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| ID | Type | Description | Link |
|---|---|---|---|
| DRU-2020-7764 | Other Identifier | FDA Office of Orphan Products Development | |
| RPD-2020-470 | Other Identifier | FDA Office of Orphan Products Development | |
| 1R01FD007540-01 | U.S. FDA Grant/Contract | View source | |
| CLIN2-13259 | Other Grant/Funding Number | California Institute of Regenerative Medicine (CIRM) |
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| Name | Class |
|---|---|
| California Institute for Regenerative Medicine (CIRM) | OTHER |
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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 30 evaluable human participants with IPEX and evaluate the impact of the CD4^LVFOXP3 infusion on the disease.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort A (≥12 years) | Experimental | 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. |
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| Cohort B (<12 years) | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CD4^LVFOXP3 | Biological | 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. |
| 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 |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Rosa Bacchetta, MD | Contact | 650-498-8369 | rosab@stanford.edu |
| Name | Affiliation | Role |
|---|---|---|
| Jessie Alexander, MD | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Lucile Packard Children's Hospital | Recruiting | Palo Alto | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17984976 | Background | 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. | |
| 15619618 | Background | Amendola M, Venneri MA, Biffi A, Vigna E, Naldini L. Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters. Nat Biotechnol. 2005 Jan;23(1):108-16. doi: 10.1038/nbt1049. Epub 2004 Dec 26. |
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| ID | Term |
|---|---|
| D001327 | Autoimmune Diseases |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
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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.
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| 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/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 | 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 (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 |
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