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

Primary Purpose

Granulomatous Disease, Chronic, X-linked

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lentiviral G1XCGD Gene Therapy
Sponsored by
University of California, Los Angeles
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Granulomatous Disease, Chronic, X-linked focused on measuring Gene Therapy, X-Linked Chronic Granulomatous Disease (X-CGD), Lentiviral Vector

Eligibility Criteria

23 Months - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

(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

Exclusion Criteria:

  • Age < 23 months
  • 10/10 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.

    1. Hematologic

      1. Anemia (hemoglobin < 8 g/dL).
      2. Neutropenia (absolute granulocyte count <1,000/mm3)
      3. Thrombocytopenia (platelet count < 150,000/mm3).
      4. PT or PTT > 2X the upper limits of normal (patients with a correctable deficiency controlled on medication will not be excluded).
      5. Cytogenetic abnormalities known to be associated with hematopoietic defect on peripheral blood or bone marrow.

    2. 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.

    3. Pulmonary

      a. Resting O2 saturation by pulse oximetry < 90% on room air.

    4. Cardiac

      1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.
      2. Uncorrected congenital cardiac malformation with clinical symptomatology.
      3. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
      4. Poor cardiac function as evidenced by LV ejection fraction < 40% on echocardiogram.

    5. Neurologic

      1. Significant neurologic abnormality by examination.
      2. Uncontrolled seizure disorder.

    6. Renal

      1. Renal insufficiency: serum creatinine ≥ 1.5 mg/dl, or ≥ 3+ proteinuria.
      2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

    7. Hepatic/GI:

      1. Serum transaminases > 5X the upper limit of normal (ULN).
      2. Serum bilirubin > 2X ULN.
      3. Serum glucose > 1.5x ULN.

    8. Oncologic

      a. Evidence of active malignant disease

    9. General

      1. Expected survival < 6 months
      2. Major congenital anomaly
      3. Ineligible for autologous HSCT by the criteria at the clinical site.
      4. Contraindication for administration of conditioning medication. (Known sensitivity to Busulfan)
      5. Administration of gamma-interferon within 30 days before the infusion of transduced, autologous CD34+ cells.
      6. Participation in another experimental therapeutic protocol within 6 months prior to baseline and during the study period.
      7. Tested positive (definitive) for the presence of multiple types (2 or more) of anti-platelet antibodies.
      8. Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful study completion.
      9. Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements.

Part B Additional exclusion criteria:

  • Patients >12 years of age at enrolment
  • Patients ≤12 years of age with a body weight >40kg at enrolment

Sites / Locations

  • University of California, Los Angeles (UCLA)
  • National Institutes of Health
  • Children's Hospital Boston

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Lentiviral G1XCGD Gene Therapy, Part A

Lentiviral G1XCGD Gene Therapy, Part B

Arm Description

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

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

Outcomes

Primary Outcome Measures

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
Measuring percentage of subjects who have ≥ 10% oxidase positive granulocytes
Oxidase positive granulocytes for each subject will be assessed by DHR flow cytometry

Secondary Outcome Measures

Full Information

First Posted
September 4, 2014
Last Updated
August 1, 2022
Sponsor
University of California, Los Angeles
Collaborators
Boston Children's Hospital, National Heart, Lung, and Blood Institute (NHLBI), Genethon, California Institute for Regenerative Medicine (CIRM)
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1. Study Identification

Unique Protocol Identification Number
NCT02234934
Brief Title
Study of Gene Therapy Using a Lentiviral Vector to Treat X-linked Chronic Granulomatous Disease
Official Title
A Two-Part, Phase I/II, Non Randomized, Multicenter, Open-Label Study of G1XCGD (Lentiviral Vector Transduced CD34+ Cells) in Patients With X-Linked Chronic Granulomatous Disease
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 29, 2015 (Actual)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, Los Angeles
Collaborators
Boston Children's Hospital, National Heart, Lung, and Blood Institute (NHLBI), Genethon, California Institute for Regenerative Medicine (CIRM)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
The therapeutic product to be evaluated is autologous CD34+ hematopoietic stem cells (HSC) modified by ex vivo transduction using the pCCLchimGP91WPRE lentiviral vector (G1XCGD Modified Autologous BM CD34 cells) containing the human CGD gene. The G1XCGD lentiviral vector is a 3rd generation self-inactivating lentiviral vector which directs gp91phox expression from a codon-optimized form of the CYBB gene preferentially to myeloid cells, with a modified WPRE (PRE4). G1XCGD is an integrative, 3rd generation replication-defective, self-inactivating (SIN) HIV-derived Lentiviral (LV) vector, with a mutated Woodchuck hepatitis virus Posttranscriptional Regulatory Element (WPRE) sequence. A LV vector derived from HIV-1 has been chosen with respect to LV natural properties: they are genetically stable, permanently integrate into the genome of transduced cells and provide long-term gene expression in vitro and in vivo. The transduction of Hematopoietic Stem Cells (HSC) with such LV can be achieved after limited pre-activation of the cells in short-term cultures with cytokines, in conditions that are compatible with the preservation of the self-renewing capacities of these cells. These properties make these LV suitable for ex-vivo gene therapy strategies using HSC. G1XCGD provirus includes a chimeric promoter designed to regulate the transgene expression in myeloid cells and a transgene called GP91 (also known as CYBB), which is a codon-optimized cDNA sequence of the human CYBB gene also known as GP91-PHOX or NOX2 gene. The promoter is a synthetic chimeric element created by the fusion of c-Fes and Cathepsin G minimal 5'-flanking regions. Cathepsin G is a serine protease stored in the azurophil granules of neutrophil granulocytes. Part of the chimeric promoter contains binding sites for myeloid transcription factors C/EBP and PU.1 from the upstream region of the transcription start site of the Cathepsin G gene. The other part of the chimeric promoter is a human c-Fes sequence that has been added to enhance the Cathepsin G promoter activity in granulocytic cells. The resulting chimeric promoter is able to i) regulate the expression of the GP91 transgene in myeloid cells in a specific manner, and ii) to effectively restore NADPH-oxidase activity in granulocytes, as reported by Santilli et al. (Santilli et al., 2011) and confirmed in preclinical studies conducted with the G1XCGD vector. The GP91 transgene codes for the 570 amino-acid cytochrome b-245, a 91 kD beta polypeptide that is also known as the NADPH-oxidase catalytic subunit gp91-phox, or cytochrome b-245 heavy chain, or gp91-phox protein.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Granulomatous Disease, Chronic, X-linked
Keywords
Gene Therapy, X-Linked Chronic Granulomatous Disease (X-CGD), Lentiviral Vector

