Combination of Ibuprofen, G-CSF and Plerixafor as Stem Cells Mobilization Regimen in Patients Affected by X-CGD

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Multicentric, Exploratory, Non-randomised, Non-controlled, Prospective, Open-label Phase II Study Evaluating Safety and Efficacy of IBU, G-CSF and Plerixafor as Stem Cell Mobilization Regimen in Patients Affected by X-CGD

Conditions
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Chronic Granulomatous Disease X-linked (X-CGD)

Intervention / Treatment
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* Drug: Ibuprofen
* Drug: Myelostim
* Drug: Mozobil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XCGD mobilization<br>Treatment with combination of Ibuprofen, Myelostim and Mozobil | Drug: Ibuprofen<br>* 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.<br>Drug: Myelostim<br>* 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.<br>Drug: Mozobil<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients experiencing adverse events | 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). | up to 30 days after the last LP | 
| Number of CD34+ collected per body weight after the last LP | 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) | Day 21-24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in number of CD34+ cells in PB before and after administration of Ibuprofen | Cytofluorimetric analysis to determine the number of CD34+ cells present in PB on day 6 and 7 compared to before the administration of Ibuprofen | Day 6 and day 7 | 
| Transduction efficiency | 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. | Through study completion, an average of 1 year | 
| DHR (dihydrorhodamine) test in myeloid progeny | Correction of the functional defects in the differentiated myeloid progeny | Through study completion, an average of 1 year | 
| Functional characterization of mobilized CD34+ cells. | Phenotype analysis (FACS). | Through study completion, an average of 1 year | 
| Functional characterization of mobilized CD34+ cells. | Clonogenic activity (CFU-C) before and after transduction. | Through study completion, an average of 1 year | 
| Functional characterization of mobilized CD34+ cells. | Repopulating activity of mobilized CD34+ cells in immunodeficient mice. | Through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic granulomatous disease X-linked, Ibuprofen, Mobilization regimen, Gene Therapy