Low-Dose Sirolimus to Increase Hematopoietic Function in Patients With RUNX1 Familial Platelet Disorder

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

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