TCRαβ+ T-cell/CD19+ B-cell Depleted Hematopoietic Grafts and a Reduced Intensity Preparative Conditioning Regimen Containing JSP191 (Briquilimab) to Achieve Engraftment and Blood Reconstitution in Patients With Fanconi Anemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Number of participants who are able to have donor engraftment persist at the same rate or better compared to alternative hematopoietic cell transplant regimens for this patient population
研究概览
简要总结
The objective of this clinical trial is to develop a cell therapy for Fanconi Anemia which enables enhanced donor hematopoietic and immune reconstitution with decreased toxicity by transplanting depleted stem cells from a donor with and without using an experimental antibody treatment called JSP-191 as a part of conditioning. This experimental treatment will hopefully cause fewer side effects than chemotherapy (the current standard of care method).
Participants will be administered the conditioning regimen, are assessed until they receive the depleted stem cell infusion, and will be followed for up to 2 years after the cell infusion.
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
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All patients must have:
- •Fanconi Anemia diagnosis as demonstrated by abnormal chromosome breakage studies with increased sensitivity to mitomycin-C (MMC) or diepoxybutane (DEB) and at least one mutation in a known Fanconi-associated gene
- •Bone marrow failure (defined by reduction in at least one cell line on two separate occasions at least one month apart (e.g., platelet count of <100,000 per cubic millimeter, hemoglobin <9 gm/dl and/or absolute neutrophil count (ANC) of <1000/mm)
- •Age of ≥2 years
- •Consenting ≥5/10 HLA-matched related or unrelated donor available for apheresis
- •Organ function defined as:
- •Serum Creatinine <2.0 mg/dL and corrected creatinine clearance/cystatin cL >60 mL/min/1.73m^2 without dialysis
- •Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) corrected for hemoglobin and volume, >50% predicted by pulmonary function tests (PFTs)
- •For patients unable to cooperate for PFTs, criteria are no evidence of dyspnea at rest, no exercise intolerance, and no requirement for supplemental oxygen with spO2 >93%
- •Shortening fraction of ≥29% or ejection fraction of ≥45% by echocardiogram
- •Serum total bilirubin of <4 x ULN
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5 x ULN
- •Prothrombin time international normalized ratio (PT INR) and partial thromboplastin time (PTT) <1.5 x ULN
- •Life expectancy of at least 2 years
- •Patients of childbearing potential must be willing to use an effective contraceptive method for the duration of the peri-transplant conditioning through hematopoietic recovery
- •Patients and/or parents or legal guardians must be able to provide written informed consent and authorize use and disclosure of personal health information in accordance with Health Insurance Portability and Accountability Act
排除标准
- •Patients with available and consenting 10/10 HLA-identical sibling donor for apheresis
- •Patients with any acute or uncontrolled infections at the time of enrollment, including bacterial, fungal or viral
- •Patients who are seropositive for HIV-I/II or HTLV-I/II.
- •Patients receiving any other investigational agents or other biological, chemotherapy, or radiation therapy within 14 days of enrollment
- •Patients with any active malignancies, myelodysplastic syndrome or other concerns for high-risk bone marrow disease
- •Patients who received androgens in last 3 months
- •Pregnant or lactating women
- •Women who are nursing and do not wish to discontinue breastfeeding
- •Lansky/Karnofsky performance score <50%.
- •Any other medical condition or history that, in the opinion of the Principal Investigator, could pose a significant safety risk to the participant or jeopardize the integrity of the study
- •Patients who, in the opinion of the Principal Investigator, may not be able to comply with the safety monitoring requirements of the study
研究组 & 干预措施
Depleted Stem Cell Transplant with JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: JSP191 (Drug)
Depleted Stem Cell Transplant with JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: CliniMACS Prodigy System (Device)
Depleted Stem Cell Transplant with JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Depleted Stem Cell Transplant (Biological)
Depleted Stem Cell Transplant with JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Rabbit Anti-Thymoglobulin (rATG) (Biological)
Depleted Stem Cell Transplant with JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Cyclophosphamide (Drug)
Depleted Stem Cell Transplant with JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Fludarabine (Drug)
Depleted Stem Cell Transplant with JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Rituximab (Drug)
Depleted Stem Cell Transplant without JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: CliniMACS Prodigy System (Device)
Depleted Stem Cell Transplant without JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Depleted Stem Cell Transplant (Biological)
Depleted Stem Cell Transplant without JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Rabbit Anti-Thymoglobulin (rATG) (Biological)
Depleted Stem Cell Transplant without JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Cyclophosphamide (Drug)
Depleted Stem Cell Transplant without JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Fludarabine (Drug)
Depleted Stem Cell Transplant without JSP-191 Conditioning
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing rATG, cyclophosphamide, fludarabine and rituximab.
干预措施: Rituximab (Drug)
结局指标
主要结局
Number of participants who are able to have donor engraftment persist at the same rate or better compared to alternative hematopoietic cell transplant regimens for this patient population
时间窗: Assessed at Day +100 post-cell infusion
Number of participants without grade 3 and 4 treatment-emergent adverse events (TEAEs) (infusion related reactions) following infusion of TCRαβ+ T-cell/CD19+ B-cell depleted hematopoietic graft transplantation
时间窗: Up to 2 years post-cell infusion
Number of participants able to achieve donor engraftment
时间窗: Assessed at Day +42 post-cell infusion
Participants have achieved engraftment when absolute Neutrophil Count (ANC) is above 500/mm\^3 for three consecutive laboratory values obtained on different days post cell transplantation with \>1% CD15 donor chimerism
Number of participants without grade 3 and 4 treatment-emergent adverse events (TEAEs) (infusion related reactions).
时间窗: From start of conditioning regimen administration until cell infusion (up to 30 days)
Recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
次要结局
- Number of participants who develop chronic graft-vs-host disease (GvHD)(Day +100 through Week +104 post-cell infusion)
- Serum concentration of rATG(Prior to start of rATG infusion; 15 minutes after first, second, and third rATG infusion; day of cell infusion; and week +1, week +2 and week +12 post cell infusion)
- Serum concentration of fludarabine(Prior to start of fludarabine infusion, and 15 minutes, 1 hour, 3 hours, and 6 hours after the fludarabine infusion)
- Serum concentration of JSP191(Prior to start of conditioning regimen, and 5 minutes, 4 hours, +2, +3, +4, +6, +8, +10 days after start of conditioning regimen, and day of cell infusion)
- Participants who do not develop mucositis(Start of conditioning regimen until +12 weeks post-cell infusion (up to 15 weeks))
- Number of participants who achieve hematopoietic recovery(Up to 107 weeks (after start of conditioning regimen through Week +104 post-cell infusion))
- Participants who do not develop veno-occlusive disease (VOD)(Start of conditioning regimen until +12 weeks post-cell infusion (up to 15 weeks))
- Number of participants who achieve donor engraftment(Weeks +1 through +104 post-cell infusion)
- Number of participants who develop Grade I-IV acute graft-vs-host disease (GvHD)(Day +100 post-cell infusion)
- Number of participants who achieve immunologic recovery(Weeks +1 through +104 post-cell infusion)
- Number of participants who achieve disease-free survival(Up to 104 weeks (from time of cell infusion through Week +104))
研究者
Rajni Agarwal
Associate Professor of Pediatrics
Stanford University