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Lentiviral G1XCGD Gene Therapy, Part A
Arm Type
Experimental
Arm Description
Transplantation with autologous CD34+ stem cells corrected with X1XCGD lentiviral vector after myeloreductive conditioning
Arm Title
Lentiviral G1XCGD Gene Therapy, Part B
Arm Type
Experimental
Arm Description
Transplantation with autologous CD34+ stem cells corrected with X1XCGD lentiviral vector after modified myeloreductive conditioning including increased monitoring and rescue treatment
Intervention Type
Biological
Intervention Name(s)
Lentiviral G1XCGD Gene Therapy
Other Intervention Name(s)
G1XCGD (pCCLChimGp91/VSVg lentiviral vector)
Intervention Description
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.
Primary Outcome Measure Information:
Title
The incidence of adverse events assessed by CTCAE v4
Description
Record clinical significant adverse events, laboratory abnormalities, monitor overall adverse events for the study as a whole, including serious adverse events
Time Frame
up to 2 years
Title
Measuring percentage of subjects who have ≥ 10% oxidase positive granulocytes
Description
Oxidase positive granulocytes for each subject will be assessed by DHR flow cytometry
Time Frame
At month 12 after transplant
Other Pre-specified Outcome Measures:
Title
Concentration of gp91 protein produced in response to the corrected gene
Description
We will look for the presence of gp91 antibodies in blood
Time Frame
up to 2 years
Title
Characterization of drug product immunophenotype
Description
Different lymphocyte subsets using flow cytometry
Time Frame
up to 2 years

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
23 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: (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 Exclusion Criteria: Age < 23 months 10/10 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 Abnormal electrocardiogram (EKG) indicating cardiac pathology. Uncorrected congenital cardiac malformation with clinical symptomatology. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension. Poor cardiac function as evidenced by LV ejection fraction < 40% on echocardiogram. Neurologic Significant neurologic abnormality by examination. Uncontrolled seizure disorder. Renal Renal insufficiency: serum creatinine ≥ 1.5 mg/dl, or ≥ 3+ proteinuria. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Hepatic/GI: Serum transaminases > 5X the upper limit of normal (ULN). Serum bilirubin > 2X ULN. Serum glucose > 1.5x ULN. Oncologic a. Evidence of active malignant disease General Expected survival < 6 months Major congenital anomaly Ineligible for autologous HSCT by the criteria at the clinical site. Contraindication for administration of conditioning medication. (Known sensitivity to Busulfan) Administration of gamma-interferon within 30 days before the infusion of transduced, autologous CD34+ cells. Participation in another experimental therapeutic protocol within 6 months prior to baseline and during the study period. Tested positive (definitive) for the presence of multiple types (2 or more) of anti-platelet antibodies. Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful study completion. Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements. Part B Additional exclusion criteria: Patients >12 years of age at enrolment Patients ≤12 years of age with a body weight >40kg at enrolment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Donald B. Kohn, MD
Organizational Affiliation
University of California, Los Angeles (UCLA)
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Caroline Y. Kuo, MD
Organizational Affiliation
University of California, Los Angeles (UCLA)
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, Los Angeles (UCLA)
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
National Institutes of Health
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Children's Hospital Boston
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
90095
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Results will be published in scientific literature once trial is completed and data analysis is done.
Citations:
PubMed Identifier
20978475
Citation
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.
Results Reference
background
PubMed Identifier
29664709
Citation
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.
Results Reference
derived

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

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