Chronic Granulomatous Disease X-linked (X-CGD)
Conditions
Keywords
Chronic granulomatous disease X-linked, Ibuprofen, Mobilization regimen, Gene Therapy
Brief summary
This is a phase II exploratory study conducted to evaluate the safety and efficacy of the combination of Ibuprofen, G-CSF and Plerixafor as stem cell mobilization regimen in patients affected by X-CGD.
Detailed description
We designed a mobilization trial with the aim of collecting a sufficient number of HSPC in X-CGD patients; it is well known that this procedure is challenging for these patients, potentially due to functional defects induced by their chronic inflammatory state. The combination of G-CSF and Plerixafor is considered state of the art for HSPC harvest in gene therapy trials; we considered to add a non-steroidal inflammatory drug to increase HSPC mobilization and reduce inflammation that could have a role in altering HSPC content. If this trial confirms the synergistic effect of the three drugs under investigation, such a regimen will be considered for a HSPC mobilization in future gene therapy trial for X-CGD patients.
Interventions
DRUGIbuprofen
Ibuprofen: 3 mg/kg tid (total daily dose: 9 mg/kg); administered orally from day 1 to day 5 and then from day 14 to the day before the last LP.
DRUGMyelostim
Myelostim (G-CSF): 5 µg/kg bid (total daily dose 10 µg/kg); administered subcutaneously from day 19 to the day of the last LP.
DRUGMozobil
Mozobil (Plerixafor): 0,24 mg/kg daily. When CD34+ are ≥ 10 /μL Plerixafor will be administered subcutaneously from the next day (or from day 24 if CD34+ are \< 10 /μL) to the day of the last LP.
Sponsors
Fondazione Telethon
IRCCS San Raffaele
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Genetic diagnosis of X-CGD * 18-45 years of age * Karnofsky Index \> 80 % * Adequate cardiac, renal, hepatic and pulmonary function. * Negative thrombophilic screen and negative history for previous thrombotic events * Written informed consent
Exclusion criteria
* Previous Bone Marrow Transplantation or previous Gene Therapy. * Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents). * Ongoing IFN-γ treatment (within 4 weeks). * Symptomatic inflammatory bowel disease. * Symptomatic viral, bacterial, or fungal infection within 6 weeks of eligibility * Neoplasia (except local skin cancer) or history of familial cancer * Myelodysplasia or other serious hematological disorder * History of uncontrolled seizures and deep venous thrombosis * Other systemic disease judged as incompatible with the procedure * Positivity for HIV and/or HCV RNA and/or HbsAg and/or HBV DNA * Active alcohol or substance abuse within 6 months of the study. * Contraindications to IBU, G-CSF, Plerixafor or Pantoprazole administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of patients experiencing adverse events | up to 30 days after the last LP | Percentage of patients experiencing adverse events, as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAe v3.0, 2006) (all grades). |
| Number of CD34+ collected per body weight after the last LP | Day 21-24 | Cytofluorimetric analysis for CD34 on PB and on collected PBSC to calculate the number of CD34+ cells collected per kg body weight. The analysis will be performed at the end of the LP(s) (Day 21-24) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in number of CD34+ cells in PB before and after administration of Ibuprofen | Day 6 and day 7 | Cytofluorimetric analysis to determine the number of CD34+ cells present in PB on day 6 and 7 compared to before the administration of Ibuprofen |
| Transduction efficiency | Through study completion, an average of 1 year | Efficient transduction of mobilized HSPC with a lentiviral vector encoding for a corrective cDNA of the human gp91phox gene. Frequency and Vector Copy Number tested by PCR. |
| DHR (dihydrorhodamine) test in myeloid progeny | Through study completion, an average of 1 year | Correction of the functional defects in the differentiated myeloid progeny |
| Functional characterization of mobilized CD34+ cells. | Through study completion, an average of 1 year | Phenotype analysis (FACS). |
Countries
Italy
Contacts
Primary ContactFabio Ciceri, MD, PhD
Backup ContactAlessandro Aiuti, MD, PhD
Outcome results
None listed