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

NCT03055247 | Recruiting Phase 2

• 1 other identifier: 2015-002356-27
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 2

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.

Conditions

Chronic Granulomatous Disease X-linked (X-CGD)

Keywords

Chronic granulomatous disease X-linked; Ibuprofen; Mobilization regimen; Gene Therapy

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Change in number of CD34+ cells in PB before and after administration of Ibuprofen

  Day 6 and day 7

• Transduction efficiency

  Through study completion, an average of 1 year

• DHR (dihydrorhodamine) test in myeloid progeny

  Through study completion, an average of 1 year

• Functional characterization of mobilized CD34+ cells.

  Through study completion, an average of 1 year

• Functional characterization of mobilized CD34+ cells.

  Through study completion, an average of 1 year

Study Arms (1)

XCGD mobilization

EXPERIMENTAL

Treatment with combination of Ibuprofen, Myelostim and Mozobil

Drug: Ibuprofen; Drug: Myelostim; Drug: Mozobil

Interventions

Ibuprofen DRUG

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.

XCGD mobilization

Myelostim DRUG

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.

XCGD mobilization

Mozobil DRUG

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.

XCGD mobilization

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Genetic diagnosis of X-CGD
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• IRCCS San Raffaele: lead
• Fondazione Telethon: collaborator

Study Sites (2)

Ospedale Pediatrico Bambino Gesù

Rome, Lazio, 00165, Italy

RECRUITING

Ospedale San Raffaele

Milan, Lombardy, 20132, Italy

RECRUITING

Related Publications (26)

• Aiuti A, Bacchetta R, Seger R, Villa A, Cavazzana-Calvo M. Gene therapy for primary immunodeficiencies: Part 2. Curr Opin Immunol. 2012 Oct;24(5):585-91. doi: 10.1016/j.coi.2012.07.012. Epub 2012 Aug 18.

  PMID: 22909900 BACKGROUND

• Chiriaco M, Farinelli G, Capo V, Zonari E, Scaramuzza S, Di Matteo G, Sergi LS, Migliavacca M, Hernandez RJ, Bombelli F, Giorda E, Kajaste-Rudnitski A, Trono D, Grez M, Rossi P, Finocchi A, Naldini L, Gentner B, Aiuti A. Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis. Mol Ther. 2014 Aug;22(8):1472-1483. doi: 10.1038/mt.2014.87. Epub 2014 May 29.

  PMID: 24869932 BACKGROUND

• Di Matteo G, Giordani L, Finocchi A, Ventura A, Chiriaco M, Blancato J, Sinibaldi C, Plebani A, Soresina A, Pignata C, Dellepiane RM, Trizzino A, Cossu F, Rondelli R, Rossi P, De Mattia D, Martire B; IPINET (Italian Network for Primary Immunodeficiencies). Molecular characterization of a large cohort of patients with Chronic Granulomatous Disease and identification of novel CYBB mutations: an Italian multicenter study. Mol Immunol. 2009 Jun;46(10):1935-41. doi: 10.1016/j.molimm.2009.03.016. Epub 2009 May 1.

  PMID: 19410294 BACKGROUND

• Edmonson JH, Hartmann LC, Long HJ, Colon-Otero G, Fitch TR, Jefferies JA, Braich TA, Maples WJ. Granulocyte-macrophage colony-stimulating factor. Preliminary observations on the influences of dose, schedule, and route of administration in patients receiving cyclophosphamide and carboplatin. Cancer. 1992 Nov 15;70(10):2529-39. doi: 10.1002/1097-0142(19921115)70:103.0.co;2-h.

  PMID: 1423182 BACKGROUND

• Gennery AR, Slatter MA, Grandin L, Taupin P, Cant AJ, Veys P, Amrolia PJ, Gaspar HB, Davies EG, Friedrich W, Hoenig M, Notarangelo LD, Mazzolari E, Porta F, Bredius RG, Lankester AC, Wulffraat NM, Seger R, Gungor T, Fasth A, Sedlacek P, Neven B, Blanche S, Fischer A, Cavazzana-Calvo M, Landais P; Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation; European Society for Immunodeficiency. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol. 2010 Sep;126(3):602-10.e1-11. doi: 10.1016/j.jaci.2010.06.015. Epub 2010 Jul 31.

  PMID: 20673987 BACKGROUND

• Grez M, Reichenbach J, Schwable J, Seger R, Dinauer MC, Thrasher AJ. Gene therapy of chronic granulomatous disease: the engraftment dilemma. Mol Ther. 2011 Jan;19(1):28-35. doi: 10.1038/mt.2010.232. Epub 2010 Nov 2.

