CD4^LVFOXP3 in Participants With IPEX

IPEX Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05241444
• Other study ID #: IRB-63373
• Secondary ID: DRU-2020-7764RPD
• Status: Recruiting
• Phase: Phase 1
• Start date: March 22, 2022
• Est. completion date: February 2037

Study information

• Verified date: April 2023
• Source: Stanford University
• Contact: Rosa Bacchetta, MD
• Phone: 650-498-8369
• Email: rosab[@]stanford.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 36 evaluable human participants with IPEX and evaluate the impact of the CD4^LVFOXP3 infusion on the disease.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: February 2037
• Est. primary completion date: February 2027
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 4 Months to 35 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 cardiac, renal, pulmonary, liver, or hematologic 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

Related Conditions & MeSH terms

• IPEX

Intervention

Biological:
• 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.

Locations

Country	Name	City	State
United States	Lucile Packard Children's Hospital	Palo Alto	California

Sponsors (2)

Lead Sponsor	Collaborator
Bacchetta, Rosa, MD	California Institute for Regenerative Medicine (CIRM)

Country where clinical trial is conducted

United States, 

References & Publications (23)

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. — View Citation

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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, Ruemmele FM, Tissandier C, Ouachee-Chardin M, Rieux-Laucat F, Cavazzana M, Qasim W, Lucarelli B, Albert MH, Kobayashi I, Alonso L, Diaz De Heredia C, Kanegane H, Lawitschka A, Seo JJ, Gonzalez-Vicent M, Diaz MA, Goyal RK, Sauer MG, Yesilipek A, Kim M, Yilmaz-Demirdag Y, Bhatia M, Khlevner J, Richmond Padilla EJ, Martino S, Montin D, Neth O, Molinos-Quintana A, Valverde-Fernandez J, Broides A, Pinsk V, Ballauf A, Haerynck F, Bordon V, Dhooge C, Garcia-Lloret ML, Bredius RG, Kalwak K, Haddad E, Seidel MG, Duckers G, Pai SY, Dvorak CC, Ehl S, Locatelli F, Goldman F, Gennery AR, Cowan MJ, Roncarolo MG, Bacchetta R; Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT). Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol. 2018 Mar;141(3):1036-1049.e5. doi: 10.1016/j.jaci.2017.10.041. Epub 2017 Dec 11. — View Citation

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Brunstein CG, Miller JS, McKenna DH, Hippen KL, DeFor TE, Sumstad D, Curtsinger J, Verneris MR, MacMillan ML, Levine BL, Riley JL, June CH, Le C, Weisdorf DJ, McGlave PB, Blazar BR, Wagner JE. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016 Feb 25;127(8):1044-51. doi: 10.1182/blood-2015-06-653667. Epub 2015 Nov 12. — View Citation

Consonni F, Ciullini Mannurita S, Gambineri E. Atypical Presentations of IPEX: Expect the Unexpected. Front Pediatr. 2021 Feb 5;9:643094. doi: 10.3389/fped.2021.643094. eCollection 2021. — View Citation

Cornetta K, Duffy L, Turtle CJ, Jensen M, Forman S, Binder-Scholl G, Fry T, Chew A, Maloney DG, June CH. Absence of Replication-Competent Lentivirus in the Clinic: Analysis of Infused T Cell Products. Mol Ther. 2018 Jan 3;26(1):280-288. doi: 10.1016/j.ymthe.2017.09.008. Epub 2017 Sep 12. — View Citation

Delville M, Bellier F, Leon J, Klifa R, Lizot S, Vincon H, Sobrino S, Thouenon R, Marchal A, Garrigue A, Olivre J, Charbonnier S, Lagresle-Peyrou C, Amendola M, Schambach A, Gross D, Lamarthee B, Benoist C, Zuber J, Andre I, Cavazzana M, Six E. A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome. Blood. 2021 Apr 29;137(17):2326-2336. doi: 10.1182/blood.2020009187. — View Citation

Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003 Apr;4(4):330-6. doi: 10.1038/ni904. Epub 2003 Mar 3. — View Citation

