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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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.
• Препарат 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.
• Препарат 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.

Первичные конечные точки

• Percentage of patients experiencing adverse events [Срок оценки: up to 30 days after the last LP]
• Number of CD34+ collected per body weight after the last LP [Срок оценки: Day 21-24]

Вторичные конечные точки (6)

• Change in number of CD34+ cells in PB before and after administration of Ibuprofen [Срок оценки: Day 6 and day 7]
• Transduction efficiency [Срок оценки: Through study completion, an average of 1 year]
• DHR (dihydrorhodamine) test in myeloid progeny [Срок оценки: Through study completion, an average of 1 year]
• Functional characterization of mobilized CD34+ cells. [Срок оценки: Through study completion, an average of 1 year]
• Functional characterization of mobilized CD34+ cells. [Срок оценки: Through study completion, an average of 1 year]
• Functional characterization of mobilized CD34+ cells. [Срок оценки: Through study completion, an average of 1 year]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Италия · 2 центра

• Ospedale Pediatrico Bambino Gesù — Rome
• Ospedale San Raffaele — Milan

Публикации

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• 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
• 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 Ital PMID 19410294
• 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
• 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 Socie PMID 20673987
• 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
• 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 M PMID 24161820
• Holland SM. Chronic granulomatous disease. Clin Rev Allergy Immunol. 2010 Feb;38(1):3-10. doi: 10.1007/s12016-009-8136-z. PMID 19504359

Идентификаторы

NCT: NCT03055247 · 2015-002356-27

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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