Part B- G1X-CGD (Lentiviral Vector Transduced CD34+ Cells) in Patients With X-Linked Chronic Granulomatous Disease
- Conditions
- Chronic Granulomatous Disease (CGD)
- Interventions
- Other: pCCLChimGp91lentiviral vector containing the human gp91 phox (CYBB) gene
- Registration Number
- NCT07113743
- Brief Summary
Background:
X-Linked Chronic Granulomatous Disease (X-CGD) is caused by a gene mutation that makes the immune system to not work properly. Researchers want to see if a lentiviral gene transfer treatment will have the ability to make the patient s immune system more normal, in particular reduce the risk of CGD related infections. The gene transfer takes a person s own stem cells, cultures them to put the normal gene in, then gives the cells back to the person.
Objective:
To test a gene transfer treatment for X-CGD.
Eligibility:
Participants aged 3-60 with X-CGD
Design:
Participants will be screened under protocol 05-I-0123. They will undergo:
Medical history
Physical exam
Heart tests
Imaging tests, as needed
Blood tests
Lung function tests, as needed
Dental and audiology exams, if needed
Quality of life questionnaire
Bone marrow aspiration. A needle will be inserted into the hip bone or breastbone to collect bone marrow.
Some screening tests will be repeated during the study.
Participants will have an apheresis procedure under protocol 94-I-0073. Stem cells will be collected.
Participants will get a series of drugs to prepare them for the gene transfer.
Participants will stay at the NIH Clinical Center for a little over a month. They will get a central line. It is a large intravenous (IV) catheter that is placed into a vein of the neck, chest, or arm. They will get chemotherapy and their corrected stem cells through their IV line.
Participants will have 12 follow-up outpatient visits in the 2 years after their gene transfer, as well as visits with their local doctor. Then they will enroll in another study for long-term follow-up visits that will last for 13 years....
- Detailed Description
Study Description:
This is a Phase I/II, non-Randomized, Single site study, open-label study of a single infusion of autologous CD34+ cells transduced ex vivo with pCCLChimGp91/VSVg lentiviral vector in 10 patients with X-Linked CGD.
Objectives:
Primary Objective:
To evaluate the safety, efficacy and stability by biochemical and functional reconstitution in progeny of engrafted cells at 12 months Secondary Objectives:
Endpoints:
* Clinical efficacy and longitudinal evaluation of clinical effect in terms of augmented immunity against bacterial and fungal infection
* Determine the number of days of antibiotic usage before compared to after gene therapy
* Transduction efficiency of CD34+ hematopoietic cells from XCGD patients by ex vivo lentivirus-mediated gene transfer
* Evaluation of engraftment kinetics and stability
Primary Endpoint:
1. The primary safety objective of this procedure will be assessed by recording the incidence of adverse events.
1. Record clinical adverse events and clinically significant laboratory abnormalities.
2. Evaluate overall incidence of adverse events for the study as a whole.
3. Monitor the incidence of serious adverse events.
2. The primary efficacy objective of this study will be determined by measuring the percentage of subjects who have \>= 10% oxidase positive granulocytes by dihydrorhodamine (DHR) flow cytometry at month 6 and 12 after transplant.
Secondary Endpoints:
1. Assess immunological reconstitution:
Restoration of neutrophil oxidase function (\> 10%) as measured by DHR flow cytometry (clinical), and/or cytochrome C (O2 production, research), at 24 months. The % DHR + neutrophils will be measured at week 4, 5, 6, 7, 8, 10, 12 and month 6, 9, 12, 18 and 24.
2. Assess hematopoietic stem cell (HSC) transduction and engraftment:
1. Determine the percentage of transduced CD34+ hematopoietic cells infused.
2. Measure the average vector copy number (VCN) in mature blood cells (at week 4, 6, 7, 8, 10, 12 and month 6, 9, 12, 18 and 24) by quantitative polymerase chain reaction (qPCR) or droplet digital polymerase chain reaction (ddPCR).
3. Assess health by:
1. The nutritional status (height, weight, serum albumin) at 24 months
2. Growth and development of pediatric subjects at 24 months
3. Frequency of severe infections or other health issues, including inflammatory complications (requiring intravenous \[IV\] antibiotics and/or hospitalization for treatment)
4. Measurement of inflammatory markers at 1, 2, 3, 6, 9, 12, 18, and 24 months, compared to baseline
5. Colitis assessment based on CDAI (Crohn s Disease Activity Index) and fecal calprotectin at 6, 12, and 24 months, compared to baseline
6. Quality of Life (QOL) questionnaire (baseline, 6, 12 and 24 months)
Exploratory Endpoints:
1. Evaluation of the human microbiome during XCGD gene therapy
2. Evaluation of inflammatory cytokines and antibody development to Gp91, etc
Recruitment & Eligibility
- Status
- ENROLLING_BY_INVITATION
- Sex
- All
- Target Recruitment
- 10
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description X-linked CGD Busulfan Non-randomized single arm X-linked CGD Tocilizumab Non-randomized single arm X-linked CGD Eltrombopag Non-randomized single arm X-linked CGD Sirolimus Non-randomized single arm X-linked CGD pCCLChimGp91lentiviral vector containing the human gp91 phox (CYBB) gene Non-randomized single arm
- Primary Outcome Measures
Name Time Method Safety Throughout the study 1\) The primary safety objective of this procedure will be assessed by recording the incidence of adverse events. a) Record clinical adverse events and clinically significant laboratory abnormalities. b) Evaluate overall incidence of adverse events for the study as a whole. c) Monitor the incidence of serious adverse events.
Efficacy 6 months and 1 year The primary efficacy objective of this study will be determined by measuring the percentage of subjects who have \>= 10% oxidase positive granulocytes by DHR flow cytometry at month 6 and 12 after transplant.
- Secondary Outcome Measures
Name Time Method Assess immunological reconstitution Week 4, 5, 6, 7, 8, 10, 12 and months 6, 9, 12, 18 and 24 months. Restoration of neutrophil oxidase function (\> 10%) as measured by DHR flow cytometry (clinical), and/or cytochrome C (O2 production, research), at 24 months. The % DHR + neutrophils will be measured at week 4, 5, 6, 7, 8, 10, 12 and months 6, 9, 12, 18 and 24 months.
Assess HSC transduction and engraftment Week 4, 6, 7, 8, 10, 12 and month 6, 9, 12, 18 and 24) a) Determine the percentage of transduced CD34+ hematopoietic cells infused. b) Measure the average vector copy number (VCN) in mature blood cells (at week 4, 6, 7, 8, 10, 12 and month 6, 9, 12, 18 and 24) by qPCR or ddPCR.
Assess health by 1, 2, 3, 6, 9, 12, 18, and 24 months, compared to baseline a) The nutritional status (height, weight, serum albumin) at 24 months b) Growth and development of pediatric subjects at 24 months c) Frequency of severe infections or other health issues, including inflammatory complications (requiring IV antibiotics and/or hospitalization for treatment) d) Measurement of inflammatory markers at 1, 2, 3, 6, 9, 12, 18, and 24 months, compared to baseline e) Colitis assessment based on CDAI (Crohn s Disease Activity Index) and fecal calprotectin at 6, 12, and 24 months, compared to baseline f) Quality of life questionnaire (baseline, 6, 12 and 24 months).
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center🇺🇸Bethesda, Maryland, United States