临床试验/NCT04774536

NCT04774536招募中1 期

Transplantation of CRISPRCas9 Corrected Hematopoietic Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease

Mark Walters, MD3 个研究点分布在 1 个国家目标入组 9 人开始时间: 2025年8月22日最近更新: 2026年4月16日

适应症

干预措施

试验速览

阶段: 1 期
状态: 招募中
发起方
入组人数: 9
试验地点: 3
主要终点: Incidence of adverse events and grade 3 or higher serious adverse events, using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE)

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is an open label, non-randomized, 2-center, phase 1/2 trial of a single infusion of sickle allele modified cluster of differentiation (CD34+) hematopoietic stem progenitor cells (HSPCs) in subjects with in subjects ≥12 years old to 35 years old severe Sickle Cell Disease (SCD). The study will evaluate the hematopoietic stem cell transplantation (HSCT) using CRISPR/Cas9 edited red blood cells (known as CRISPR_SCD001 Drug Product).

详细描述

This is an open label, non-randomized, 2-center, phase 1/2 trial of a single infusion of sickle allele modified CD34+ HSPCs in subjects with severe SCD. The primary endpoint of the trial will determine the safety of CRISPR_SCD001 through a 3+3 design with staggered enrollment and a pause in enrollment for safety review after each of the first 3 patients has had drug product infused. After safety is assessed in the 3rd patient, enrollment of the next 3 patients will not be staggered. The first six subjects will be adults. If CRISPR_SCD001 is determined to be safe in the first six subjects, the trial will continue to enroll 3 adolescents 12 - 18 years of age to evaluate the safety in younger patients. The younger age cohort also will follow staggered enrollment.

研究设计

研究类型: Interventional
分配方式: Na
干预模型: Single Group
主要目的: Treatment
盲法: None

入排标准

年龄范围: 12 Years 至 35 Years（Child, Adult）
性别: All
接受健康志愿者: 否

入选标准

•Male or female 12.00 - 34.99 years of age (at time of consent) who have one or more of the following:
•History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea); ACS is defined as a new radiodensity on chest imaging accompanied by fever and/or respiratory symptoms, treated in the hospital with supplemental oxygen at a minimum.
•History of at least 4 severe vaso-occlusive pain events in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea); painful episodes related to or any sickle-related acute event are acceptable; a severe painful vaso-occlusive event is defined as receiving analgesic treatment (opioid or other analgesic via parenteral (PN) route) for longer than 24 -hours in a hospital or emergency room (ER) observation unit visit or at least 2 visits in a day unit or ER over 72 hours with both visits requiring parenteral analgesics.
•2 or more episodes of splenic sequestration, defined as an acute decrease in hemoglobin by at least 2 g/dL accompanied by splenomegaly in the 2 years before enrollment.
•Recurrent priapism (episodes lasting at least 4 hours at least twice in the last 12 months or 3 times in the last 24 months before enrollment) recalcitrant to medical treatment
•Any episode of hepatic sequestration defined as right upper quadrant pain, hepatomegaly, and rapidly decreasing hemoglobin level with hepatic dysfunction within the 2 years before enrollment.
•Leg ulcer recalcitrant to treatment within 2 years prior to enrollment.
•Participants must have adequate physical function as measured by all of the following:
•Karnofsky performance score ≥
•Cardiac function: Left ventricular ejection fraction (LVEF) >40%; or LV shortening fraction > 26% by cardiac echocardiogram or by (multiple-gated acquisition) MUGA scan.
•Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥85% and diffusion capacity of lung for carbon monoxide(DLCO) > 40% (corrected for hemoglobin).
•Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m
•Hepatic function:
•i. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded.
•ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AS < 5 times upper limit of normal as per local laboratory.
•Participants who have liver iron concentration (LIC) on liver MRI of ≥12 mg Fe/g liver dry weight should also have MR elastography (MRE) or Ultrasound elastography obtained. If severe fibrosis is present, no liver biopsy will be performed and participant is excluded. Children with LIC >12 and negative elastography imaging are eligible if a clinically indicated liver biopsy shows no significant fibrosis.
•Baseline prothrombin time or partial thromboplastin time <1.5 ULN except if receiving a prophylactic anticoagulant which causes an elevated prothrombin or partial thromboplastin time.
•Written informed consent or assent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.

