Overview
To learn about the safety and effects of low-dose sirolimus in participants with RUNX1-FPD.
Description
Primary Objective:
• Evaluate the safety and tolerability of low-dose sirolimus in participants with RUNX1 familial platelet disorder (RUNX1-FPD)
Secondary Objectives:
- Evaluate increases in platelet counts during and after treatment with low-dose sirolimus
- Evaluate changes in somatic mutation variant allele frequency (VAF)
- Monitor the rate of somatic mutation acquisition (ie, mutation burden)
- Assess change in platelet aggregation score
- Measure the change from baseline in bleeding score (ISTH-BAT)
- Evaluate change in mTORC1 downstream signaling (pS6/EBP)
Exploratory Objectives:
- Measure rescue of elevated cytokine profiles
- Evaluate reversal of myeloid skewing using flow cytometry
- Determine changes in bone marrow (eg, megakaryocytic atypia and cellularity)
- Assess changes in patient-reported outcomes measures (eg, EORTC and PRO-CTCAE)
- Describe the pharmacokinetics of sirolimus in patients with RUNX1-FPD
- Determine the correlation between sirolimus trough levels and each endpoint
Eligibility
Inclusion Criteria:
- Participants has provided signed, informed consent before initiation of any study specific procedures
- Aged ≥18 years at the time of signing the informed consent
- Confirmed P/LP germline RUNX1 variant per ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) RUNX1-specific variant curation rules80
- Participants must be willing to provide bone marrow sample at time of screening and at the end of treatment with sirolimus
- Platelet count of ≥50,000/µL
- Adequate renal function: estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation, >30 mL/min/1.73m2
- Adequate hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 × upper limit of normal (ULN) and total bilirubin <1.5 × ULN
- Adequate cardiac function: left ventricular ejection fraction >50%
Exclusion Criteria:
- Known allergy to sirolimus
- History of lymphoma or other hematologic malignancies
- Uncontrolled bleeding
- Any prior diagnosis of myelodysplastic syndrome 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; eg, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, and clarithromycin), strong inducers of CYP3A4 (eg, rifampin and rifabutin), other drugs that could increase sirolimus blood concentrations (eg, bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, protease inhibitors [eg, ritonavir, indinavir, boceprevir, and telaprevir], metoclopramide, nicardipine, troleandomycin, and verapamil), other drugs that could decrease sirolimus blood concentrations (eg, carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort [Hypericum perforatum]), or drugs with blood concentrations that could increase (eg, verapamil) within 7 days before study day 1
- Use of cannabidiol, which can increase blood levels of sirolimus, within 7 days before study day 1
- 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 (eg, 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 (eg, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid) within 28 days before study day 1
- Known diagnosis of chronic viral infection (eg, hepatitis B or C or HIV, and Epstein-Barr) or tuberculosis
- Women who are pregnant, may become pregnant, or who are breastfeeding