Clinical trial NCT05241444: CD4^LVFOXP3 in Participants With IPEX
Official title: Phase 1 Study of Autologous CD4^LVFOXP3 in Participants With Immune Dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: IPEX
Keywords: Treg cells
Regulatory T cells
Gene therapy
autoimmunity
Immune Dysregulation Polyendocrinopathy Enteropathy X-linked
FOXP3
Lentiviral
CD271
NGFR
immune suppression
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: California Institute for Regenerative Medicine (CIRM)
First posted: 2022-02-15
Enrollment: 30
Sex: MALE
Minimum age (years): 4
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Escalating doses of CD4\^LVFOXP3 will be administered in 2-6 participants per dose 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.
Primary purpose: TREATMENT

Brief 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 30 evaluable human participants with IPEX and evaluate the impact of the CD4\^LVFOXP3 infusion on the disease.

Detailed 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.

Eligibility criteria: 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 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

Primary outcomes:
measure: Meet target cell number for dose manufacturing
timeFrame: Time at release from manufacturing (by Day 0 [infusion day] for each participant)
measure: Find the safe maximum tolerated dose
timeFrame: Up to 60 days post-infusion for each participant
Secondary outcomes:
measure: Change in Diarrhea incidence
timeFrame: 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)
measure: Change in GI Symptoms - Gastrointestinal Symptoms Rating Scale
timeFrame: Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4, Month 6, Month 12)
measure: Change in Body Mass Index (BMI)
timeFrame: 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)
measure: Change in age-specific percentiles of height
timeFrame: Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Month 12)
measure: Change in age-specific percentiles of bodyweight
timeFrame: 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)
measure: Change in Bilirubin levels
timeFrame: 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)
measure: Change in Liver Enzyme - Alanine Transaminase (ALT)
timeFrame: 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)
measure: Change in Liver Enzyme - Aspartate Transaminase (AST)
timeFrame: 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)
measure: Change in Liver Enzyme - Alkaline Phosphatase (ALP)
timeFrame: 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)
measure: Change in Liver Enzyme - Gamma Glutyltranspeptidase (GGT)
timeFrame: 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)
measure: Change in INR level
timeFrame: Baseline/screening (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4; Month 3, 6, 12)
measure: Skin Disease (EASI) - Changes from Baseline/ Pre-infusion
timeFrame: 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)
measure: Skin Disease (POEM) - Changes from Baseline/ Pre-infusion
timeFrame: 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)
measure: Skin Disease (PASI) - Changes from Baseline/ Pre-infusion
timeFrame: 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)
measure: Skin Disease (MTLSS) - Changes from Baseline/ Pre-infusion
timeFrame: 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)
measure: Change in skin barrier function
timeFrame: 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)
measure: Change in Hemolytic Anemia (RBC)
timeFrame: 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)
measure: Change in Hemolytic Anemia (Reticulocyte)
timeFrame: 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)
measure: Change in Thrombocytopenia
timeFrame: 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)
measure: Change in Neutropenia
timeFrame: 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)
measure: Change in C-peptide - Type 1 diabetes Pre-onset
timeFrame: Baseline taken 60-30 days before infusion of CD4^LVFOXP3; Post-infusion (Week 4, Month 3, 6 and 12).
measure: Change in HbA1c - Type 1 diabetes Pre-onset
timeFrame: Baseline taken 60-30 days before infusion of CD4^LVFOXP3; Post-infusion (Week 4, Month 3, 6 and 12).
measure: Change in Daily insulin requirement - Type 1 diabetes monitoring
timeFrame: Baseline taken 60-30 days before infusion of CD4^LVFOXP3 and post-infusion (over 7 consecutive days preceding each study visit);
measure: Change in hyper-/hypo-glycemic events - Type 1 diabetes monitoring
timeFrame: Baseline taken 60-30 days before infusion of CD4^LVFOXP3 and post-infusion (over 7 consecutive days preceding each study visit);
measure: Change in Autoantibody Profile
timeFrame: Screening/ Baseline, Post-infusion (Month 6 and 12)
measure: Change in Creatinine as a measure of Kidney Function
timeFrame: Baseline taken 60-30 days before infusion of CD4^LVFOXP3, Pre-infusion, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12
measure: Change in PedsQL General Well-Being Scale - Quality of Life
timeFrame: Pre-Infusion; Month 6, 12
measure: Change in PedsQL Generic Core Scale - Quality of Life
timeFrame: Pre-Infusion; Month 6, 12
measure: Change in PedsQL Gastrointestinal Symptoms Scale - Quality of Life
timeFrame: Pre-Infusion; Month 6, 12
measure: Disease-free Survival - Changes from Baseline
timeFrame: Up to 15 years
measure: Overall Survival - Changes from Baseline
timeFrame: Up to 15 years
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital
state: California
Study officials:
affiliation: Stanford University
name: Jessie Alexander, MD
role: PRINCIPAL_INVESTIGATOR
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