排除标准

•Participants with uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
•Participants with evidence of HIV infection or seropositivity for HIV or active hepatitis B or C.
•Participants who have received a Hematopoietic Cell Transplant (HCT)
•Participants who have received a solid organ transplant.
•Participants who have participated in another clinical trial in which the participant received an investigational or off-label use of a drug or device within 3 months prior to enrollment.
•Females who are pregnant or breast feeding.
•Females of child bearing potential (to include all female participants > 10 years of age, unless postmenopausal for a minimum of 1 year before the time of consent or surgically sterilized) who do not agree to practice two (2) effective methods of contraception at the same time, or who do not agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing of informed consent through 12 months post-stem cell infusion.
•Males (even if surgically sterilized) who do not agree to practice effective barrier contraception, or who do not agree to practice true abstinence from the time of signing informed consent through 12 months post-stem cell infusion.
•Participants who have had a stroke OR who are receiving red blood cell (RBC) transfusions to prevent primary stroke or silent cerebral infarction.
•Patients who have a suitable human leukocyte antigen identical (HLA-ID) sibling donor willing and able to donate bone marrow.
•Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
•Any non-homozygous sickle hemoglobin (HbSS) genotype of SCD
•Either or both of the following findings on screening bone marrow aspirate/biopsy:
•diagnosis of myelodysplastic syndrome (MDS) based on morphology and/or cytogenetics (based on WHO definitions) OR
•any evidence of a pathogenic clonal variant in any candidate gene detected by a standard, licensed next-generation sequencing clinical assay for gene mutations associated with hematological malignancies.
•The participant has an identified pathogenic mutation associated with myeloid malignancy as identified by RHP or a variant of unknown significance (VUS) judged to be pathogenic for myeloid malignancy as determined by one or more members of the adjudication panel.

研究组 & 干预措施

CRISPR_SCD001 Drug Product

Experimental

CRISPR_SCD001 Drug Product (autologous CD34+ cell-enriched population that contains cells modified by the CRISPR-Cas9 ribonucleoprotein) dose will be ≥3.0×106 CD34+ cells/kg recipient weight for each subject and the upper limit cell dose is 20 ×106 CD34+ cells/kg.

干预措施: CRISPR_SCD001 (Drug)

结局指标

主要结局

Incidence of adverse events and grade 3 or higher serious adverse events, using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE)

时间窗: 24 months post-transplant

The adverse event rate will be summarized using descriptive statistics, together with 95% confidence intervals where appropriate. No formal statistical hypothesis testing will be performed. Adverse events defined: failure of engraftment, malignant clonal expansion related to genomic editing or death.

次要结局

Graft rejection defined as having an absolute neutrophil count (ANC) < 500 at 42 days post-infusion(42 days post-transplant)
Rate of normalization in hemoglobin (hgb) level as measured by clinical hematology (laboratory) test.(baseline, through 24 months post-transplant)
Frequency of hepatic veno-occlusive disease (VOD) as measured by Seattle or Baltimore Criteria for VOD Diagnosis.(24 months post-transplant)
Frequency of hepatic idiopathic pneumonia syndrome (IPS) as measured by the Idiopathic pneumonia syndrome (IPS) criteria.(24 months post-transplant)
Change in the annualized vaso-occlusive pain event (VOE) rates.(24 months pre-transplant to 24 months post-transplant)
Time to neutrophil recovery defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count (ANC) of ≥500/µL after transplant.(24 months post-transplant)
Frequency of central nervous system (CNS) toxicity (reversible posterior leukoencephalopathy syndrome [RPLS] or posterior reversible encephalopathy syndrome [PRES], hemorrhage, and seizures).(24 months post-transplant)
Frequency of sickle gene-editing (correction and insertion/deletion) and off-target site-1 editing in marrow and peripheral blood mononuclear cells.(3 months, 1 and 2 years post-transplant)
Time to platelet recovery is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count > 50,000/µL AND did not receive a platelet transfusion in the previous 7 days.(baseline, through 24 months post-transplant)
Rate of improvement in Hemoglobin S (HbS) fraction as measured by hemoglobin electrophoresis, as percent of total.(baseline, through 24 months post-transplant)
Rate of normalization of lactate dehydrogenase (LDH), reticulocyte count, and haptoglobin, as measured by clinical hematology and serum chemistry (laboratory) tests.(baseline, through 24 months post-transplant)
Frequency of cytomegalovirus (CMV) infection, invasive fungal infection, and any other serious viral or bacterial infection(24 months post-transplant)

研究者

发起方

Mark Walters, MD

申办方类型

Other

责任方

Sponsor Investigator

主要研究者

Mark Walters, MD

Professor in Residence

University of California, San Francisco

研究点 (3)

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