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Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, Bonfanti R, Sznajer Y, Tommasini A, Lawitschka A, Junker A, Dunstheimer D, Heidemann PH, Cazzola G, Cipolli M, Friedrich W, Janic D, Azzi N, Richmond E, Vignola S, Barabino A, Chiumello G, Azzari C, Roncarolo MG, Bacchetta R. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol. 2008 Dec;122(6):1105-1112.e1. doi: 10.1016/j.jaci.2008.09.027. Epub 2008 Oct 25. — View Citation

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Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Derkowska I, Juscinska J, Owczuk R, Szadkowska A, Witkowski P, Mlynarski W, Jarosz-Chobot P, Bossowski A, Siebert J, Trzonkowski P. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. Clin Immunol. 2014 Jul;153(1):23-30. doi: 10.1016/j.clim.2014.03.016. Epub 2014 Apr 1. — View Citation

Passerini L, Barzaghi F, Curto R, Sartirana C, Barera G, Tucci F, Albarello L, Mariani A, Testoni PA, Bazzigaluppi E, Bosi E, Lampasona V, Neth O, Zama D, Hoenig M, Schulz A, Seidel MG, Rabbone I, Olek S, Roncarolo MG, Cicalese MP, Aiuti A, Bacchetta R. Treatment with rapamycin can restore regulatory T-cell function in IPEX patients. J Allergy Clin Immunol. 2020 Apr;145(4):1262-1271.e13. doi: 10.1016/j.jaci.2019.11.043. Epub 2019 Dec 23. — View Citation

Passerini L, Rossi Mel E, Sartirana C, Fousteri G, Bondanza A, Naldini L, Roncarolo MG, Bacchetta R. CD4(+) T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci Transl Med. 2013 Dec 11;5(215):215ra174. doi: 10.1126/scitranslmed.3007320. — View Citation

