临床试验/NCT06145282

NCT06145282

进行中（未招募）

1 期

Non-myeloablative Phase I/II Haploidentical HCT Study for Patients With Sickle Cell Disease, Including Compromised Organ Function

National Heart, Lung, and Blood Institute (NHLBI)2 个研究点分布在 1 个国家目标入组 6 人2023年12月28日

适应症Sickle Cell Disease

干预措施Briquilimab Abatacept Sirolimus Cyclophosphamide Filgrastim

概览

阶段: 1 期
干预措施: Briquilimab
疾病 / 适应症: Sickle Cell Disease
发起方: National Heart, Lung, and Blood Institute (NHLBI)
入组人数: 6
试验地点: 2
主要终点: Evaluate the regimen success rate where success defined as successful engraftment and absence of acute grade 3 or higher GVHD or moderate to severe chronic GVHD evaluated at 1 yr post-transplant
状态: 进行中（未招募）
最后更新: 3天前

概览研究者入排标准研究组 & 干预措施结局指标研究点相似试验

概览

简要总结

Background:

Sickle cell disease (SCD) is a genetic disorder where red blood cells, that carry oxygen, are stiff and become stuck in small blood vessels. As a result, affected patients can experience severe pain and serious organ damage. SCD can be cured with a hematopoietic cell transplant (HCT), that is, when they receive blood stem cells from a family donor. But HCT can also have serious side effects, especially in people with organ damage. Researchers want to find ways to make HCT safer for everyone.

Objective:

To test a new combination of drugs (briquilimab, abatacept, and alemtuzumab), used along with radiation, in people undergoing HCT for SCD.

Eligibility:

People aged 16 and older with SCD. They must be eligible for HCT and have a family member who is a good donor match. Donors must be aged 4 and older.

Design:

Participants with SCD will be screened. They will have blood tests and tests of organs including their heart and lung function. Donors will have blood drawn.

Participants with SCD will have a tube inserted into a blood vessel in their chest (intravenously). This line will remain in place up to 2 months; it will be used to draw blood and administer the donor cells and other medications.

Briquilimab will be administered intravenously 1 time, along with other drugs used to prepare for HCT. Participants will receive abatacept 6 times, from just before they receive their donor cells until 6 months after. Participants will undergo radiation therapy and take other drugs that are standard for HCT. Most HCT recipients remain in the hospital for about 30 days after HCT.

Follow-up visits will continue for 5 years....

详细描述

Study Description: Haploidentical hematopoietic cell transplantation offers a widely available curative option for individuals with sickle cell disease. The goal is to reverse SCD while avoiding unacceptable graft rejection, graft-versus-host disease, infectious complications, and hyperinflammatory responses. We hypothesize that a moderate amount of immunosuppression will maximize efficacy while avoiding unacceptable toxicity. Objectives: Primary Objective: -Evaluate the regimen success rate where success is defined as successful engraftment (persistent donor chimerism and free of acute SCD complications) and absence of acute grade 3 or higher GVHD or moderate to severe chronic GVHD evaluated at 1 year posttransplant. Secondary Objectives: * Event-free survival and overall survival. * Incidence of recipient-type hemoglobin defined as HbS \>10% when donors have HbAA and HbS \>50% when donors have sickle cell trait (HbAS). * The proportion of patients with myeloid chimerism \>= 95% at 1 and 2 years post-HCT. * Incidence of acute and chronic GVHD. * Prevalence of donor type hemoglobin at 1-year post-transplant in SCD patients who have not been transfused in the previous 3 months. * Incidence of viral reactivation and disease. * Incidence of autoimmune and hyperinflammatory complications. * Incidence of hematologic malignancies. * Transplant-related mortality. Exploratory Objective: * Perform gene therapy research involving cell culture or genetic manipulation to produce normal or therapeutic hemoglobin on excess autologous CD34+ cells collected from recipients. * Evaluate the impact of this non-myeloablative conditioning regimen on organs including the heart, lung, kidneys, liver, brain, neurocognitive function, and endocrine organs * Evaluate the impact of this non-myeloablative conditioning regimen on quality of life. Endpoints: Primary Endpoint: -The percentage of SCD patients at 1 year (+/- 3 months) posttransplant who have not experienced graft failure and who are without severe graft-versus-host disease (defined as grade 3 and higher acute GVHD and moderate to severe chronic GVHD). Secondary Endpoints: * Total hemoglobin and percent HbS levels * Percent donor myeloid chimerism and donor CD3 chimerism * Day of neutrophil engraftment * Day of platelet engraftment * RBC transfusion requirement * Rates of acute and chronic GVHD * Rates of viral reactivation and disease * Rates of autoimmune and hyperinflammatory complications * Transplant-related mortality * Non-transplant-related mortality * Rates of graft failure * Rates of leukemia and related disorders Exploratory Endpoint: Completion of gene therapy research involving cell culture or genetic manipulation to produce normal or therapeutic hemoglobin on excess autologous CD34+ cells collected from recipients. Organ function and quality of life