  PMID: 21045810 BACKGROUND

• Gungor T, Teira P, Slatter M, Stussi G, Stepensky P, Moshous D, Vermont C, Ahmad I, Shaw PJ, Telles da Cunha JM, Schlegel PG, Hough R, Fasth A, Kentouche K, Gruhn B, Fernandes JF, Lachance S, Bredius R, Resnick IB, Belohradsky BH, Gennery A, Fischer A, Gaspar HB, Schanz U, Seger R, Rentsch K, Veys P, Haddad E, Albert MH, Hassan M; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet. 2014 Feb 1;383(9915):436-48. doi: 10.1016/S0140-6736(13)62069-3. Epub 2013 Oct 23.

  PMID: 24161820 BACKGROUND

• Holland SM. Chronic granulomatous disease. Clin Rev Allergy Immunol. 2010 Feb;38(1):3-10. doi: 10.1007/s12016-009-8136-z.

  PMID: 19504359 BACKGROUND

• Hong KT, Kang HJ, Kim NH, Kim MS, Lee JW, Kim H, Park KD, Shin HY, Ahn HS. Successful mobilization using a combination of plerixafor and G-CSF in pediatric patients who failed previous chemomobilization with G-CSF alone and possible complications of the treatment. J Hematol Oncol. 2012 Mar 30;5:14. doi: 10.1186/1756-8722-5-14.

  PMID: 22458355 BACKGROUND

• Hoggatt J, Mohammad KS, Singh P, Hoggatt AF, Chitteti BR, Speth JM, Hu P, Poteat BA, Stilger KN, Ferraro F, Silberstein L, Wong FK, Farag SS, Czader M, Milne GL, Breyer RM, Serezani CH, Scadden DT, Guise TA, Srour EF, Pelus LM. Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature. 2013 Mar 21;495(7441):365-9. doi: 10.1038/nature11929. Epub 2013 Mar 13.

  PMID: 23485965 BACKGROUND

• Kang EM, Choi U, Theobald N, Linton G, Long Priel DA, Kuhns D, Malech HL. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood. 2010 Jan 28;115(4):783-91. doi: 10.1182/blood-2009-05-222760. Epub 2009 Dec 1.

  PMID: 19965657 BACKGROUND

• Kang HJ, Bartholomae CC, Paruzynski A, Arens A, Kim S, Yu SS, Hong Y, Joo CW, Yoon NK, Rhim JW, Kim JG, Von Kalle C, Schmidt M, Kim S, Ahn HS. Retroviral gene therapy for X-linked chronic granulomatous disease: results from phase I/II trial. Mol Ther. 2011 Nov;19(11):2092-101. doi: 10.1038/mt.2011.166. Epub 2011 Aug 30.

  PMID: 21878903 BACKGROUND

• Martinez CA, Shah S, Shearer WT, Rosenblatt HM, Paul ME, Chinen J, Leung KS, Kennedy-Nasser A, Brenner MK, Heslop HE, Liu H, Wu MF, Hanson IC, Krance RA. Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease. J Allergy Clin Immunol. 2012 Jan;129(1):176-83. doi: 10.1016/j.jaci.2011.10.005. Epub 2011 Nov 12.

  PMID: 22078471 BACKGROUND

• Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kuhlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Luthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006 Apr;12(4):401-9. doi: 10.1038/nm1393. Epub 2006 Apr 2.

  PMID: 16582916 BACKGROUND

• Panch SR, Yau YY, Kang EM, De Ravin SS, Malech HL, Leitman SF. Mobilization characteristics and strategies to improve hematopoietic progenitor cell mobilization and collection in patients with chronic granulomatous disease and severe combined immunodeficiency. Transfusion. 2015 Feb;55(2):265-74. doi: 10.1111/trf.12830. Epub 2014 Aug 21.

  PMID: 25143186 BACKGROUND

• Pham HP, Patel N, Semedei-Pomales M, Bhatia M, Schwartz J. The use of plerixafor in hematopoietic progenitor cell collection in pediatric patients: a single center experience. Cytotherapy. 2012 Apr;14(4):467-72. doi: 10.3109/14653249.2012.658912. Epub 2012 Feb 20.

  PMID: 22339604 BACKGROUND

• Roos D, Kuhns DB, Maddalena A, Bustamante J, Kannengiesser C, de Boer M, van Leeuwen K, Koker MY, Wolach B, Roesler J, Malech HL, Holland SM, Gallin JI, Stasia MJ. Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update). Blood Cells Mol Dis. 2010 Apr 15;44(4):291-9. doi: 10.1016/j.bcmd.2010.01.009. Epub 2010 Feb 18.

