CD4^LVFOXP3 i Deltakere med IPEX
Fase 1 studie av autolog CD4^LVFOXP3 hos deltakere med immun dysregulering polyendokrinopati enteropati X-linked (IPEX) syndrom
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.
Studieoversikt
Detaljert beskrivelse
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.
Studietype
Registrering (Faktiske)
Fase
- Fase 1
Kontakter og plasseringer
Studiesteder
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California
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Palo Alto, California, Forente stater, 94305
- Lucile Packard Children's Hospital
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Deltakelseskriterier
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
Tar imot friske frivillige
Kjønn som er kvalifisert for studier
Beskrivelse
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
Studieplan
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Ikke-randomisert
- Intervensjonsmodell: Sekvensiell tildeling
- Masking: Ingen (Open Label)
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
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Eksperimentell: 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.
Andre navn:
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Eksperimentell: 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.
Andre navn:
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Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
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Meet target cell number for dose manufacturing
Tidsramme: 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
Tidsramme: 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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Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
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Endring i aldersspesifikke prosentiler av høyde
Tidsramme: Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3) gjennom post-infusjon (måned 12)
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Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3) gjennom post-infusjon (måned 12)
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Endring i aldersspesifikke persentiler av kroppsvekt
Tidsramme: Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 1, 2, 3, uke 1, 2, 3, 4; måned 2, 3, 6, 9, 12)
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Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 1, 2, 3, uke 1, 2, 3, 4; måned 2, 3, 6, 9, 12)
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Endring i bilirubinnivåer
Tidsramme: Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Endring i leverenzym - alanintransaminase (ALT)
Tidsramme: Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Endring i leverenzym - aspartattransaminase (AST)
Tidsramme: Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Endring i leverenzym - alkalisk fosfatase (ALP)
Tidsramme: Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Endring i leverenzym - Gamma Glutyltranspeptidase (GGT)
Tidsramme: Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Baseline (opptil 60 dager før infusjon av CD4^LVFOXP3), pre-infusjon gjennom post-infusjon (dag 2, uke 1, 2, 3, 4; måned 2, 3, 6, 9 og 12)
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Endring i C-peptid - Type 1 diabetes Pre-debut
Tidsramme: Baseline tatt 60-30 dager før infusjon av CD4^LVFOXP3; Post-infusjon (uke 4, måned 3, 6 og 12).
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Baseline tatt 60-30 dager før infusjon av CD4^LVFOXP3; Post-infusjon (uke 4, måned 3, 6 og 12).
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Endring i HbA1c - Type 1 diabetes Pre-debut
Tidsramme: Baseline tatt 60-30 dager før infusjon av CD4^LVFOXP3; Post-infusjon (uke 4, måned 3, 6 og 12).
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Baseline tatt 60-30 dager før infusjon av CD4^LVFOXP3; Post-infusjon (uke 4, måned 3, 6 og 12).
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Endring i PedsQL General Well-Being Scale - Quality of Life
Tidsramme: Pre-infusjon; Måned 6, 12
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Pre-infusjon; Måned 6, 12
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Endring i PedsQL Generic Core Scale - Livskvalitet
Tidsramme: Pre-infusjon; Måned 6, 12
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Pre-infusjon; Måned 6, 12
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Change in Diarrhea incidence
Tidsramme: 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
Tidsramme: 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)
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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)
Tidsramme: 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)
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: Up to 15 years
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Participant survival |
Up to 15 years
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Samarbeidspartnere og etterforskere
Sponsor
Samarbeidspartnere
Etterforskere
- Hovedetterforsker: Jessie Alexander, MD, Stanford University
Publikasjoner og nyttige lenker
Generelle publikasjoner
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Ytterligere relevante MeSH-vilkår
Andre studie-ID-numre
- IRB-63373
- DRU-2020-7764 (Annen identifikator: FDA Office of Orphan Products Development)
- RPD-2020-470 (Annen identifikator: FDA Office of Orphan Products Development)
- CLIN2-13259 (Annet stipend/finansieringsnummer: California Institute of Regenerative Medicine (CIRM))
- 1R01FD007540 (U.S. FDA-bevilgning/-kontrakt)
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