CD4^LVFOXP3 in Participants With IPEX

Официальное название

Phase 1 Study of Autologous CD4^LVFOXP3 in Participants With Immune Dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) Syndrome

Обзор

This first-in-human, Phase 1 clinical trial will test the feasibility of the manufacturing and the safety of the administration of CD4\^LVFOXP3 in up to 30 evaluable human participants with IPEX and evaluate the impact of the CD4\^LVFOXP3 infusion on the disease.

Подробное описание

Treatment with CD4\^LVFOXP3 is expected to replace the defective Treg cells of the participants, and restore control of the immune system and therefore ameliorate symptoms of IPEX.

We expect to learn the following from this study:

1. That CD4\^LVFOXP3 can be consistently produced and be of expected quality to be used in humans, 2. That CD4\^LVFOXP3 are safe in children and young adults with IPEX, and determine its effects, both good and bad, 3. That CD4\^LVFOXP3 can improve overall health and allow reduction of medication/s.

This Phase 1 (feasibility and safety) trial will gather data about CD4\^LVFOXP3 in vivo persistency and early signs of impact on symptoms of IPEX.

Вмешательства

• Биопрепарат CD4^LVFOXP3
  Infusion of autologous CD4+ T cells that have undergone lentiviral-mediated gene transfer of: i) healthy human FOXP3 gene leading to persistent high FOXP3 expression and acquisition of Treg-like cell function; and ii) human CD271 surface marker gene that allows tracking and quantification of the CD4\^LVFOXP3 in the blood.

Первичные конечные точки

• Meet target cell number for dose manufacturing [Срок оценки: Time at release from manufacturing (by Day 0 [infusion day] for each participant)]
• Find the safe maximum tolerated dose [Срок оценки: Up to 60 days post-infusion for each participant]

Вторичные конечные точки (12)

• Change in Diarrhea incidence [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (daily for the first month followed by monthly at Month 2, 3, 6, 9, 12)]
• Change in GI Symptoms - Gastrointestinal Symptoms Rating Scale [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4, Month 6, Month 12)]
• Change in Body Mass Index (BMI) [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 1, 2, 3, Week 1, 2, 3, 4; Month 2, 3, 6, 9, 12)]
• Change in age-specific percentiles of height [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Month 12)]
• Change in age-specific percentiles of bodyweight [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 1, 2, 3, Week 1, 2, 3, 4; Month 2, 3, 6, 9, 12)]
• Change in Bilirubin levels [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)]
• Change in Liver Enzyme - Alanine Transaminase (ALT) [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)]
• Change in Liver Enzyme - Aspartate Transaminase (AST) [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)]
• Change in Liver Enzyme - Alkaline Phosphatase (ALP) [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)]
• Change in Liver Enzyme - Gamma Glutyltranspeptidase (GGT) [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)]
• Change in INR level [Срок оценки: Baseline/screening (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4; Month 3, 6, 12)]
• Skin Disease (EASI) - Changes from Baseline/ Pre-infusion [Срок оценки: Baseline (up to 60 days before infusion of CD4^LVFOXP3), through post-infusion (Day 1; Week 1, 2, 3, 4; Month 3, 6 and 12)]

Критерии участия

Критерии включения

• Body weight greater than 8 kg, unless assessed as able to tolerate leukapheresis
• FOXP3 gene mutation
• Medical history of progressive symptoms of IPEX with persistency of some symptoms and/or signs requiring immune suppressive medication. The participant may or may not be on immunosuppression at time of starting the study.
• Uncontrolled IPEX disease but unable to tolerate immune suppressive medication
• Recurrent IPEX symptoms, requiring immune suppressive medications, in participants who have had prior allogeneic (allo) blood stem cell transplantation (HSCT).
• ≥ 50% Performance rating on Lansky/Karnofsky Scale
• Organ and marrow function within acceptable levels of function
• Absence of ongoing infections
• Must be able to consent if an adult

Критерии исключения

• Medical instability
• Less than 6 months life expectancy
• Inability to meet limits for steroid dosing
• Eligible for an HLA matched sibling or matched unrelated donor blood stem cell transplant, and be willing to undergo transplant.
• Unrelated or comorbid disease
• Allergy to any study medication, product, or intervention
• Currently receiving another experimental treatment
• History of malignancy, unless disease free for at least 2 years, with the exception of non melanoma skin cancer or carcinoma in situ

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Lucile Packard Children's Hospital — Palo Alto

Публикации

• Allan SE, Alstad AN, Merindol N, Crellin NK, Amendola M, Bacchetta R, Naldini L, Roncarolo MG, Soudeyns H, Levings MK. Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol Ther. 2008 Jan;16(1):194-202. doi: 10.1038/sj.mt.6300341. Epub 2007 Nov 6. PMID 17984976
• Amendola M, Venneri MA, Biffi A, Vigna E, Naldini L. Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters. Nat Biotechnol. 2005 Jan;23(1):108-16. doi: 10.1038/nbt1049. Epub 2004 Dec 26. PMID 15619618
• Baecher-Allan CM, Hafler DA. The purification and functional analysis of human CD4+CD25high regulatory T cells. Curr Protoc Immunol. 2006 May;Chapter 7:7.4B.1-7.4B.12. doi: 10.1002/0471142735.im0704bs72. PMID 18432975
• Barzaghi F, Passerini L, Gambineri E, Ciullini Mannurita S, Cornu T, Kang ES, Choe YH, Cancrini C, Corrente S, Ciccocioppo R, Cecconi M, Zuin G, Discepolo V, Sartirana C, Schmidtko J, Ikinciogullari A, Ambrosi A, Roncarolo MG, Olek S, Bacchetta R. Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun. 2012 Feb;38(1):49-58. doi PMID 22264504
• Barzaghi F, Amaya Hernandez LC, Neven B, Ricci S, Kucuk ZY, Bleesing JJ, Nademi Z, Slatter MA, Ulloa ER, Shcherbina A, Roppelt A, Worth A, Silva J, Aiuti A, Murguia-Favela L, Speckmann C, Carneiro-Sampaio M, Fernandes JF, Baris S, Ozen A, Karakoc-Aydiner E, Kiykim A, Schulz A, Steinmann S, Notarangelo LD, Gambineri E, Lionetti P, Shearer WT, Forbes LR, Martinez C, Moshous D, Blanche S, Fisher A, R PMID 29241729
• Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005 Jun 15;105(12):4743-8. doi: 10.1182/blood-2004-10-3932. Epub 2005 Mar 3. PMID 15746082
• Bluestone JA, Tang Q. Treg cells-the next frontier of cell therapy. Science. 2018 Oct 12;362(6411):154-155. doi: 10.1126/science.aau2688. No abstract available. PMID 30309932
• Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov 25;7(315):315ra189. doi: 10.1126/scitranslmed.aad4134. PMID 26606968

Идентификаторы

NCT: NCT05241444 · IRB-63373 · DRU-2020-7764 · RPD-2020-470 · 1R01FD007540-01 · CLIN2-13259

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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