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Sato Y, Passerini L, Piening BD, Uyeda MJ, Goodwin M, Gregori S, Snyder MP, Bertaina A, Roncarolo MG, Bacchetta R. Human-engineered Treg-like cells suppress FOXP3-deficient T cells but preserve adaptive immune responses in vivo. Clin Transl Immunology. 2020 Nov 25;9(11):e1214. doi: 10.1002/cti2.1214. eCollection 2020. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Meet target cell number for dose manufacturing	No more than two products fail the target cell dose and established release criteria.	Time at release from manufacturing (by Day 0 [infusion day] for each participant)
Primary	Find the safe maximum tolerated dose	No more than 1 out of 6 participants may experience a related dose limiting toxicity or treatment emergent adverse events.	Up to 60 days post-infusion for each participant
Secondary	Change in Diarrhea incidence	Stool Diary records - extent of diarrhea as measured by frequency and volume of stools, and the presence or absence of blood and/or mucus, and stool studies at specified time points (for all ages).	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)
Secondary	Change in GI Symptoms - Gastrointestinal Symptoms Rating Scale	Gastrointestinal Symptoms Rating Scale (GSRS) (for patients =12 years old).	Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4, Month 6, Month 12)
Secondary	Change in Body Mass Index (BMI)	BMI measured as kg/m^2.	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)
Secondary	Change in age-specific percentiles of height		Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Month 12)
Secondary	Change in age-specific percentiles of bodyweight		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)
Secondary	Change in Bilirubin levels		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)
Secondary	Change in Liver Enzyme - Alanine Transaminase (ALT)		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)
Secondary	Change in Liver Enzyme - Aspartate Transaminase (AST)		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)
Secondary	Change in Liver Enzyme - Alkaline Phosphatase (ALP)		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)
Secondary	Change in Liver Enzyme - Gamma Glutyltranspeptidase (GGT)		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)
Secondary	Change in INR level	International normalized ratio (INR) to determine prothrombin time.	Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4; Month 3, 6, 12)
Secondary	Skin Disease (EASI) - Changes from Baseline/ Pre-infusion	Scoring of areas of involvement in each anatomical region (area), calculation of intensity using Eczema Area and Severity Index (EASI).	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)
Secondary	Skin Disease (POEM) - Changes from Baseline/ Pre-infusion	Scoring of areas of involvement in each anatomical region (area), calculation of intensity using Patient oriented eczema measure (POEM).	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)
Secondary	Skin Disease (PASI) - Changes from Baseline/ Pre-infusion	Changes in the extent (%) and severity of skin lesions and their complications (i.e. infections, atrophy, itching) using Psoriasis Area and Severity Index (PASI).	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)
Secondary	Skin Disease (MTLSS) - Changes from Baseline/ Pre-infusion	Changes in the extent (%) and severity of skin lesions and their complications (i.e. infections, atrophy, itching) using Modified Total Lesional Sign Score (MTLSS).	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)
Secondary	Change in skin barrier function	Biophysical Skin Evaluation: Skin measurement of transepidermal water loss to monitor skin barrier function and erythema	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)
Secondary	Change in Hemolytic Anemia (RBC)	Measurement of the number of red blood cells (Complete Blood Counts with Differential [CBCD]).	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)
Secondary	Change in Hemolytic Anemia (Reticulocyte)	Measurement of the number of reticulocytes.	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)
Secondary	Change in Thrombocytopenia	Measure the number of platelets (Complete Blood Counts with Differential (CBCD)).	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)
Secondary	Change in Neutropenia	Measure the number of neutrophils (Complete Blood Counts with Differential [CBCD]).	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)
Secondary	Change in C-peptide - Type 1 diabetes Pre-onset		Baseline taken 60-30 days before infusion of CD4^LVFOXP3; Post-infusion (Week 4, Month 3, 6 and 12).
Secondary	Change in HbA1c - Type 1 diabetes Pre-onset		Baseline taken 60-30 days before infusion of CD4^LVFOXP3; Post-infusion (Week 4, Month 3, 6 and 12).
Secondary	Change in Daily insulin requirement - Type 1 diabetes monitoring	Mean daily insulin use recorded over 7 consecutive days preceding each evaluation timepoint for patients with Type 1 Diabetes.	Baseline taken 60-30 days before infusion of CD4^LVFOXP3 and post-infusion (over 7 consecutive days preceding each study visit);
Secondary	Change in hyper-/hypo-glycemic events - Type 1 diabetes monitoring	Continuous glucose monitoring (CGM) metrics to log episodes of hyper/hypoglycemic events.	Baseline taken 60-30 days before infusion of CD4^LVFOXP3 and post-infusion (over 7 consecutive days preceding each study visit);
Secondary	Change in Autoantibody Profile	Measure autoantibodies to organs involved in the disease (participant-specific): anti-insulin (IAA), anti-islet antigens (IA), anti-glutamic acid decarboxylase (GAD), anti-zinc transporter8 (ZNT8), anti-islet cells (ICA), anti-liver kidney microsome (LKM), anti-thyroperoxidase (TPO), anti-thyroglobulin (TG), anti-enterocytes, anti-SMA	Screening/ Baseline, Post-infusion (Week 4, Month 6 and 12)
Secondary	Change in Creatinine as a measure of Kidney Function	Measure kidney functional parameters, i.e., creatinine, in the blood and urine.	Baseline taken 60-30 days before infusion of CD4^LVFOXP3, Pre-infusion, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12
Secondary	Change in PedsQL General Well-Being Scale - Quality of Life		Pre-Infusion; Month 6, 12
Secondary	Change in PedsQL Generic Core Scale - Quality of Life		Pre-Infusion; Month 6, 12
Secondary	Change in PedsQL Gastrointestinal Symptoms Scale - Quality of Life	Measured with Gastrointestinal Symptoms Scale: minimum value = 0 (never a problem), maximum value = 4 (almost always a problem). Higher scores mean a worse outcome.	Pre-Infusion; Month 6, 12
Secondary	Disease-free Survival - Changes from Baseline	The length of time from cell infusion to the point at which the participant survives without any new or worsening of existing signs or symptoms of disease. The data will be compared with historical disease-free survival probability. Probability of disease-free survival will be computed with the use of Kaplan-Meier estimator.	Up to 15 years
Secondary	Overall Survival - Changes from Baseline	Participant survival	Up to 15 years