A Phase 1, Open-label, Single-arm Study of APR 2020 in Transfusion Dependent, Steroid Resistant Pediatric and Adolescent Subjects With RPS19 Deficient Diamond Blackfan Anemia by Transplantation of Autologous CD34+ Stem Cells Transduced With CLIN LV EFS coRPS19 PRE* (APR-2020)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 4
- 试验地点
- 2
- 主要终点
- Fraction of reticulocytes greater than the baseline value where reticulocyte increases are sustained over 3 consecutive measurements within 4 weeks
研究概览
简要总结
Brief summary
The goal of this clinical trial is to learn if APR-2020 is safe and can help treat Diamond-Blackfan Anemia (DBA) in adolescents and children. The main questions it aims to answer are:
- Is APR-2020 safe and well tolerated?
- Does APR-2020 modify or correct an underlying genetic condition which causes DBA?
- Does APR-2020 reduce or eliminate the need for blood transfusions and/or restore certain blood counts affected by DBA?
Participants will:
- Take the drug one time as an infusion.
- Undergo two rounds of a cellular harvest procedure in which their own cells will be used in the manufacturing of their own participant-specific product.
- Initially return to the clinic for two years of follow up at increasingly sparse intervals.
详细描述
This open-label, single-arm study evaluates the safety and efficacy of APR-2020 in transfusion-dependent, steroid-resistant pediatric and adolescent patients with RPS19-deficient Diamond-Blackfan Anemia (DBA).
Disease Background: DBA is a congenital bone marrow (BM) failure syndrome characterized by early-onset hypoplastic anemia secondary to selective erythroid aplasia. The cardinal hematologic manifestation is a severe normochromic, macrocytic anemia in the presence of preserved leukocyte and platelet counts. In approximately 90% of affected individuals, hematologic abnormalities manifest within the first year of life; the median age at clinical presentation is approximately 2 months, with a median age at diagnosis of 3 months (Sieff 2023).
Genotype-phenotype data have demonstrated substantial clinical heterogeneity both within and across molecular subtypes. Accordingly, the term DBA syndrome has been adopted to reflect the broader phenotypic spectrum, encompassing classic DBA-estimated to occur at an incidence of 5 to 10 per million live births with no significant sex predilection-as well as non-classical or attenuated presentations. Most patients exhibit a reticulocytopenic (hyporegenerative) anemia, consistent with impaired erythroid progenitor differentiation and maturation, with or without associated congenital anomalies or growth abnormalities (Vlachos et al. 2018).
DBA is primarily caused by heterozygous pathogenic variants in genes encoding ribosomal proteins (RPs), resulting in ribosomal haploinsufficiency and defective ribosome biogenesis. The most frequently implicated genes include RPS19 (25-30%), RPL5 (7-12%), RPS26 (6-9%), RPL11 (5-7%), RPS24 (2-3%), and RPS10 (1-3%). Additional RP gene variants have been identified at lower frequencies (Sieff 2023; Wlodarski et al. 2024). RPS19 remains the most commonly mutated gene in DBA (Da Costa et al. 2020; Sieff 2023; Wlodarski et al. 2024). Rare pathogenic variants in non-ribosomal protein genes associated with DBA-like phenotypes-such as GATA1, TSR2, and EPO-have also been described but collectively account for fewer than 1% of cases (Da Costa et al. 2020; Wlodarski et al. 2024).
Patients eligible for inclusion in the present study have a confirmed diagnosis of DBA attributable to pathogenic variants in RPS19.
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
- 2 Years 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed diagnosis of RPS19-deficient DBA.
- •Signed informed consent by the subject or legally authorized representative.
- •Bone marrow analysis demonstrates normal cytogenetics except for RPS19-deficient DBA.
- •Between 2 and 25 years of age, inclusive.
- •Eligible for allogeneic marrow or stem cell transplant for DBA (noncritical cardiac and hepatic iron overload).
- •Corticosteroid resistance
- •Transfusion-dependent anemia
- •Willingness to return for long-term follow-up
- •Adequate renal and pulmonary function
- •Able to undergo hematopoietic stem cell transplant (HSCT) mobilization and apheresis procedures.
