IPEXの参加者におけるCD4^LVFOXP3
免疫調節不全多発性内分泌障害腸症X連鎖（IPEX）症候群の参加者における自己CD4 ^ LVFOXP3の第1相研究
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.
調査の概要
詳細な説明
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.
研究の種類
入学 (実際)
段階
- フェーズ 1
連絡先と場所
研究場所
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California
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Palo Alto、California、アメリカ、94305
- Lucile Packard Children's Hospital
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：順次割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
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実験的：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. If there is no toxicity observed in any participants in Dose Level 3, participants will then be administered 10 x 10^6 CD4^LVFOXP3 /kg (± 20%) at two time points 21-42 days apart. |
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.
他の名前：
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実験的：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. If there is no toxicity observed in any participants in Dose Level 3, participants will then be administered 10 x 10^6 CD4^LVFOXP3 /kg (± 20%) at two time points 21-42 days apart. |
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.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Meet target cell number for dose manufacturing
時間枠：Time at release from manufacturing (by Day 0 [infusion day] for each participant)
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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)
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Find the safe maximum tolerated dose
時間枠：Up to 60 days post-infusion for each participant
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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
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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身長の年齢別パーセンタイルの変化
時間枠：ベースライン (CD4^LVFOXP3 の注入の 60 日前まで) から注入後 (12 か月目)
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ベースライン (CD4^LVFOXP3 の注入の 60 日前まで) から注入後 (12 か月目)
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体重の年齢別パーセンタイルの変化
時間枠：ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (1、2、3 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (1、2、3 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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ビリルビン値の変化
時間枠：ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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肝臓酵素の変化 - アラニントランスアミナーゼ (ALT)
時間枠：ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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肝臓酵素の変化 - アスパラギン酸トランスアミナーゼ (AST)
時間枠：ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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肝臓酵素 - アルカリホスファターゼ (ALP) の変化
時間枠：ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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肝臓酵素の変化 - ガンマグルチルトランスペプチダーゼ (GGT)
時間枠：ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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ベースライン (CD4^LVFOXP3 の注入の 60 日前まで)、注入前から注入後 (2 日目、1、2、3、4 週目、2、3、6、9、12 月目)
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Cペプチドの変化 - 1型糖尿病 発症前
時間枠：ベースラインは CD4^LVFOXP3 の注入の 60 ～ 30 日前に取得。注入後 (第 4 週、第 3、6、および 12 か月)。
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ベースラインは CD4^LVFOXP3 の注入の 60 ～ 30 日前に取得。注入後 (第 4 週、第 3、6、および 12 か月)。
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HbA1cの変化 - 1型糖尿病 発症前
時間枠：ベースラインは CD4^LVFOXP3 の注入の 60 ～ 30 日前に取得。注入後 (第 4 週、第 3、6、および 12 か月)。
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ベースラインは CD4^LVFOXP3 の注入の 60 ～ 30 日前に取得。注入後 (第 4 週、第 3、6、および 12 か月)。
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PedsQL の一般的な健康尺度の変化 - 生活の質
時間枠：注入前; 6、12月
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注入前; 6、12月
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PedsQL ジェネリック コア スケールの変更 - 生活の質
時間枠：注入前; 6、12月
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注入前; 6、12月
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Change in Diarrhea incidence
時間枠：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)
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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)
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Change in GI Symptoms - Gastrointestinal Symptoms Rating Scale
時間枠：Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4, Month 6, Month 12)
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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)
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Change in Body Mass Index (BMI)
時間枠：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)
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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)
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Change in INR level
時間枠：Baseline/screening (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4; Month 3, 6, 12)
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International normalized ratio (INR) to determine prothrombin time. |
Baseline/screening (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4; Month 3, 6, 12)
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Skin Disease (EASI) - Changes from Baseline/ Pre-infusion
時間枠：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)
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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)
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Skin Disease (POEM) - Changes from Baseline/ Pre-infusion
時間枠：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)
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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)
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Skin Disease (PASI) - Changes from Baseline/ Pre-infusion
時間枠：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)
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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)
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Skin Disease (MTLSS) - Changes from Baseline/ Pre-infusion
時間枠：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)
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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)
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Change in skin barrier function
時間枠：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)
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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)
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Change in Hemolytic Anemia (RBC)
時間枠：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)
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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)
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Change in Hemolytic Anemia (Reticulocyte)
時間枠：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)
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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)
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Change in Thrombocytopenia
時間枠：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)
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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)
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Change in Neutropenia
時間枠：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)
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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)
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Change in Daily insulin requirement - Type 1 diabetes monitoring
時間枠：Baseline taken 60-30 days before infusion of CD4^LVFOXP3 and post-infusion (over 7 consecutive days preceding each study visit);
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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);
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Change in hyper-/hypo-glycemic events - Type 1 diabetes monitoring
時間枠：Baseline taken 60-30 days before infusion of CD4^LVFOXP3 and post-infusion (over 7 consecutive days preceding each study visit);
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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);
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Change in Autoantibody Profile
時間枠：Screening/ Baseline, Post-infusion (Month 6 and 12)
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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 (Month 6 and 12)
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Change in Creatinine as a measure of Kidney Function
時間枠：Baseline taken 60-30 days before infusion of CD4^LVFOXP3, Pre-infusion, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12
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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
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Change in PedsQL Gastrointestinal Symptoms Scale - Quality of Life
時間枠：Pre-Infusion; Month 6, 12
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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
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Disease-free Survival - Changes from Baseline
時間枠：Up to 15 years
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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
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Overall Survival - Changes from Baseline
時間枠：Up to 15 years
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Participant survival |
Up to 15 years
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協力者と研究者
スポンサー
捜査官
- 主任研究者：Jessie Alexander, MD、Stanford University
出版物と役立つリンク
一般刊行物
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研究記録日
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本研究に関する用語
その他の研究ID番号
- IRB-63373
- DRU-2020-7764 (その他の識別子：FDA Office of Orphan Products Development)
- RPD-2020-470 (その他の識別子：FDA Office of Orphan Products Development)
- CLIN2-13259 (その他の助成金/資金番号：California Institute of Regenerative Medicine (CIRM))
- 1R01FD007540 (米国FDA認可/契約)
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