Phase 1 Study of Autologous CD4^LVFOXP3 in Participants With Immune Dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Find the safe maximum tolerated dose
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 4 Months 至 35 Years（Child, Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Cohort A (≥12 years)
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.
干预措施: CD4^LVFOXP3 (Biological)
Cohort B (<12 years)
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.
干预措施: CD4^LVFOXP3 (Biological)
结局指标
主要结局
Find the safe maximum tolerated dose
时间窗: Up to 60 days post-infusion for each participant
No more than 1 out of 6 participants may experience a related dose limiting toxicity or treatment emergent adverse events.
Meet target cell number for dose manufacturing
时间窗: Time at release from manufacturing (by Day 0 [infusion day] for each participant)
No more than two products fail the target cell dose and established release criteria.
次要结局
- Change in Diarrhea incidence(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(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)(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(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(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(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(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(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(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)(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)(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(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(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(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(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(Screening/ Baseline, Post-infusion (Month 6 and 12))
- Change in Creatinine as a measure of Kidney Function(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(Pre-Infusion; Month 6, 12)
- Disease-free Survival - Changes from Baseline(Up to 15 years)
- Overall Survival - Changes from Baseline(Up to 15 years)
研究者
Jessie L. Alexander
Professor of Pediatrics
Stanford University