CD4^LVFOXP3 em participantes com IPEX
Estudo de fase 1 de CD4^LVFOXP3 autólogo em participantes com desregulação imunológica Poliendocrinopatia Enteropatia Síndrome ligada ao cromossomo X (IPEX)
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.
Visão geral do estudo
Descrição detalhada
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.
Tipo de estudo
Inscrição (Real)
Estágio
- Fase 1
Contactos e Locais
Locais de estudo
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California
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Palo Alto, California, Estados Unidos, 94305
- Lucile Packard Children's Hospital
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
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
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Não randomizado
- Modelo Intervencional: Atribuição sequencial
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Experimental: 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.
Outros nomes:
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Experimental: 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.
Outros nomes:
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O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
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Meet target cell number for dose manufacturing
Prazo: 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
Prazo: 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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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
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Mudança nos percentis de altura específicos para a idade
Prazo: Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3) até pós-infusão (Mês 12)
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Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3) até pós-infusão (Mês 12)
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Mudança nos percentis de peso corporal específicos para a idade
Prazo: Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 1, 2, 3, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9, 12)
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Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 1, 2, 3, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9, 12)
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Alteração nos níveis de bilirrubina
Prazo: Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Alteração na Enzima Hepática - Alanina Transaminase (ALT)
Prazo: Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Alteração na Enzima Hepática - Aspartato Transaminase (AST)
Prazo: Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Alteração na Enzima Hepática - Fosfatase Alcalina (ALP)
Prazo: Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Alteração na Enzima Hepática - Gama Glutiltranspeptidase (GGT)
Prazo: Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Linha de base (até 60 dias antes da infusão de CD4^LVFOXP3), pré-infusão até pós-infusão (Dia 2, Semana 1, 2, 3, 4; Mês 2, 3, 6, 9 e 12)
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Alteração no peptídeo C - diabetes tipo 1 pré-início
Prazo: Linha de base tomada 60-30 dias antes da infusão de CD4^LVFOXP3; Pós-infusão (Semana 4, Mês 3, 6 e 12).
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Linha de base tomada 60-30 dias antes da infusão de CD4^LVFOXP3; Pós-infusão (Semana 4, Mês 3, 6 e 12).
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Alteração na HbA1c - diabetes tipo 1 pré-início
Prazo: Linha de base tomada 60-30 dias antes da infusão de CD4^LVFOXP3; Pós-infusão (Semana 4, Mês 3, 6 e 12).
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Linha de base tomada 60-30 dias antes da infusão de CD4^LVFOXP3; Pós-infusão (Semana 4, Mês 3, 6 e 12).
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Mudança na Escala Geral de Bem-Estar PedsQL - Qualidade de Vida
Prazo: Pré-Infusão; Mês 6, 12
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Pré-Infusão; Mês 6, 12
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Mudança na Escala Central Genérica PedsQL - Qualidade de Vida
Prazo: Pré-Infusão; Mês 6, 12
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Pré-Infusão; Mês 6, 12
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Change in Diarrhea incidence
Prazo: 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
Prazo: 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)
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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)
Prazo: 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)
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: Up to 15 years
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Participant survival |
Up to 15 years
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Investigador principal: Jessie Alexander, MD, Stanford University
Publicações e links úteis
Publicações Gerais
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Outros números de identificação do estudo
- IRB-63373
- DRU-2020-7764 (Outro identificador: FDA Office of Orphan Products Development)
- RPD-2020-470 (Outro identificador: FDA Office of Orphan Products Development)
- CLIN2-13259 (Número de outro subsídio/financiamento: California Institute of Regenerative Medicine (CIRM))
- 1R01FD007540 (Concessão/Contrato da FDA dos EUA)
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