注册库

clinicaltrials.gov

开始日期

2023年12月28日

结束日期

2027年11月26日

最后更新

3天前

研究类型

Interventional

研究设计

Sequential

性别

All

研究者

发起方

National Heart, Lung, and Blood Institute (NHLBI)

责任方

Sponsor

入排标准

入选标准

•INCLUSION CRITERIA:
•Participants must fulfill one disease category, either at least one organ damage or no other access to curative therapy.
•Adult patients with sickle cell disease at high risk for disease-related morbidity or mortality, according to A, B, C, D, or E or complication(s) not ameliorated by SICKLE CELL-SPECIFC THERAPIES (F):
•A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination (\>=200 m/s); OR
•B. Silent cerebral infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2- weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s); OR
•C. Sickle cell-related renal insufficiency defined by a creatinine level \>=1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome; OR
•D. Tricuspid regurgitant jet velocity (TRV) of \>=2.5 m/s at least 3 weeks after a vaso-occlusive crisis and/or right heart catheterization-documented pulmonary hypertension; OR
•E. Sickle hepatopathy defined as EITHER ferritin \>1000 mcg/L OR direct bilirubin \>0.4 mg/dL at baseline AND a platelet count \<250 K/microliter (without vaso-occlusive crisis); OR
•F. Any one of the below complications:
•Complication: Vaso-occlusive crises; Eligible for HCT: \>1 hospital admission per year while on a therapeutic dose of a SCD treatment/medication

排除标准

•An individual who meets any of the following criteria will be excluded from participation in this study:
•Available HLA-matched sibling donor
•ECOG performance status of 3 or more.
•DLCO \<35% predicted (corrected for hemoglobin).
•Baseline oxygen saturation of \<85% or PaO2 \<70 mmHg
•Left ventricular ejection fraction: \<35% estimated by ECHO
•Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen. HCT candidates with pre-transplant respiratory viral infections will undergo careful clinical assessment with the help of our transplant infectious disease team for lower respiratory tract disease, which may include thorough physical examination, imaging, and/or bronchoalveolar lavage. In case of lower respiratory tract disease or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity, the transplant will be delayed until resolution.
•Major anticipated illness or organ failure incompatible with survival from PBSC transplant.
•Pregnant or breastfeeding
•Donor specific anti-HLA antibodies (DSAs) \>=2000 Mean Fluorescence Intensity (MFI)

研究组 & 干预措施

PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

Stem cell recipients with Sickle Cell Disease will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors. This group will receive a single dose of PT-Cy; 50 mg/kg, on day +3 post-HCT

干预措施: Briquilimab

PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

干预措施: Abatacept

PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

干预措施: Sirolimus

PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

干预措施: Cyclophosphamide

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

干预措施: Briquilimab

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

干预措施: Abatacept

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

干预措施: Sirolimus

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

干预措施: Cyclophosphamide

Human Leukocyte Antigens (HLA) Haploidentical Related Stem Cell Donor

A haploidentical relative donor will receive filgrastim (G-CSF) 10 to 16 µg/kg/d subcutaneously or intravenously for up to 6 days with apheresis collections of peripheral blood hematopoietic progenitor cells (PBPC) after the 5th day (and after the 6th day if required).

干预措施: Filgrastim

结局指标

主要结局

Evaluate the regimen success rate where success defined as successful engraftment and absence of acute grade 3 or higher GVHD or moderate to severe chronic GVHD evaluated at 1 yr post-transplant

时间窗: 1 year (+/- 3 months)

The percentage of SCD patients at 1 year (+/- 3 months) post-transplant who have not experienced graft failure and who are without severe graft-versus-host disease (defined as grade 3 and higher acute GVHD and moderate to severe chronic GVHD).

Number of Participants With Successful Engraftment and Absence of Acute Grade 3 or Higher GVHD

时间窗: Up to 1 year

Number of participants at 1 year post stem cell transplant who have not experienced graft failure and who are without severe graft-versus-host disease (defined as grade 3 and higher acute GVHD). Graft failure is defined as the absence of or insufficient donor chimerism associated with the return of acute complications of sickle cell disease. As defined by CIMBTR criteria for Organ Stages of Acute GVHD: Grade III: Skin = Rash on \>50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea \> 1500 mL/day. Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin \>15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.

Number of Participants With Successful Engraftment and Absence of Moderate to Severe Chronic Graft-versus-host Disease

时间窗: Up to 1 year

Number of participants at 1 year post stem cell transplant who have not experienced graft failure and who are without moderate to severe chronic graft-versus-host disease (GVHD) Graft failure is defined as the absence of or insufficient donor chimerism associated with the return of acute complications of sickle cell disease. CIMBTR criteria definition for Chronic GVHD: Moderate chronic GVHD involves EITHER 3 organs/sites with no clinically significant functional impairment OR a less than or equal to 1 organ/site with clinically significant functional impairment, but no major disability. Severe GVHD is associated with a major disability caused by chronic GVHD.