low-dose sirolimus to increase hematopoietic function in patients with runx1 familial platelet disorder

Conditions: Familial Platelet Disorder; Hematopoietic

Summary: to learn about the safety and effects of low-dose sirolimus in participants with runx1-fpd.

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 criteria:
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