CD4^LVFOXP3 in Participants With IPEX

Study Overview
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Brief Summary
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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.

Detailed Description
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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: That CD4^LVFOXP3 can be consistently produced and be of expected quality to be used in humans, That CD4^LVFOXP3 are safe in children and young adults with IPEX, and determine its effects, both good and bad, 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.

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

Conditions
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IPEX

Intervention / Treatment
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* Biological: CD4^LVFOXP3


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 4 Months
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Escalating doses of CD4^LVFOXP3 will be administered in 2-6 participants per cohort in two age cohorts (Cohort A: ≥ 12 years of age; Cohort B: < 12 years of age) using a 2+4 dose escalation design. Cohort B will be started at the second dose level.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A (≥12 years)<br>The first participant in Dose Level 1 will be administered 1.0 x 10^6 CD4^LVFOXP3 /kg (± 20%). If there is no toxicity observed in the first participant, the following participants in Dose Level 1 will be administered the same dose of 1.0 x 10^6 CD4^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 1, participants will be enrolled into Dose Level 2 and administered 3 x 10^6 CD4^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 2, participants will be enrolled into Dose Level 3 and administered 10 x 10^6 CD4^LVFOXP3 /kg (± 20%). If in any dose level 1 of 2 participants show toxicity, that dose level will be expanded to 6 participants. | Biological: CD4^LVFOXP3<br>* 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.<br>* Other names: CD4^LVFOXP3 Treg-like cells;|
| Experimental: Cohort B (<12 years)<br>Participants in Cohort B will always follow treatment of participants in Cohort A for the same dose level. Cohort B will start at Dose Level 2 and be administered 3 x 10^6 CD4^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 2, participants will be enrolled into Dose Level 3 and administered 10 x 10^6 CD4^LVFOXP3 /kg (± 20%). If in any dose level 1 of 2 participants show toxicity, that dose level will be expanded to 6 participants. | Biological: CD4^LVFOXP3<br>* 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.<br>* Other names: CD4^LVFOXP3 Treg-like cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| Change in age-specific percentiles of height |  | Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Month 12) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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). | 
| 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). | 
| 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); | 
| 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); | 
| 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) | 
| 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 | 
| Change in PedsQL General Well-Being Scale - Quality of Life |  | Pre-Infusion; Month 6, 12 | 
| Change in PedsQL Generic Core Scale - Quality of Life |  | Pre-Infusion; Month 6, 12 | 
| 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 | 
| 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 | 
| Overall Survival - Changes from Baseline | Participant survival | Up to 15 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treg cells, Regulatory T cells, Gene therapy, autoimmunity, immune suppression, Immune Dysregulation Polyendocrinopathy Enteropathy X-linked, Lentiviral, CD271, NGFR, FOXP3