排除标准
- •Availability of a suitable, consenting HLA-identical sibling donor.
- •Positive viral serology.
- •Clinically significant, active bacterial, viral, or fungal infection.
- •Any prior or current malignancy, myeloproliferative disorder, or myelodysplastic syndrome, except where therapy was curative excision (ie, in situ squamous cell carcinoma).
- •Any concerning cytogenetic abnormalities in hematopoietic cells.
- •Previous receipt of an allogeneic transplant or gene therapy.
- •Immediate family member with a known or suspected Familial Cancer Syndrome (including, but not limited to breast, colorectal, ovarian, prostate, and pancreatic cancers, excluding DBA).
- •Diagnosis of significant psychiatric disorder that could impact the subject's ability to participate in the study, in the opinion of the Investigator.
- •History of complex allo-immunization, as determined by the Investigator.
- •Female subjects who are lactating/breast feeding or who plan to breastfeed within 6 months following APR-2020 infusion.
- •Male and female subjects of childbearing potential who are unwilling to practice highly effective methods of birth control from screening until ≥ 6 months after APR-2020 infusion.
- •Female subjects with a positive serum pregnancy test at Screening or who are planning to become pregnant during the study period.
- •Liver disease, as evidenced by critical iron overload with magnetic resonance imaging (MRI)
- •Heart disease or Type 1 diabetes.
- •Evidence of significant pulmonary hypertension, per Investigator assessment.
- •Any other condition that would render the subject ineligible for HSCT, as determined by the Investigator.
- •Contraindication to stem cell or bone marrow aspiration, mobilization or collection including allergies to filgrastim or plerixafor.
- •Currently enrolled in another investigational drug study or received an investigational study drug or procedure within 90 days of study enrollment.
- •A physical, functional, or emotional status that would prevent giving informed consent, protocol compliance, or adequate follow-up.
- •An assessment by the Investigator that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol.
- •Taking prohibited medications.
- •Has insufficient personal history of RBC transfusions over the 13 weeks prior to the end of screening.
研究组 & 干预措施
APR-2020
干预措施: APR-2020 (Biological)
结局指标
主要结局
Fraction of reticulocytes greater than the baseline value where reticulocyte increases are sustained over 3 consecutive measurements within 4 weeks
时间窗: 24 Months
Baseline is defined as the average of 3 measurements prior to APR-2020 infusion
Proportion of subjects with hemoglobin level of at least 8 g/dL starting 90 days after last RBC transfusion, sustained over 2 consecutive measurements that are approximately 1 month apart
时间窗: 24 Months
Incidence and severity of treatment emergent adverse events (TEAEs), assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
时间窗: 24 Months
Monitoring laboratory parameters, frequency and severity of TEAEs, assessed by the NCI CTCAE
时间窗: 24 Months
Proportion of subjects with a hemoglobin level of ≥ 8 g/dL starting 90 days after the last RBC transfusion, sustained over 2 consecutive measurements that are approximately 1 month apart
时间窗: 24 Months
Incidence and severity of treatment emergent adverse events, assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
时间窗: 24 Months
Monitoring of laboratory parameters, frequency and severity of clinical adverse events (AEs), assessed by the NCI CTCAE
时间窗: 24 Months
Incidence of protocol-defined dose limiting toxicities (DLTs) for APR-2020
时间窗: 30 Days
次要结局
- Change from baseline in vector copy number in mononuclear cells(24 Months)
- Number of subjects who achieve engraftment(24 Months)
- Change from baseline in vector copy number(24 Months)
- Incidence of treatment related mortality(100 Days, 1 Year and 2 Years)
- Change from baseline in the frequency and/or dose of iron chelation therapy(12 and 24 Months)
- Change from baseline in iron stores present in cardiac and hepatic tissue(6, 12, and 24 Months)
- Change from baseline in subject and family responses on the QoL survey(12 Months)
- Change from baseline in erythroid progenitors(6 and 24 Months)