, Charrier S, Stein S, Kunkel H, Abriss D, Muller-Kuller U, Gaspar B, Modlich U, Galy A, Schambach A, Thrasher AJ, Grez M. Non-Clinical Efficacy and Safety Studies on G1XCGD, a Lentiviral Vector for Ex Vivo Gene Therapy of X-Linked Chronic Granulomatous Disease. Hum Gene Ther Clin Dev. 2018 Jun;29(2):69-79. doi: 10.1089/humc.2017.245. Epub 2018 Apr 17.

  PMID: 29664709 DERIVED

MeSH Terms

Conditions

Granulomatous Disease, Chronic

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Donald B. Kohn, MD

  University of California, Los Angeles

  STUDY CHAIR

• Caroline Y. Kuo, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 4, 2014
• First Posted: September 9, 2014
• Study Start: October 29, 2015
• Primary Completion: September 1, 2024
• Study Completion: December 1, 2024
• Last Updated: May 2, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)