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

Sponsor

IRCCS San Raffaele (Other)

Overall Status

Unknown status

CT.gov ID

NCT03055247

Collaborator

Fondazione Telethon (Other)

Enrollment

Locations

Arm

Duration (Months)

1.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Granulomatous Disease X-linked (X-CGD)	Drug: Ibuprofen Drug: Myelostim Drug: Mozobil	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

3 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Study Start Date :

Nov 1, 2015

Anticipated Primary Completion Date :

Sep 1, 2017

Anticipated Study Completion Date :

Aug 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: XCGD mobilization Treatment with combination of Ibuprofen, Myelostim and Mozobil	Drug: Ibuprofen 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. Drug: Myelostim 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. Drug: Mozobil 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.

Arm

Intervention/Treatment

Experimental: XCGD mobilization

Treatment with combination of Ibuprofen, Myelostim and Mozobil

Drug: Ibuprofen

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.

Drug: Myelostim

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.

Drug: Mozobil

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.

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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).
Functional characterization of mobilized CD34+ cells. [Through study completion, an average of 1 year]
Clonogenic activity (CFU-C) before and after transduction.
Functional characterization of mobilized CD34+ cells. [Through study completion, an average of 1 year]
Repopulating activity of mobilized CD34+ cells in immunodeficient mice.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedale Pediatrico Bambino Gesù	Rome	Lazio	Italy	00165
2	Ospedale San Raffaele	Milan	Lombardia	Italy	20132

Sponsors and Collaborators

IRCCS San Raffaele
Fondazione Telethon

Investigators

Principal Investigator: Fabio Ciceri, MD, PhD, Ospedale San Raffaele
Principal Investigator: Franco Locatelli, MD, PhD, Ospedale Pediatrico Bambino Gesù