Low-Dose Sirolimus to Increase Hematopoietic Function in Patients With RUNX1 Familial Platelet Disorder - Part II
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Incidence of grade 3+ treatment-related adverse events (TRAEs)
研究概览
简要总结
This phase I trial studies the safety and side effects of low-dose sirolimus in treating patients with RUNX1 familial platelet disorder (FPD). RUNX1-FPD is a rare inherited disorder with symptoms such as mild to moderately low platelet count, abnormal platelet function, and an increased risk of developing cancers like myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It is caused by changes (variants) in the RUNX1 gene that is passed down (inherited) from an affected parent. Sirolimus is typically given to help prevent organ rejection in patients receiving kidney transplants. However, sirolimus may also be able to prevent RUNX1-FPD from progressing to cancers like MDS and AML by targeting another protein called mTORC1. Sirolimus may be a safe treatment for patients with RUNX1-FPD.
详细描述
PRIMARY OBJECTIVE:
I. Evaluate the safety and tolerability of low-dose sirolimus in patients with RUNX1 familial platelet disorder (RUNX1-FPD).
SECONDARY OBJECTIVES:
I. Evaluate platelet counts. II. Evaluate changes in somatic mutation variant allele frequency (VAF). III. Evaluate somatic mutation acquisition (i.e., mutation burden). IV. Evaluate the change in platelet function. V. Evaluate the change from baseline in bleeding score (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool [ISTH-BAT]).
VI. Evaluate the change in mTORC1 downstream signaling.
研究设计
- 研究类型
- 干预性
- 分配方式
- 不适用
- 干预模型
- 单组
- 主要目的
- 治疗
- 盲法
- 开放（无盲法）
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- Patient has provided signed, informed consent before initiation of any study specific procedures
- Aged ≥ 18 years at the time of signing the informed consent
- Confirmed pathogenic/likely pathogenic (P/LP) germline RUNX1 variant per ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) RUNX1-specific variant curation rules
- Patient must be willing to provide a bone marrow sample at time of screening and at the end of treatment with sirolimus
- Platelet count of ≥ 50,000/µL
- Creatinine clearance (CrCl) of ≥ 60 mL/min; estimated using the Cockcroft Gault formula or measured by 24 hour urine collection. Exceptions will be allowed, at the discretion of the investigator, for cases of a concomitant medication that alters renal function
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × upper limit of normal (ULN)
- Total bilirubin < 1.5 × ULN
- Left ventricular ejection fraction (EF) > 50% or at the discretion of the investigator
排除标准
- Known allergy to sirolimus
- History of major bleeding events that are clinically relevant in the judgement of the investigator or non-major bleeding events that cannot be controlled using SOC practices
- Any known history of lymphoma, myelodysplastic syndrome (MDS), or other hematologic malignancy using International Working Group criteria
- Prior treatment with sirolimus or a rapalog, mTOR inhibitor, or B-cell-depleting therapy within 28 days before study day 1
- Treatment with strong inhibitors of cytochrome P450 3A4 (CYP3A4; e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, and clarithromycin), strong inducers of CYP3A4 (e.g., rifampin and rifabutin), other drugs that could increase sirolimus blood concentrations (e.g., bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, protease inhibitors [e.g., ritonavir, indinavir, boceprevir, and telaprevir], metoclopramide, nicardipine, troleandomycin, and verapamil), other drugs that could decrease sirolimus blood concentrations (e.g., carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort [Hypericum perforatum]), or drugs with blood concentrations that could increase (e.g., verapamil) within 7 days before study day 1, or at the discretion of the investigator
- Use of cannabidiols that increase blood levels of sirolimus, within 7 days before study day 1 or at the discretion of the investigator
- Myocardial infarction within 6 months before study day 1, congestive heart failure (New York Heart Association > class II)
- Total cholesterol > 300 mg/dL or triglyceride > 400 mg/dL
- Arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months before study day 1
- Infection requiring intravenous anti-infective treatment within 1 week of study day 1
- Live vaccines (e.g., measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin [BCG], yellow fever, varicella, and TY21a typhoid) within 28 days before study day 1
- Known diagnosis of tuberculosis is exclusionary to provide protection against reactivation of infections by the immunosuppressive activity of the study drug sirolimus
- The enrollment of a patient with a history of infection with hepatitis B virus (HBV) but with undetectable HBV deoxyribonucleic acid (DNA) by standard institutional testing can be considered after consultation with the investigator
- Patients with history of chronic hepatitis C virus (HCV) must have documentation of completed curative standard of care (SOC) antiviral therapy
- Patients with history of HIV infection must be well-managed with SOC antiretroviral therapy (highly active antiretroviral therapy [HAART])
- Patients with history of Epstein-Barr may be considered after consultation with the treating physician
- Participants who are pregnant may become pregnant, or who are breastfeeding
- Because adequate and well-controlled studies of the impact of sirolimus on fetuses currently do not exist, study approved contraception must be used from start of study therapy to 12 weeks after the last dose of sirolimus
- Adequate and well-controlled studies of infants fed breastmilk from patients undergoing sirolimus therapy do not exist and breastfeeding during study treatment is prohibited
研究组 & 干预措施
Treatment (sirolimus)
Patients receive sirolimus PO QD on days 1-168 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and bone marrow biopsy and/or aspiration throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (sirolimus)
Patients receive sirolimus PO QD on days 1-168 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and bone marrow biopsy and/or aspiration throughout the study.
干预措施: Bone Marrow Aspiration (Procedure)
Treatment (sirolimus)
Patients receive sirolimus PO QD on days 1-168 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and bone marrow biopsy and/or aspiration throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Treatment (sirolimus)
Patients receive sirolimus PO QD on days 1-168 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and bone marrow biopsy and/or aspiration throughout the study.
干预措施: Questionnaire Administration (Other)
Treatment (sirolimus)
Patients receive sirolimus PO QD on days 1-168 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and bone marrow biopsy and/or aspiration throughout the study.
干预措施: Sirolimus (Drug)
结局指标
主要结局
Incidence of grade 3+ treatment-related adverse events (TRAEs)
时间窗: From study day 1 (week 1) to 30 days after the last dose of sirolimus
The incidence of grade 3+ TRAEs and the total proportion of participants who experienced grade 3+ TRAEs will be estimated and presented with the corresponding 95% exact Clopper Pearson confidence intervals.
次要结局
- Change in platelet count(From screening, pre dose on study day 1 (week 1) to end of treatment (EOT) (week 24, day 168))
- Change in variant allele frequency for existing clones(From screening to end of study (EOS) (week 52, day 365))
- Change in number of clonal hematopoiesis of indeterminate potential mutations(From screening to EOS (week 52, day 365))
- Change in percent positivity based on activated GPIIb IIIa and surface P selectin and CD42b(From screening, pre dose on study day 1 (week 1) to EOT (week 24, day 168))
- Change in aggregation from baseline based on thromboelastography (TEG)(From screening, pre dose on study day 1 (week 1) to EOT (week 24, day 168))
- Change in the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool score(From study day 1 (week 1) to EOS (week 52, day 365))
- Change in the relative amount of the protein 4eBP1(From screening, pre dose on study day 1 (week 1) to EOS (week 52, day 365))
研究者
研究点 (1)
标识符
- NCT 编号
- NCT07844694
- 其他研究编号
- STUDY00028610, NCI-2026-03902, STUDY00028610, P30CA069533
日期
- 首次提交
- (9天前)
- 首次发布
- (前天)
- 主要完成日期
- (3年后)
- 研究完成日期
- (4年后)
- 最近核实
- (29天前)
- 最近更新
- (前天)
监管与共享
- FDA 监管药物
- 是
- FDA 监管器械
- 否
- 是否有结果
- 否