  PMID: 20167518 BACKGROUND

• Sevilla J, Schiavello E, Madero L, Pardeo M, Guggiari E, Baragano M, Luksch R, Massimino M. Priming of hematopoietic progenitor cells by plerixafor and filgrastim in children with previous failure of mobilization with chemotherapy and/or cytokine treatment. J Pediatr Hematol Oncol. 2012 Mar;34(2):146-50. doi: 10.1097/MPH.0b013e31821c2cb8.

  PMID: 22009006 BACKGROUND

• Seger RA. Modern management of chronic granulomatous disease. Br J Haematol. 2008 Feb;140(3):255-66. doi: 10.1111/j.1365-2141.2007.06880.x.

  PMID: 18217895 BACKGROUND

• 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.

  PMID: 20978475 BACKGROUND

• Seger RA. Chronic granulomatous disease: recent advances in pathophysiology and treatment. Neth J Med. 2010 Nov;68(11):334-40.

  PMID: 21116026 BACKGROUND

• Son MH, Kang ES, Kim DH, Lee SH, Yoo KH, Sung KW, Koo HH, Kim DW, Kim JY, Cho EJ. Efficacy and toxicity of plerixafor for peripheral blood stem cell mobilization in children with high-risk neuroblastoma. Pediatr Blood Cancer. 2013 Aug;60(8):E57-9. doi: 10.1002/pbc.24506. Epub 2013 Mar 4.

  PMID: 23460590 BACKGROUND

• Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, Schmidt M, Kramer A, Schwable J, Glimm H, Koehl U, Preiss C, Ball C, Martin H, Gohring G, Schwarzwaelder K, Hofmann WK, Karakaya K, Tchatchou S, Yang R, Reinecke P, Kuhlcke K, Schlegelberger B, Thrasher AJ, Hoelzer D, Seger R, von Kalle C, Grez M. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med. 2010 Feb;16(2):198-204. doi: 10.1038/nm.2088. Epub 2010 Jan 24.

  PMID: 20098431 BACKGROUND

• Yannaki E, Karponi G, Zervou F, Constantinou V, Bouinta A, Tachynopoulou V, Kotta K, Jonlin E, Papayannopoulou T, Anagnostopoulos A, Stamatoyannopoulos G. Hematopoietic stem cell mobilization for gene therapy: superior mobilization by the combination of granulocyte-colony stimulating factor plus plerixafor in patients with beta-thalassemia major. Hum Gene Ther. 2013 Oct;24(10):852-60. doi: 10.1089/hum.2013.163.

  PMID: 24001178 BACKGROUND

• Yannaki E, Papayannopoulou T, Jonlin E, Zervou F, Karponi G, Xagorari A, Becker P, Psatha N, Batsis I, Kaloyannidis P, Tahynopoulou V, Constantinou V, Bouinta A, Kotta K, Athanassiadou A, Anagnostopoulos A, Fassas A, Stamatoyannopoulos G. Hematopoietic stem cell mobilization for gene therapy of adult patients with severe beta-thalassemia: results of clinical trials using G-CSF or plerixafor in splenectomized and nonsplenectomized subjects. Mol Ther. 2012 Jan;20(1):230-8. doi: 10.1038/mt.2011.195. Epub 2011 Sep 27.

  PMID: 21952171 BACKGROUND

• Wu C, Dunbar CE. Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity. Front Med. 2011 Dec;5(4):356-71. doi: 10.1007/s11684-011-0159-1. Epub 2011 Dec 27.

  PMID: 22198747 BACKGROUND

MeSH Terms

Conditions

Granulomatous Disease, Chronic

Interventions

Ibuprofen; plerixafor

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals

Study Officials

• Fabio Ciceri, MD, PhD

  Ospedale San Raffaele

  PRINCIPAL INVESTIGATOR

• Franco Locatelli, MD, PhD

  Ospedale Pediatrico Bambino Gesù

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Fabio Ciceri, MD, PhD

CONTACT

39 02.2643.3903; ciceri.fabio@hsr.it

Alessandro Aiuti, MD, PhD

CONTACT

+390226434875; aiuti.alessandro@hsr.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director Hematology and BMT Unit

Study Record Dates

• First Submitted: July 21, 2016
• First Posted: February 16, 2017
• Study Start: November 6, 2015
• Primary Completion: July 13, 2023
• Study Completion (Estimated): July 18, 2026
• Last Updated: September 18, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2)